Synthesis of a Series of Diaminoindoles

Article abstract of DOI:10.1021/acs.joc.1c00652

A selection of 3,4-diaminoindoles were required for a recent drug discovery project. To this end, a 10-step synthesis was developed from 4-nitroindole. This synthesis was subsequently adapted and used to synthesize 3,5-; 3,6-; and 3,7-diaminoindoles from

Full text of DOI:10.1021/acs.joc.1c00652

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Synthesis of a Series of Diaminoindoles
James S. Martin, Claire J. Mackenzie, and Ian H. Gilbert*
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ABSTRACT: A selection of 3,4-diaminoindoles were required for a recent drug
discovery project. To this end, a 10-step synthesis was developed from 4-
nitroindole. This synthesis was subsequently adapted and used to synthesize
3,5-; 3,6-; and 3,7-diaminoindoles from the corresponding 5-, 6-, or 7-
nitroindole. These novel intermediates feature orthogonal protecting groups
that allow them to be further diversified. This is the first reported synthesis of
these types of compounds.
INTRODUCTION
■
Indoles are an important feature of many drugs.1 A recent
search through DrugBank revealed 100 compounds in which
an indole was a component. A search of ChEMBL indicated
that there were 1688 structures with a 3-aminoindole
embedded in the structure. Further, indoles are found in
many natural products2 and dyes.3
During a recent drug discovery campaign, we required a
selection of 3,4-diaminoindoles. It was important that each
amino group could be differentially derivatized in order to
carry out a hit expansion. However, literature searches revealed
that the only published examples of diaminoindoles are 2,3-
diaminoindole4 and 6,7-diaminoindole.5 Some dinitroindoles
are known;6 however, conversion of these to diaminoindoles
has not been reported. A 2-substituted 3-amino-4-nitroindole
is also known.7 It is unusual that such simple cores are
unknown in the literature. Our initial focus was on the
synthesis of 3,4-diaminoindoles; however, this synthesis turned
out to be problematic. In this article, we describe our synthesis
of the differentially protected 3,4-diaminoindole, which was
suitable for further modification. Once this was successfully
completed, the 3,5-, 3,6-, and 3,7-analogues were also prepared,
with all shown in Figure 1.
Figure 1. TopIndole numbering scheme. Middle3,4-Diaminoin-
dole and 3,5-diaminoindole. Bottom3,6-Diaminoindole and 3,7-
diaminoindole.
be converted to 3-aminoindoles and related derivatives.
However, the required 4-aminoindole-3-carboxylic acid inter-
mediate is not commercially available or synthetically known.
Typically, indole-3-carboxylic acids can be synthesized by
reacting indoles with trifluoroacetic anhydride (TFAA) to give
the corresponding trifluoroketone, which subsequently under-
goes base hydrolysis in a pseudo-haloform reaction to give the
carboxylic acid,8 or alternatively by oxidation of the
corresponding aldehyde.9
RESULTS AND DISCUSSION
■
To illustrate the challenges of preparation of the diaminoin-
doles, we report some of our initial approaches to access this
system. It is known that the most reactive position on an
indole ring is the 3-position, so we focused on introducing the
required amine here. The synthesis was started with the
nitrogen on the phenyl ring masked as a nitro group or as the
Boc-protected or Cbz-protected amine. However, our attempts
to functionalize the 3-position via typical means such as
Buchwald−Hartwig couplings, nitrations, and azidations
proved unsuccessful (Scheme 1).
However, we found that in the case of 4-nitroindole or
protected 4-aminoindoles, these routes were unsuccessful.
Received: March 18, 2021
We had previously found that a Curtius rearrangement could
be used to convert indole-3-carboxylic acids into the
corresponding indole-3-isocyanates, which could subsequently
© XXXX The Authors. Published by
American Chemical Society
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Scheme 1. Attempted Synthesis of 3-Amino-4-nitroindoles
2,4-(Boc)amino-3-nitroindole 4, and 3-Azido-4-nitroindole
6
Scheme 2. TopAttempted Synthesis of 4-Nitro-1-TIPS-
indole-3-carboxylic Acid 8; BottomSynthesis of tert-Butyl
4-((tert-Butoxycarbonyl)amino)-1-(triisopropylsilyl)-1H-
indole-3-carboxylate 12
Instead, it was proposed that brominating the 3-position of
4-nitroindole to give 7 would allow a lithium halogen exchange
to occur by treating with n-butyl lithium, and the resulting
anion could be quenched with CO2 to give the required
carboxylic acid 8 as shown in Scheme 2. However, no lithium
halogen exchange was observed in this case, likely due to the
electron withdrawing effect of the nitro group.
An analogous reaction was attempted where the nitro group
was substituted with the Cbz-protected amine 9 and the CO2
substituted with Boc anhydride (Scheme 2). This reaction was
unsuccessful, and instead, the di-Boc-protected amine 10 was
found to be the main product. It was observed that by
brominating this product and then treating it with n-butyl
lithium, a novel Boc migration occurred, yielding ester 12. This
presumably occurred via lithiation, followed by transfer of the
Boc group to the 3-position of the indole as shown in Scheme
2. This allowed access to the carboxylic acid and subsequently
the synthesis of the desired 3,4-diaminoindoles.
using tetra-n-butylammonium fluoride (TBAF) to give indole
17. The remaining Boc group and tert-butyl ester were cleaved
using TFA, and the free amine 18 reprotected with Cbz to give
carboxylic acid 19. Treating this acid with diphenylphosphoryl
azide (DPPA) in DCM gave the acyl azide which was then
heated in tert-butanol to induce the rearrangement to give the
isocyanate and subsequently the required bisprotected 3,4-
diaminoindole 20. The overall yield of this synthesis was 15%
over 10 steps.
It was noted that no other examples of 3,x-diaminoindoles
were identified in the literature, so the synthesis of 3,4-
diaminoindole was modified to allow access to these
compounds. It was found that the first step, forming the
protected indole, was extremely challenging with 7-nitroindole
and ultimately the product was unstable.
This key step allowed us to prepare the diprotected 3,4-
diaminoindole (Scheme 3). A number of different strategies,
protecting groups, and orders of reactions were investigated.
Eventually, the following route was found to be successful. 4-
Nitroindole 13 was protected with a triisopropylsilyl (TIPS)-
protecting group 14, and the nitro group reduced to amine 15
using hydrogen and palladium on carbon. The di-Boc-
protected compound 10 was formed in two steps, initially
via treatment with Boc anhydride and 4-dimethylaminopyr-
idine (DMAP) to give the mono-protected compound 16 and
then with more forcing conditions using n-butyl lithium and
Boc anhydride. Bromination with N-bromosuccinimide (NBS),
followed by rearrangement using n-butyl lithium, gave the
required ester 12. Deprotection of the indole NH was achieved
It was subsequently found that on attempting to lithiate the
3-bromo derivatives of 5- and 6-aminoindole 22a and 22b later
in this synthesis, no transfer of a carboxylate occurred. This is
probably due to the lack of proximity of the diprotected amino
group to the lithiated center (Scheme 4).
The pseudo-haloform reaction had previously been shown
not to work when attempting the synthesis of 3,4-
diaminoindole but was attempted again here as shown in
Scheme 5 as the reactivity of these compounds appeared
significantly different from that seen when synthesizing 3,4-
diaminoindole. Reacting the appropriate nitroindoles 24a−c
with TFAA gave trifluoroketones 25a−c which were readily
hydrolyzed to carboxylic acids 26a−c using sodium hydroxide.
Attempting to reduce the nitro groups to amines using
B
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Scheme 3. Synthesis of Benzyl tert-Butyl (1H-Indole-3,4-diyl)dicarbamate 20
Scheme 4. Attempted Synthesis of tert-Butyl 5-
(Boc)aminoindole-3-carboxylate 23a and tert-Butyl 6-
(Boc)aminoindole-3-carboxylate 23b
ammonium chloride to give amines 28a−c. The resulting
amino compounds could be protected with a Cbz group to give
the protected amino acids 29a−c. Removal of the MOM-
protecting groups with TFA gave carboxylic acids 30a−c; the
Curtius rearrangement could then be carried out. The
carboxylic acid was converted to the acyl azide using DPPA;
then, by heating in tert-butanol, the desired bisprotected
diaminoindoles 31a−c were isolated.
