Straightforward protocol for the efficient synthesis of varied N 1-acylated (aza)indole 2-/3-alkanoic acids and esters: Optimization and scale-up

Article abstract of DOI:10.1016/j.tet.2012.08.044

A library of approximately 40 N¹-acylated (aza)indole alkanoic esters and acids was prepared employing a microwave-assisted approach. The optimized synthetic route allows for parallel synthesis, variation of the indole substitution pattern, and high overall yield. Additionally, the procedure has been scaled up to yield multi-gram amounts of preferred indole compounds, e.g.: 2′-des-methyl indomethacin 2. The reported compounds were designed as biomedical tools for primary and secondary in vitro and in