The final 3,4-, 3,5-, 3,6-, and 3,7-diaminoindoles synthesized
here feature an orthogonal protecting group on each amine,
allowing them to be selectively functionalized at each position
to give compounds of interest to ongoing drug discovery
projects.
CONCLUSIONS
■
Here, we have developed the first reported synthesis of 3,4-
diaminoindole, a novel core of interest in a drug discovery
campaign. This synthesis was further developed to produce the
novel 3,5-, 3,6-, and 3,7-diaminoindoles. These compounds are
protected with orthogonal protecting groups to allow required
chemistry to be undertaken on these attractive intermediates.
This represents the first known route to this class of
compounds.
hydrogen and palladium resulted in a lot of degradation to give
a complex mixture, so alternatives were investigated. A transfer
hydrogenation using ammonium chloride and iron gave the
expected amino acid cleanly.
EXPERIMENTAL SECTION
■
General Methods. Chemicals and solvents were purchased from
commercial sources and were used without any further purification
unless noted otherwise. Air- and water-sensitive reactions were carried
out under an inert nitrogen atmosphere in oven-dried glassware.
Reactions which required heating were heated in DrySyn heating
blocks. Analytical thin-layer chromatography (TLC) was performed
on precoated TLC plates (layer 0.20 mm silica gel 60 with fluorescent
indicator UV254, from Merck). Developed plates were air-dried and
analyzed under a UV lamp (UV254/365 nm) and by staining with
permanganate or ninhydrin. Flash column chromatography was
performed on prepacked silica gel cartridges (230−400 mesh, 35−
70 μm, from RediSep) using a Teledyne ISCO Combiflash Rf or
However, residual ammonium chloride could not be
completely separated from the product and inhibited the
next step. To allow separation of the product and ammonium
chloride, various carboxylic acid-protecting groups were
investigated. In the case of a methyl group or a
trimethylsilylethoxymethyl (SEM) group, the required chem-
istry was found to be successful; however, the protecting
groups could not be cleaved. Ultimately, the methoxymethyl
(MOM)-protecting group was found to facilitate the required
chemistry and could be cleaved when required using TFA.
Therefore, the carboxylic acids were protected as MOM esters
27a−c. The nitro groups were then reduced with iron and
1
Combiflash Rf 200i. H (500 MHz), 13C (126 MHz), and 2D NMR
spectra were recorded in dimethyl sulfoxide (DMSO)-d6 using a
C
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Scheme 5. Synthesis of Benzyl tert-Butyl (1H-Indole-3,5-diyl)dicarbamate 31a, Benzyl tert-Butyl (1H-Indole-3,6-
diyl)dicarbamate 31b, and Benzyl tert-Butyl (1H-Indole-3,7-diyl)dicarbamate 31c
Bruker AVANCE spectrometer. Proton chemical shifts are reported in
ppm relative to the residual DMSO peak (δ = 2.50 ppm).
Multiplicities are given as s (singlet), d (doublet), t (triplet), q
(quartet), hept (heptet), m (multiplet), brs (broad singlet), dd
(doublet of doublets), or a combination of these. Coupling constants
(J) are quoted to the nearest 0.1 Hz. 13C chemical shifts are reported
in ppm relative to the residual DMSO peak (δ = 39.5 ppm).
Assignment of proton and carbon signals was achieved using
correlation spectroscopy, heteronuclear single-quantum coherence,
and heteronuclear multiple bond correlation experiments, which are
reported using the indole number scheme in Figure 1. High-resolution
electrospray measurements were performed on a Bruker Daltonics
MicrOTOF mass spectrometer.
tert-Butyl (tert-Butoxycarbonyl)(1-(triisopropylsilyl)-1H-indol-4-
yl)carbamate 10. tert-Butyl (1-(Triisopropylsilyl)-1H-indol-4-yl)-
carbamate 16 (4.38 g, 10.7 mmol, 1 equiv) was dissolved in THF
(50 mL) under nitrogen and cooled to −78 °C. n-Butyl lithium (2.5
M in hexane) (6.42 mL, 16.1 mmol, 1.5 equiv) was added dropwise,
and the reaction mixture was stirred at −78 °C for 30 min. Ditert-
butyl dicarbonate (4.92 mL, 21.4 mmol, 2 equiv) was added, and the
reaction mixture was allowed to slowly warm up to room temperature.
After 3 h, the reaction mixture was quenched with 20 mL of saturated
ammonium chloride solution, diluted with 20 mL of water, and 50 mL
of DCM. The layers were separated, and the aqueous layer was
extracted 2x with 50 mL of DCM. The combined organics were
washed with brine, dried over MgSO4, passed through a phase
separator, and evaporated to dryness. The residue was purified by
flash chromatography (0−30% ethyl acetate in heptane) to give tert-
butyl (tert-butoxycarbonyl)(1-(triisopropylsilyl)-1H-indol-4-yl)-
carbamate 10 (5.26 g, 96%) as a colorless oil which crystallized on
standing. 1H (500 MHz, DMSO-d6): δ 7.49 (1H, d, J = 8.3 Hz, H7),
7.39 (1H, d, J = 3.1 Hz, H2), 7.11 (1H, t, J = 7.9 Hz, H6), 6.86 (1H,
d, J = 7.5 Hz, H5), 6.38 (1H, d, J = 3.1 Hz, H3), 1.75 (3H, hept, J =
7.4 Hz, Si(CH)3), 1.35 (18H, s, Boc CH3), 1.09 (18H, d, J = 7.5 Hz,
TIPS CH3); 13C{1H} (126 MHz, DMSO-d6): δ 151.6 (CO), 141.3
(C7a), 132.0 (C2), 130.9 (C4), 128.8 (C3a), 121.2 (C6), 118.8 (C5),
112.9 (C7), 101.6 (C3), 81.7 (C(CH3)3), 27.4 (Boc CH3), 17.8
(TIPS CH3), 11.9 (SiCH(CH3)2); HRMS (ESI/TOF) m/z: [M +
H]+ calcd for C27H45N2O4Si, 489.3143; found, 489.3161.
tert-Butyl (3-Bromo-1-(triisopropylsilyl)-1H-indol-4-yl)-
carbamate 11. tert-Butyl (tert-butoxycarbonyl)(1-(triisopropylsilyl)-
1H-indol-4-yl)carbamate 10 (8.59 g, 17.6 mmol, 1 equiv) was
dissolved in THF (75 mL), and freshly recrystallized NBS (3.13 g,
17.6 mmol, 1 equiv) was added. The reaction mixture was stirred at
room temperature for 1 h. The reaction mixture was diluted with 75
mL of water and extracted 3x with 75 mL of diethyl ether. The
combined organics were washed with 75 mL of saturated NaHCO3
solution and 75 mL of brine, dried over MgSO4, passed through a
phase separator, and evaporated to dryness to give tert-butyl (3-
bromo-1-(triisopropylsilyl)-1H-indol-4-yl)carbamate 11 (9.00 g,
1
90%) as a brown powder. H (500 MHz, DMSO-d6): δ 7.56 (1H,
d, J = 8.5 Hz, H7), 7.44(1H, s, H2), 7.18 (1H, t, J = 8.0 Hz, H6), 6.90
(1H, d, J = 7.5 Hz, H5), 1.76 (3H, hept, J = 7.4 Hz, Si(CH)3), 1.32
(18H, s, Boc CH3), 1.08 (18H, d, J = 7.5, TIPS CH3); 13C{1H} (126
MHz, DMSO-d6): δ 151.0 (CO), 140.9 (C7a), 131.3 (C2), 131.0
(C4), 125.1 (C3a), 122.3 (C6), 120.8 (C5), 114.0 (C7), 89.6 (C3),
81.4 (C(CH3)3), 27.5 (Boc CH3), 17.7 (TIPS CH3), 11.8
(SiCH(CH3)2); HRMS (ESI/TOF) m/z: [M + H]+ calcd for
C27H44N2O4SiBr, 567.2248; found, 567.2250.
tert-Butyl 4-((tert-Butoxycarbonyl)amino)-1-(triisopropylsilyl)-
1H-indole-3-carboxylate 12. tert-Butyl (3-Bromo-1-(triisopropylsil-
yl)-1H-indol-4-yl)carbamate 11 was dissolved in THF (75 mL) under
nitrogen and cooled to −78 °C. n-Butyl lithium (2.5 M in hexane)
(8.44 mL, 21.1 mmol, 1.2 equiv) was added portionwise over 30 min,
and the reaction mixture was stirred at −78 °C for a further 30 min.
The reaction mixture was quenched with 50 mL of saturated
ammonium chloride solution, diluted with 50 mL of water, and
extracted 3x with 50 mL of diethyl ether. The combined organic layers
were washed with brine, dried over MgSO4, passed through a phase
separator, and evaporated to dryness. The residue was purified by
flash chromatography (0−20% ethyl acetate in heptane) to give tert-
butyl 4-((tert-butoxycarbonyl)amino)-1-(triisopropylsilyl)-1H-indole-
1
3-carboxylate 12 (7.08 g, 82%) yield as a white powder. H (500
MHz, DMSO-d6): δ 10.91 (1H, br s, NH), 7.91 (1H, d, J = 7.9 Hz,
H5), 7.89 (1H, s, H2), 7.23 (1H, d, J = 8.3 Hz, H7), 7.17 (1H, t, J =
8.1 Hz, H6), 1.74 (3H, hept, J = 7.3 Hz, Si(CH)3), 1.57 (9H, s,
CH3), 1.49 (9H, s, CH3), 1.09 (18H, d, J = 7.5, TIPS CH3); 13C{1H}
(126 MHz, DMSO-d6): δ 165.9 (CO ester), 152.6 (CO
D
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carbamate), 142.1 (C7a), 139.3 (C2), 132.7 (C4) 123.8 (C6), 117.4
(C3a), 110.5 (C3), 109.9 (C5), 108.5 (C7), 81.0 (C(CH3)3), 78.9
(C(CH3)3), 28.0 (CH3), 27.9 (CH3), 17.7 (TIPS CH3), 11.8
(SiCH(CH3)2); HRMS (ESI/TOF) m/z: [M + H]+ calcd for
C27H45N2O4Si, 489.3143; found, 489.3154.
yl)-1H-indole-3-carboxylate 12 (7.08 g, 10.9 mmol, 1 equiv) was
dissolved in THF (50 mL) under nitrogen, and TBAF (16.3 mL, 16.3
mmol, 1.5 equiv) was added dropwise. After 45 min, 50 mL of water
was added, and the mixture extracted 3x with 50 mL of DCM. The
combined organics were dried over MgSO4, passed through a phase
separator, and evaporated to dryness. The residue was purified by
flash chromatography (0−30% ethyl acetate in heptane) to give tert-
butyl 4-((tert-butoxycarbonyl)amino)-1H-indole-3-carboxylate 17
4-Nitro-1-(triisopropylsilyl)-1H-indole 14. 4-Nitroindole 13 (2.00
g, 12.3 mmol, 1 equiv) was dissolved in dry THF (20 mL) and cooled
to 0 °C under nitrogen. Sodium hydride (60% in mineral oil) (592
mg, 14.8 mmol, 1.2 equiv) was added, and the reaction mixture was
stirred at 0 °C for 30 min. Triisopropylsilyl chloride (3.4 mL, 16.0
mmol, 1.3 equiv) was added dropwise, and the reaction mixtures were
stirred at 0 °C for 30 min. The reaction mixture was quenched with
20 mL of saturated ammonium chloride and extracted 3x with 20 mL
of DCM. The combined organics were washed with brine, dried over
MgSO4, passed through a phase separator, and evaporated to dryness.
The residue was purified by flash chromatography (0−30% ethyl
acetate in heptane) to give 4-nitro-1-(triisopropylsilyl)-1H-indole 14
(4.34 g, 100%) as a yellow powder. 1H (500 MHz, DMSO-d6): δ 8.10
(1H, d, J = 8.0 Hz, H5), 8.04 (1H, d, J = 8.2 Hz, H7), 7.78 (1H, d, J =
3.1 Hz, H2), 7.36 (1H, t, J = 8.1 Hz, H6), 7.26 (1H, d, J = 3.0 Hz,
H3), 1.81 (3H, hept, J = 7.5 Hz, Si(CH)3), 1.09 (18H, d, J = 7.5,
CH3); 13C{1H} (126 MHz, DMSO-d6): δ 142.5 (C7a), 139.5 (C4),
137.0 (C2), 124.8 (C3a), 121.0 (C7), 120.8 (C6), 117.4 (C5), 104.4
(C3), 17.7 (CH3), 11.8 (SiCH(CH3)2); HRMS (ESI/TOF) m/z: [M
+ H]+ calcd for C17H27N2O2Si, 319.1836; found, 319.1836.
1
(2.49 g, 65%) yield as a white powder. H (500 MHz, DMSO-d6):
δ 11.99 (1H, br s, NH), 11.01 (1H, br s, NH), 7.99 (1H, s, H2), 7.88
(1H, d, J = 7.2 Hz, H5), 7.13 (2H, m, H6, H7), 1.57 (9H, s, CH3),
1.49 (9H, s, CH3); 13C{1H} (126 MHz, DMSO-d6): δ 166.5 (CO),
152.5 (CO), 137.9 (C7a), 133.7 (C2), 132.6 (C4), 123.4 (C6),
115.1 (C3a), 108.8 (C5), 107.3 (C3), 106.5 (C7), 80.5 (C(CH)3),
78.8 (C(CH)3), 28.0 (Boc CH3, t-Butyl CH3); HRMS (ESI/TOF)
m/z: [M + H]+ calcd for C18H25N2O4, 333.1809; found, 333.1820.
4-(((Benzyloxy)carbonyl)amino)-1H-indole-3-carboxylic Acid 19.
tert-Butyl 4-((tert-Butoxycarbonyl)amino)-1H-indole-3-carboxylate
17 (2.19 g, 6.57 mmol, 1 equiv) was dissolved in DCM (44 mL)
under nitrogen. TFA (44 mL, 65.7 mmol, 10 equiv) was added, and
the reaction mixture was stirred for 1 h. The reaction mixture was
evaporated to dryness to give the intermediate as an off-white powder.
The residue was dissolved in DCM (45 mL) under nitrogen, and
pyridine (2.66 mL, 32.8 mmol, 5 equiv) was added. Benzyl
chloroformate (1.84 mL, 13.1 mmol, 2 equiv) was added dropwise.
The reaction mixture was stirred at room temperature overnight. The
reaction mixture was evaporated to dryness to remove the residual
pyridine, and the residue was dissolved in 50 mL of water and
acidified to pH 1 with concentrated HCl. The resulting precipitate
was isolated by vacuum filtration and then purified by reverse phase
flash chromatography (C18 column) (5−95% acetonitrile in water
(0.1% formic acid)) to give 4-(((benzyloxy)carbonyl)amino)-1H-
indole-3-carboxylic acid 19 (1.31 g, 61%) as a white powder. 1H (500
MHz, DMSO-d6): δ 12.60 (1H, br s, COOH), 12.00 (1H, br s, H1),
11.85 (1H, br s, NH), 8.08 (1H, d, J = 2.8 Hz, H2), 7.91 (1H, d, J =
7.4 Hz, H5), 7.46−7.30 (5H, m, Cbz-CH), 7.2−7.1 (2H, m, H6, H7),
5.19 (2H, s, CH2); 13C{1H} (126 MHz, DMSO-d6): δ 168.7
(COOH), 153.0 (carbamate CO), 138.0 (C7a), 136.8 (Cbz-C),
133.9 (C2), 132.2 (C4) 128.4 (Cbz-CH), 127.8 (Cbz-CH), 127.5
(Cbz-CH), 123.5 (C6), 115.4 (C3a), 108.6 (C5), 106.8 (C7), 106.4
(C3), 65.4 (CH2); HRMS (ESI/TOF) m/z: [M + H]+ calcd for
C17H15N2O4, 311.1026; found, 311.1027.
Benzyl tert-Butyl (1H-Indole-3,4-diyl)dicarbamate 20. Caution!
Azides are potentially explosive substances and can decompose
violently. 4-(((Benzyloxy)carbonyl)amino)-1H-indole-3-carboxylic
acid 19 (500 mg, 1.53 mmol, 1 equiv) was suspended in DCM (25
mL) under nitrogen. Triethylamine (0.43 mL, 3.06 mmol, 2 equiv)
was added, and the mixture was stirred until everything had dissolved.
DPPA (0.38 mL, 1.68 mmol, 1.1 equiv) was added dropwise, and the
reaction mixture was stirred at room temperature overnight. 25 mL of
DCM was added, and the mixture was extracted with 25 mL of 1 N
HCl. The aqueous layer was extracted a further 2x with 25 mL of
DCM, and the combined organic layers were washed with 25 mL of
saturated NaHCO3 and brine, dried over MgSO4, and passed through
a phase separator into a well-dried flask, with the volume reduced by
half in vacuo. The solution was diluted with tert-butanol (25 mL), and
then, the volume reduced to ∼20 mL to remove the residual DCM.
Acetic acid (0.18 mL, 3.06 mmol, 2 equiv) was added, and the
reaction mixture was heated to 60 °C under nitrogen for 3 days. The
reaction mixture was cooled to room temperature and evaporated to
dryness. The residue was dissolved in 25 mL of DCM and washed
with 25 mL of water. The aqueous layer was extracted 2x with 25 mL
of DCM, and the combined organics were washed with 25 mL of
saturated NaHCO3 and 25 mL of brine, dried over MgSO4, passed
through a phase separator, and evaporated to dryness. The residue
was purified by flash chromatography (0−50% ethyl acetate in
heptane) to give benzyl tert-butyl (1H-indole-3,4-diyl)dicarbamate 20
(389 mg, 63%) as a white powder. 1H (500 MHz, DMSO-d6): δ 11.01
(1H, br s, H1) 8.83 (1H, br s, Cbz NH), 8.42 (1H, br s, Boc NH),
7.40 (5H, m, Cbz-CH), 7.25 (1H, d, J = 6.1 Hz, H5), 7.21 (1H, d, J =
1-(Triisopropylsilyl)-1H-indol-4-amine Hydrochloride 15. 4-
Nitro-1-TIPS-indole 14 (4.34 g, 12.3 mmol, 1 equiv) was suspended
in ethanol (50 mL) with 10% Pd/C (69 mg, 0.06 mmol, 0.5 mol %)
under a nitrogen atmosphere. The reaction mixture was purged 3x
with hydrogen and then stirred under a hydrogen atmosphere for 4
days. The reaction mixture was purged 3x with nitrogen, filtered
through Celite, and evaporated to dryness. The residue was dissolved
in 20 mL of diethyl ether, and 6 N HCl was added dropwise until the
precipitate stopped forming. The precipitate was isolated by vacuum
filtration and washed 3x with diethyl ether and then dried under
vacuum to give 1-(triisopropylsilyl)-1H-indol-4-amine hydrochloride
1
15 (3.52 g, 83%) as a white powder. H (500 MHz, DMSO-d6): δ
10.09 (3H, br s, NH3), 7.53 (1H, d, J = 7.8 Hz, H7), 7.48 (1H, d, J =
2.3 Hz, H2), 7.17 (1H, t, J = 7.8 Hz, H6), 7.06 (1H, br s, H5), 6.84
(1H, br s, H3), 1.76 (3H, hept, J = 7.5 Hz, Si(CH)3), 1.08 (18H, d, J
= 7.5 Hz, TIPS CH3); 13C{1H} (126 MHz, DMSO-d6): δ 141.3
(C7a), 132.4 (C2), 121.6 (C6), 113.4 (C5), 113.3 (C7), 101.9 (C3),
17.7 (CH3), 11.8 (SiCH(CH3)2); HRMS (ESI/TOF) m/z: [M + H]+
calcd for C17H29N2Si, 289.2095; found, 289.2105.
tert-Butyl (1-(Triisopropylsilyl)-1H-indol-4-yl)carbamate 16. 1-
(Triisopropylsilyl)-1H-indol-4-amine hydrochloride 15 (3.52 g, 10.8
mmol, 1 equiv) was dissolved in pyridine (20 mL) with DMAP (132
mg, 1.1 mmol, 10 mol %) and stirred under nitrogen. Ditert-butyl
dicarbonate (2.59 g, 11.9 mmol, 1.1 equiv) was added, and a rapid
evolution of gas was observed after about 30 s. The reaction mixture
was stirred at room temperature overnight. The reaction mixture was
evaporated to dryness, and the residue was dissolved in 20 mL of
DCM and washed with 20 mL of 0.5 N HCl. The aqueous layer was
extracted 2x with 10 mL of DCM, washed with saturated NaHCO3
solution and brine, dried over MgSO4, passed through a phase
separator, and evaporated to dryness. The residue was purified by
flash chromatography (0−20% ethyl acetate in heptane) to give tert-
butyl (1-(triisopropylsilyl)-1H-indol-4-yl)carbamate 16 (4.38 g, 99%)
as a colorless oil which crystallized on standing. 1H (500 MHz,
DMSO-d6): δ 8.96 (1H, br s, NH), 7.35 (1H, d, J = 7.7 Hz, H5), 7.27
(1H, d, J = 3.0 Hz, H2), 7.21 (1H, d, J = 8.3 Hz, H7), 7.01 (1H, t, J =
8.0 Hz, H6), 6.90 (1H, d, J = 3.0 Hz, H3), 1.72 (3H, hept, J = 7.5 Hz,
Si(CH)3), 1.50 (9H, s, Boc CH3), 1.08 (18H, d, J = 7.5 Hz, TIPS
CH3); 13C{1H} (126 MHz, DMSO-d6): δ 153.25 (CO), 141.0
(C7a), 131.0 (C4), 130.0 (C2), 121.4 (C6), 110.7 (C5), 108.8 (C7),
102.9 (C3), 78.7 (Boc C(CH3)3), 28.1 (Boc CH3), 17.8 (TIPS CH3),
11.9 (SiCH(CH3)2); HRMS (ESI/TOF) m/z: [M + H]+ calcd for
C22H37N2O2Si, 389.2614; found, 389.2619.
tert-Butyl 4-((tert-Butoxycarbonyl)amino)-1H-indole-3-carboxy-
late 17. tert-Butyl 4-((tert-Butoxycarbonyl)amino)-1-(triisopropylsil-
E
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1.4 Hz, H2), 7.13 (1H, d, J = 8.2 Hz, H7), 7.05 (1H, t, J = 7.9 Hz,
H6), 5.17 (2H, s, CH2), 1.41 (9H, s, CH3); 13C{1H} (126 MHz,
DMSO-d6): δ 155.6 (Boc CO), 153.9 (Cbz CO), 136.6 (Cbz
C), 135.7 (C7a), 129.5 (C4), 128.4 (Cbz-CH), 128.0 (Cbz-CH),
128.0 (Cbz-CH), 121.4 (C5), 120.2 (C2), 116.3 (C3a), 112.6 (C3),
112.0 (C5), 108.1 (H7), 78.8 (C(CH3)3), 65.9 (CH2), 20.1 (CH3);
15N (50 MHz, DMSO-d6): δ 128.4 (N1), 109.7 (Boc NH), 967 (Cbz
NH); HRMS (ESI/TOF) m/z: [M + H]+ calcd for C21H24N3O4,
382.1761; found, 382.1763.
General Method 1Synthesis of Trifluoroketone 25. The
appropriate nitroindole (1 equiv) was dissolved in DMF (5 mL/
mmol) under nitrogen, and TFAA (2 equiv) was added. The reaction
mixture was heated to 80 °C overnight. The reaction mixture was
diluted with water and extracted 3x with ethyl acetate, and the
combined organic layers were washed 2x with 10% LiCl solution and
brine, dried over MgSO4, passed through a phase separator, and
evaporated to dryness azeotroping 3x from toluene to give the
products.
2,2,2-Trifluoro-1-(5-nitro-1H-indol-3-yl)ethan-1-one 25a. 2,2,2-
Trifluoro-1-(5-nitro-1H-indol-3-yl)ethan-1-one 25a (723 mg, 100%)
as a yellow powder. 1H{19F} (500 MHz, DMSO-d6): δ 13.20 (1H, br
s, NH), 8.97 (1H, d, J = 2.2 Hz, H4), 8.74 (1H, s, H2), 8.21 (1H, dd,
J = 8.9, 2.3 Hz, H6), 7.77 (1H, d, J = 9.0 Hz, H7); 13C{1H} (126
MHz, DMSO-d6): δ 174.3 (d, J = 35.2 Hz, CO), 143.7 (C5), 140.9
(q, J = 4.2 Hz, C2), 139.9 (C7a), 125.2 (C3a), 119.6 (C6), 117.1
(C4), 113.9 (C7), 110.0 (C3); 19F{1H} (470 MHz, DMSO-d6): δ
−71.94 (s); HRMS (ESI/TOF) m/z: [M − H]− calcd for
C10H4N2O3F3, 257.0180; found, 257.0191.
2,2,2-Trifluoro-1-(6-nitro-1H-indol-3-yl)ethan-1-one 25b. 2,2,2-
Trifluoro-1-(6-nitro-1H-indol-3-yl)ethan-1-one 25b (745 mg, 99%)
as a brown powder. 1H{19F} (500 MHz, DMSO-d6): δ 13.19 (1H, br
s, NH), 8.80 (1H, s, H2), 8.44 (1H, d, J = 2.1 Hz, H7), 8.33 (1H, d, J
= 8.8 Hz, H4), 8.19 (1H, dd, J = 8.8, 2.1 Hz, H5); 13C{1H} (126
MHz, DMSO-d6): δ 174.2 (d, J = 34.9 Hz, CO), 144.1 (C6), 141.8
(q, J = 4.3 Hz, C2), 135.5 (C7a), 130.6 (C3a), 121.4 (C4), 118.2
(C5), 109.4 (C7), 108.9 (C3); 19F{1H} (470 MHz, DMSO-d6): δ
−71.94 (s), HRMS (ESI/TOF) m/z: [M − H]− calcd for
C10H4N2O3F3, 257.0180; found, 257.0187.
MHz, DMSO-d6): δ 165.1 (CO), 142.7 (C6), 137.7 (C2), 135.0
(C7a), 130.8 (C3a), 120.8 (C4), 116.0 (C5), 108.9 (C7), 108.3
(C3); HRMS (ESI/TOF) m/z: [M − H]− calcd for C9H5N2O4;
found, 205.0260.
7-Nitro-1H-indole-3-carboxylic Acid 26c. 7-Nitro-1H-indole-3-
carboxylic acid 26c (233 mg, 95%) as a yellow powder. 1H (500 MHz,
DMSO-d6): δ 12.44 (2H, br s, NH, COOH), 8.50 (1H, d, J = 7.8 Hz,
H6), 8.18 (1H, d, J = 8.0 Hz, H4), 8.07 (1H, d, J = 2.8 Hz, H2), 7.41
(1H, t, J = 7.9 Hz, H5); 13C{1H} (126 MHz, DMSO-d6): δ 164.9
(CO), 134.6 (C2), 133.2 (C7), 129.6 (C3a), 128.8 (C6), 128.5
(C7a), 120.9 (C5), 119.45 (C4), 109.0 (C3); HRMS (ESI/TOF) m/
z: [M − H]− calcd for C9H5N2O4, 205.0255; found, 205.0262.
General Method 3Synthesis of MOM Ester 27. The
appropriate carboxylic acid 26 (1 equiv) was suspended in THF (5
mL/mmol) under nitrogen and cooled to 0 °C. Triethylamine (3
equiv) was added, and the reaction mixture was stirred at 0 °C for 5
min. MOMCl (1.5 equiv) was added dropwise, and the reaction
mixture was allowed to warm up to room temperature overnight. The
reaction mixture was diluted with water and extracted 3x with ethyl
acetate. The combined organic extracts were washed with saturated
NaHCO3 solution and brine, dried over MgSO4, passed through a
phase separator, and evaporated to dryness. The residue was purified
by flash chromatography (0−50% ethyl acetate in heptane) to give the
desired products.
Methoxymethyl 5-Nitro-1H-indole-3-carboxylate 27a. Methox-
ymethyl 5-nitro-1H-indole-3-carboxylate 27a (491 mg, 40%) as a
1
yellow powder. H (500 MHz, DMSO-d6): δ 12.62 (1H, br s, NH),
8.88 (1H, d, J = 2.3 Hz, H4), 8.43 (1H, s, H2), 8.11 (1H, dd, J = 9.0,
2.3 Hz, H6), 7.69 (1H, d, J = 9.0 Hz, H7), 5.47 (2H, s, CH2), 3.49
(3H, s, CH3); 13C{1H} (126 MHz, DMSO-d6): δ 162.9 (CO),
142.5 (C5), 139.6 (C7a), 136.7 (C2), 125.0 (C3a), 117.8 (C6), 116.8
(C4), 113.3 (C7), 108.0 (C3) 89.4 (CH2), 56.9 (CH3); HRMS (ESI/
TOF) m/z: [M + H]+ calcd for C11H11N2O5, 251.0662; found,
251.0662.
Methoxymethyl 6-Nitro-1H-indole-3-carboxylate 27b. Methox-
ymethyl 6-nitro-1H-indole-3-carboxylate 27b (642 mg, 56%) as a
1
yellow powder. H (500 MHz, DMSO-d6): δ 12.63 (1H, br s, NH),
8.52 (1H, s, H2), 8.42 (1H, d, J = 2.0 Hz, H7), 8.17 (1H, d, J = 8.8
Hz, H4), 8.09 (1H, dd, J = 8.9, 2.0 Hz, H5), 5.45 (2H, s, CH2), 3.48
(3H, s, CH3); 13C{1H} (126 MHz, DMSO-d6): δ 162.9 (CO),
142.9 (C6), 138.5 (C2), 135.2 (C7a), 130.5 (C3a), 120.6 (C4), 116.5
(C5), 109.1 (C7), 106.9 (C3), 89.3 (CH2), 56.9 (CH3); HRMS
(ESI/TOF) m/z: [M + H]+ calcd for C11H11N2O5, 251.0662; found,
251.0659.
2,2,2-Trifluoro-1-(7-nitro-1H-indol-3-yl)ethan-1-one 25c. 2,2,2-
Trifluoro-1-(7-nitro-1H-indol-3-yl)ethan-1-one 25c (462 mg, 100%)
1
as an orange powder. H{19F} (500 MHz, DMSO-d6): δ 13.14 (1H,
br s, NH), 8.62 (1H, dd, J = 7.9, 1.1 Hz, H4), 8.37 (1H, s, H2), 8.28
(1H, dd, J = 8.1, 1.1 Hz, H6), 7.56 (1H, t, J = 8.0 Hz, H5); 13C{1H}
(126 MHz, DMSO-d6): δ 174.5 (d, J = 35.1 Hz, CO), 138.9 (q, J =
4.3 Hz, C2), 133.8 (C7), 129.0 (C3a), 128.9 (C4), 128.8 (C7a),
123.4 (C5), 121.0 (C6), 116.4 (q, J = 291.2 Hz, CF3), 109.5 (C3);
19F{1H} (470 MHz, DMSO-d6): δ −72.00 (s), HRMS (ESI/TOF)
m/z: [M − H]− calcd for C10H4N2O3F3, 257.0180; found, 257.0177.
General Method 2Synthesis of Carboxylic Acid 26. The
appropriate trifluoroketone 25 (1 equiv) was suspended in 4 M
sodium hydroxide solution (20 equiv) and stirred at 60 °C overnight.
The reaction mixture was cooled to room temperature, diluted with
water, and extracted 3x with diethyl ether. The aqueous layer was
acidified by addition of concentrated HCl to pH 1, and the precipitate
was isolated by vacuum filtration. The precipitate was washed 2x with
water, 5x with diethyl ether, and then dried under vacuum to give the
desired products.
5-Nitro-1H-indole-3-carboxylic Acid 26a. 5-Nitro-1H-indole-3-
carboxylic acid 26a (419 mg, 90%) as a yellow powder. 1H (500 MHz,
DMSO-d6): δ 12.48 (2H, m, NH, COOH), 8.89 (1H, d, J = 1.9 Hz,
H4), 8.26 (1H, s, H2), 8.09 (1H, dd, J = 9.0, 2.0 Hz, H6), 7.67 (1H,
d, J = 9.0 Hz, H7); 13C{1H} (126 MHz, DMSO-d6): δ 165.1 (CO),
142.2 (C5), 139.6 (C7a), 135.6 (C2), 125.3 (C3a), 117.5 (C6), 117.0
(C4), 113.0 (C7), 109.5 (C3); HRMS (ESI/TOF) m/z: [M − H]−
calcd for C9H5N2O4, 205.0255; found, 205.0266.
Methoxymethyl 7-Nitro-1H-indole-3-carboxylate 27c. Methox-
ymethyl 7-nitro-1H-indole-3-carboxylate 27c (989 mg, 86%) as a
1
yellow powder. H (500 MHz, DMSO-d6): δ 12.61 (1H, br s, NH),
8.50 (1H, d, J = 7.9 Hz, H6), 8.21 (1H, d, J = 8.1 Hz, H4), 8.20 (1H,
s, H2), 7.46 (1H, t, J = 8.0 Hz, H5), 5.45 (2H, s, CH2), 3.48 (3H, s,
CH3); 13C{1H} (126 MHz, DMSO-d6): δ 162.9 (CO), 135.4 (C2),
133.4 (C7), 129.3 (C3a), 128.6 (C6), 121.4 (C5), 119.7 (C4), 107.7
(C3), 89.4 (CH2), 56.9 (CH3); HRMS (ESI/TOF) m/z: [M + H]+
calcd for C11H11N2O5, 251.0662; found, 251.0656.
General Method 4Reduction of Nitro Group 28. The
appropriate nitro compound 27 (1 equiv) was dissolved in methanol,
THF, and water (1:1:1) (25 mL/mmol). Ammonium chloride (6.7
equiv) was added, followed by iron (4.2 equiv), and the reaction
mixture was stirred at 60 °C overnight. The reaction mixture was
filtered through Celite, rinsing with methanol, and the volatiles were
removed in vacuo. The aqueous residue was diluted with water,
saturated NaHCO3 solution, and extracted 3x with ethyl acetate. The
combined organics were washed with brine, dried over MgSO4,
passed through a phase separator, and evaporated to dryness to give
the desired products.
Methoxymethyl 5-Amino-1H-indole-3-carboxylate 28a. Methox-
ymethyl 5-amino-1H-indole-3-carboxylate 28a (495 mg, 100%) as a
brown gum. 1H (500 MHz, DMSO-d6): δ 11.55 (1H, br s, NH), 7.89
(1H, s, H2), 7.19 (1H, d, J = 1.9 Hz, H4), 7.16 (1H, d, J = 8.6 Hz,
H7), 6.57 (1H, dd, J = 8.6, 2.1 Hz, H6), 5.36 (2H, s, CH2), 4.75 (2H,
br s, NH2), 3.44 (3H, s, CH3); 13C{1H} (126 MHz, DMSO-d6): δ
6-Nitro-1H-indole-3-carboxylic Acid 26b. 6-Nitro-1H-indole-3-
1
carboxylic acid 26b (388 mg, 88%) as a yellow powder. H (500
MHz, DMSO-d6): δ 12.53 (1H, br s, NH), 12.35 (1H, br s, COOH),
8.40 (1H, d, J = 2.0 Hz, H7), 8.37 (1H, d, J = 3.0 Hz, H2), 8.16 (1H,
d, J = 8.9 Hz, H4), 8.05 (1H, dd, J = 8.9, 2.1 Hz, H5); 13C{1H} (126
F
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163.8 (CO), 143.7 (C5), 132.0 (C2), 129.6 (C7a), 127.1 (C3a),
112.6 (C6), 112.4 (C7), 104.6 (C3), 103.4 (C4) 84.4 (CH2), 56.6
(CH3); HRMS (ESI/TOF) m/z: [M + H]+ calcd for C11H13N2O3,
221.0921; found, 221.0920.
HRMS (ESI/TOF) m/z: [M + H]+ calcd for C19H19N2O5, 355.1288;
found, 355.1303.
General Method 6Deprotection of MOM Ester 30. The
appropriate protected ester 29 (1 equiv) was dissolved in DCM (8
mL/mmol) under nitrogen and cooled to 0 °C. TFA (10 equiv) was
added, and the reaction mixture was stirred at 0 °C for 1 h. The
reaction mixture was evaporated to dryness, and the residue was
purified by reverse-phase flash chromatography (C18 column) [5−
95% acetonitrile in water (0.1% formic acid)] to give the desired
products.
Methoxymethyl 6-Amino-1H-indole-3-carboxylate 28b. Methox-
ymethyl 6-amino-1H-indole-3-carboxylate 28b (573 mg, 100%) as an
1
orange powder. H (500 MHz, DMSO-d6): δ 11.38 (1H, br s, NH),
7.80 (1H, s, H2), 7.63 (1H, d, J = 8.5 Hz, H4), 6.62 (1H, d, J = 1.4
Hz, H7), 6.56 (1H, dd, J = 8.5, 1.8 Hz, H5), 5.36 (2H, s, CH2), 4.89
(2H, br s, NH2), 3.43 (3H, s, CH3); 13C{1H} (126 MHz, DMSO-d6):
δ 163.7 (CO), 145.0 (C6), 138.1 (C7a), 130.1 (C2), 120.5 (C4),
117.0 (C3a), 112.0 (C5), 106.0 (C3), 95.5 (C7), 88.5 (CH2), 56.6
(CH3); HRMS (ESI/TOF) m/z: [M + H]+ calcd for C11H13N2O3,
221.0921; found, 221.0919.
Methoxymethyl 7-Amino-1H-indole-3-carboxylate 28c. Methox-
ymethyl 7-amino-1H-indole-3-carboxylate 28c (930.4 mg, 99%) as a
gray powder. 1H (500 MHz, DMSO-d6): δ 11.56 (1H, br s, NH), 8.07
(1H, s, H2), 7.26 (1H, d, J = 7.9 Hz, H4), 6.91 (1H, t, J = 7.7 Hz,
H5), 6.43 (1H, d, J = 7.5 Hz, H6), 5.39 (2H, s, CH2), 5.19 (2H, br s,
NH2), 3.45 (3H, s, CH3); 13C{1H} (126 MHz, DMSO-d6): δ 164.3
(CO), 134.9 (C7), 132.1 (C2), 127.1 (C3a), 126.2 (C7a), 123.1
(C5), 109.1 (C4), 106.8 (C3), 106.6 (C6), 89.2 (CH2), 57.2 (CH3);
HRMS (ESI/TOF) m/z: [M + H]+ calcd for C11H13N2O3, 221.0921;
found, 221.0923.
General Method 5Protection of Amine 29. The appropriate
amine 28 (1 equiv) was dissolved in DCM (10 mL/mmol) with
pyridine (5 equiv) under nitrogen. CbzCl (2.4 equiv) was added, and
the reaction mixture was stirred at room temperature overnight. The
reaction mixture was diluted with water and extracted 3x with DCM.
The combined organics were washed with brine, dried over MgSO4,
passed through a phase separator, and evaporated to dryness. The
residue was purified by flash chromatography (0−100% ethyl acetate
in heptane) to give the desired products.
Methoxymethyl 5-(((Benzyloxy)carbonyl)amino)-1H-indole-3-
carboxylate 29a. Methoxymethyl 5-(((benzyloxy)carbonyl)amino)-
1H-indole-3-carboxylate 29a (492 mg, 75%) as an off-white powder.
1H (500 MHz, DMSO-d6): δ 11.89 (1H, br s, NH), 9.63 (1H, br s,
5-(((Benzyloxy)carbonyl)amino)-1H-indole-3-carboxylic Acid
30a. 5-(((Benzyloxy)carbonyl)amino)-1H-indole-3-carboxylic acid
1
30a (189 mg, 47%) as a white powder. H (500 MHz, DMSO-d6):
δ 11.80 (1H, br s, COOH), 11.67 (1H, br s, NH), 9.55 (1H, br s,
NH), 8.19 (1H, s, H4), 7.93 (1H, d, J = 3.0 Hz, H2), 7.44 (2H, d, J =
7.1 Hz, Cbz-CH), 7.40 (2H, t, J = 7.5 Hz, Cbz-CH), 7.34 (2H, m, H7,
Cbz-CH), 7.26 (1H, d, J = 8.6 Hz, H6), 5.15 (2H, s, CH2); 13C{1H}
(126 MHz, DMSO-d6): δ 165.8 (COOH), 153.6 (carbamate CO),
136.9 (Cbz-C), 132.9 (C7a), 132.7 (C5), 132.6 (C2), 128.3 (Cbz-
CH), 127.9 (Cbz-CH), 127.8 (Cbz-CH), 126.1 (C3a), 115.2 (C6),
112.0 (C7), 110.4 (C4), 107.2 (C3), 65.4 (Cbz-CH2); HRMS (ESI/
TOF) m/z: [M − H]− calcd for C17H13N2O4, 309.0881; found,
309.0883.
6-(((Benzyloxy)carbonyl)amino)-1H-indole-3-carboxylic Acid
30b. 6-(((Benzyloxy)carbonyl)amino)-1H-indole-3-carboxylic acid
1
30b (234 mg, 72%) as a white powder. H (500 MHz, DMSO-d6):
δ 11.81 (1H, br s, COOH), 11.64 (1H, d, J = 1.4 Hz, NH) 9.70 (1H,
br s, NH), 7.89 (1H, d, J = 2.8 Hz, H2), 7.84 (1H, d, J = 8.6 Hz, H4),
7.79 (1H, br s, H7), 7.44 (2H, d, J = 7.2 Hz, Cbz-CH), 7.40 (2H, t, J
= 7.5 Hz, Cbz-CH), 7.34 (1H, t, J = 7.2 Hz, Cbz-CH), 7.16 (1H, dd, J
= 8.6, 1.6 Hz, H5), 5.16 (2H, s, CH2); 13C{1H} (126 MHz, DMSO-
d6): δ 165.8 (COOH), 153.5 (carbamate CO), 136.7 (C7a), 136.7
(Cbz-C), 134.2 (C6), 131.6 (C2) 128.4 (Cbz-CH), 128.0 (Cbz-CH),
127.9 (Cbz-CH), 121.6 (C3a), 120.4 (C4), 113.5 (C5), 107.2 (C3),
101.4 (C7), 65.5 (CH2); HRMS (ESI/TOF) m/z: [M − H]− calcd
for C17H13N2O4, 309.0881; found, 309.0885.
7-(((Benzyloxy)carbonyl)amino)-1H-indole-3-carboxylic Acid
30c. 7-(((Benzyloxy)carbonyl)amino)-1H-indole-3-carboxylic acid
NH), 8.21 (1H, br s, H4), 8.09 (1H, s, H2), 7.44 (2H, d, J = 7.3 Hz,
Cbz-CH), 7.40 (3H, m, H7, Cbz-CH), 7.33 (2H, m, H6, Cbz-CH),
5.40 (2H, s, MOM-CH2), 5.16 (2H, s, Cbz-CH2), 3.48 (3H, s, CH3);
13C{1H} (126 MHz, DMSO-d6): δ 164.1 (ester CO), 154.2
1
30c (332 mg, 40%) as a white powder. H (500 MHz, DMSO-d6):
δ 11.91 (1H, br s, NH), 11.49 (1H, br s, COOH), 9.49 (1H, br s,
NH), 7.98 (1H, d, J = 3.0 Hz, H2), 7.76 (1H, d, J = 8.0 Hz, H4), 7.41
(6H, m, Cbz-CH, H6), 7.10 (1H, t, J = 7.9 Hz, H5), 5.20 (2H, s,
CH2); 13C{1H} (126 MHz, DMSO-d6): δ 163.7 (COOH), 153.7
(carbamate CO), 136.5 (Cbz-C), 131.9 (C2), 128.4 (Cbz-CH),
128.1 (Cbz-CH), 128.0 (Cbz-CH), 127.3 (C3a), 123.8 (C7), 121.2
(C5), 116.2 (C4), 107.7 (C3), 66.0 (CH2); HRMS (ESI/TOF) m/z:
[M − H]− calcd for C17H13N2O4, 309.0881; found, 309.0885.
General Method 7Synthesis of Boc-Protected Amine 31.
Caution! Azides are potentially explosive substances and can
decompose violently. The appropriate carboxylic acid 30 (1 equiv)
was suspended in DCM (30 mL/mmol) under nitrogen. Triethyl-
amine (2 equiv) was added and stirred until everything dissolved.
DPPA (1.1 equiv) was added, and the reaction mixture was stirred at
room temperature overnight. The reaction mixture was washed with 1
N HCl, and the aqueous layer was extracted 2x with DCM. The
combined organics were washed with saturated NaHCO3 solution and
brine, dried over MgSO4, and passed through a phase separator, with
the volume reduced to ∼5 mL in vacuo. t-Butanol (30 mL/mmol)
was added, and the residual DCM was removed in vacuo. Acetic acid
(2 equiv) was added, and the reaction mixture was stirred at 60 °C for
24 h under nitrogen. The solvent was removed in vacuo, and the
residue was partitioned between DCM and water. The layers were
separated, and the aqueous layer was extracted 2x with DCM; the
combined organics were washed with saturated NaHCO3 solution and
brine, dried over MgSO4, passed through a phase separator, and
evaporated to dryness. The residue was purified by flash
chromatography (0−50% ethyl acetate in heptane) to give the
desired products.
(carbamate CO), 137.4 (Cbz-C), 133.9 (C2), 133.3 (C7a), 128.9
(Cbz-CH), 128.5 (Cbz-CH), 128.4 (Cbz-CH), 126.4 (C3a), 116.0
(C6), 112.8 (C7), 110.6 (C4), 106.4 (C3), 89.3 (MOM-CH2), 66.0
(Cbz-CH2), 57.3 (CH3); HRMS (ESI/TOF) m/z: [M + NH4]+ calcd
for C19H22N3O5, 372.1554; found, 372.1566.
Methoxymethyl 6-(((Benzyloxy)carbonyl)amino)-1H-indole-3-
carboxylate 29b. Methoxymethyl 6-(((benzyloxy)carbonyl)amino)-
1H-indole-3-carboxylate 29b (439 mg, 48%) as an off-white powder.
1H (500 MHz, DMSO-d6): δ 11.86 (1H, br s, NH), 9.74 (1H, br s,
NH), 8.05 (1H, s, H2), 7.85 (2H, m, H2, H4), 7.39 (5H, m, Cbz-
CH), 7.21 (1H, dd, J = 8.6, 1.6 Hz, H5), 5.39 (2H, s, MOM-CH2),
5.17 (2H, s, Cbz-CH2), 3.45 (3H, s, CH3); 13C{1H} (126 MHz,
DMSO-d6): δ 163.6 (ester CO), 153.5 (carbamate CO), 136.8
(C7a), 136.7 (Cbz-CH), 134.5 (C6), 132.5 (C2) 128.4 (Cbz-CH),
128.0 (Cbz-CH), 127.9 (Cbz-CH), 121.2 (C3a), 120.3 (C4), 113.9
(C5), 106.0 (C3), 101.6 (C7), 88.8 (MOM-CH2), 65.6 (Cbz-CH2),
56.7 (CH3); HRMS (ESI/TOF) m/z: [M + H]+ calcd for
C19H19N2O5, 355.1288; found, 355.1294.
Methoxymethyl 7-(((Benzyloxy)carbonyl)amino)-1H-indole-3-
carboxylate 29c. Methoxymethyl 7-(((benzyloxy)carbonyl)amino)-
1H-indole-3-carboxylate 29c (1170 mg, 74%) as an off-white powder.
1H (500 MHz, DMSO-d6): δ 11.70 (1H, br s, NH), 9.53 (1H, br s,
NH), 8.14 (1H, s, H2), 7.77 (1H, d, J = 8.0 Hz, H4), 7.43 (6H, m,
Cbz-CH, H6), 7.17 (1H, d, J = 7.9 Hz, H5), 5.46 (2H, s, MOM-
CH2), 5.21 (2H, s, Cbz-CH2), 3.46 (3H, s, CH3); 13C{1H} (126
MHz, DMSO-d6): δ 163.5 (ester CO), 153.67 (carbamate CO),
136.4 (Cbz-C), 132.7 (C2), 128.4 (Cbz-CH), 128.1 (Cbz-CH), 128.0
(Cbz-CH), 127.0 (C3a), 124.1 (C7), 121.7 (C5), 116.0 (C4), 113.7
(C6), 106.4 (C3), 88.9 (MOM-CH2), 66.1 (Cbz-CH2), 56.7 (CH3);
Benzyl tert-Butyl (1H-Iindole-3,5-diyl)dicarbamate 31a. Benzyl
tert-butyl (1H-indole-3,5-diyl)dicarbamate 31a (10.7 mg, 17%) as a
G
https://doi.org/10.1021/acs.joc.1c00652
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1
white powder. H (500 MHz, DMSO-d6): δ 10.60 (1H, br s, NH),
ACKNOWLEDGMENTS
■
9.39 (1H, br s, NH), 8.88 (1H, br s, NH), 7.80 (1H, s, H4), 7.42 (4H,
m, Cbz-CH), 7.30 (2H, m, H2, Cbz-CH), 7.20 (21, m, H7), 7.07
(1H, d, J = 7.5 Hz, H6), 5.15 (2H, s, CH2), 1.48 (9H, s, CH3);
13C{1H} (126 MHz, DMSO-d6): δ 153.8 (carbamate CO), 137.0
(Cbz-C), 130.8 (C7a), 130.0 (C5), 128.4 (Cbz−CH), 127.9 (Cbz-
CH), 127.8 (Cbz-CH), 121.6 (C3a), 116.5 (C2), 115.2 (C6), 114.9
(C3), 111.1 (C7), 108.8 (C4), 78.1 (C(CH3)3), 65.3 (Cbz-CH2),
28.22 (CH3); HRMS (ESI/TOF) m/z: [M + H]+ calcd for
C21H24N3O4, 382.1761; found, 382.1764.
We would like to acknowledge the University of Dundee for a
Nicholl-Lindsey studentship (J.S.M.) and Medicines for
Malaria Venture for financial support. This work was
supported by a Wellcome Trust Centre Award [203134/Z/
16/Z].
REFERENCES
■
(1) Kaushik, N.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C.; Verma,
A.; Choi, E. Molecules 2013, 18, 6620.
(2) Lindsay, A. C.; Kim, S. H.; Sperry, J. Nat. Prod. Rep. 2018, 35,
1347.
Benzyl tert-Butyl (1H-Indole-3,6-diyl)dicarbamate 31b. Benzyl
tert-butyl (1H-indole-3,6-diyl)dicarbamate 31b (33 mg, 54%) as a
1
white powder. H (500 MHz, DMSO-d6): δ 10.53 (1H, br s, NH),
9.55 (1H, br s, NH) 8.99 (1H, br s, NH), 7.61 (2H, m, H4, H7), 7.42
(4H, m, Cbz-CH), 7.34 (1H, t, J = 7.2 Hz, Cbz-CH), 7.29 (1H, br s,
H2), 6.95 (1H, d, J = 8.6 Hz, H5), 5.15 (2H, s, CH2), 1.48 (9H, s,
CH3); 13C{1H} (126 MHz, DMSO-d6): δ 153.4 (carbamate CO),
153.3 (carbamate CO), 136.8 (Cbz-C), 134.1 (C7a), 133.4 (C6),
128.4 (Cbz-CH), 128.0 (Cbz-CH), 127.9 (Cbz-CH), 118.1 (C4),
116.9 (C3a), 115.2 (C3), 113.5 (C2), 110.9 (C5), 100.7 (C7), 78.2
(C(CH3)3), 65.4 (CH2), 28.2 (CH3); HRMS (ESI/TOF) m/z: [M +
H]+ calcd for C21H24N3O4, 382.1761; found, 382.1767.
(3) Seferoglu, Z.; Ertan, N. Russ. J. Org. Chem. 2007, 43, 1035.
(4) Mannes, P. Z.; Onyango, E. O.; Gribble, G. W. J. Org. Chem.
2016, 81, 12478.
(5) Edin, M.; Grivas, S. ARKIVOC 2000, 2000, 1.
(6) Noland, W. E.; Rush, K. R. J. Org. Chem. 1966, 31, 70.
(7) Wang, S.; Wan, N. C.; Harrison, J.; Miller, W.; Chuckowree, I.;
Sohal, S.; Hancox, T. C.; Baker, S.; Folkes, A.; Wilson, F.; Thompson,
D.; Cocks, S.; Farmer, H.; Boyce, A.; Freathy, C.; Broadbridge, J.;
Scott, J.; Depledge, P.; Faint, R.; Mistry, P.; Charlton, P. J. Med. Chem.
2004, 47, 1339.
Benzyl tert-Butyl (1H-Indole-3,7-diyl)dicarbamate 31c. Benzyl
tert-butyl (1H-indole-3,7-diyl)dicarbamate 31c (16 mg, 26%) as a
(8) Wang, X.; Liu, Y.; Xu, J.; Jiang, F.; Kang, C. J. Chem. Res. 2016,
40, 588.
1
white powder. H (500 MHz, DMSO-d6): δ 10.44 (1H, br s, NH),
9.38 (1H, br s, NH), 9.05 (1H, br s, NH), 7.44 (8H, m, H2, H4, H5,
Cbz-CH), 6.93 (1H, t, J = 7.8 Hz, H5), 5.21 (2H, s, CH2), 1.50 (9H,
s, CH3); 13C{1H} (126 MHz, DMSO-d6): δ 153.8 (carbamate C
O), 153.5 (carbamate CO), 136.6 (Cbz-C), 128.5 (Cbz-CH),
128.1 (Cbz-CH), 128.1 (Cbz-CH), 125.9 (C7a), 123.1 (C7), 122.3
(C3a), 118.2 (C5), 115.8 (C3), 114.4 (C4), 114.0 (C6), 112.3 (C2),
78.4 (CCH3), 66.00 (CH2), 28.3 (CH3); HRMS (ESI/TOF) m/z:
[M + H]+ calcd for C21H24N3O4, 382.1761; found, 382.1754.
(9) Marcin, L. R.; Higgins, M. A.; Zusi, F. C.; Zhang, Y.; Dee, M. F.;
Parker, M. F.; Muckelbauer, J. K.; Camac, D. M.; Morin, P. E.;
Ramamurthy, V.; Tebben, A. J.; Lentz, K. A.; Grace, J. E.;
Marcinkeviciene, J. A.; Kopcho, L. M.; Burton, C. R.; Barten, D.
M.; Toyn, J. H.; Meredith, J. E.; Albright, C. F.; Bronson, J. J.; Macor,
J. E.; Thompson, L. A. Bioorg. Med. Chem. Lett. 2011, 21, 537.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00652.
Copies of NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Ian H. Gilbert − Wellcome Centre for Anti-Infectives Research,
Division of Biological Chemistry and Drug Discovery,
University of Dundee, Dundee DD1 5EH, U.K.;
orcid.org/0000-0002-5238-1314; Email: i.h.gilbert@
dundee.ac.uk
Authors
James S. Martin − Wellcome Centre for Anti-Infectives
Research, Division of Biological Chemistry and Drug
Discovery, University of Dundee, Dundee DD1 5EH, U.K.
Claire J. Mackenzie − Wellcome Centre for Anti-Infectives
Research, Division of Biological Chemistry and Drug
Discovery, University of Dundee, Dundee DD1 5EH, U.K.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00652
Author Contributions
All the experiments were conducted by J.S.M. The manuscript
was written through contributions of all authors. All authors
have given approval to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
H
https://doi.org/10.1021/acs.joc.1c00652
J. Org. Chem. XXXX, XXX, XXX−XXX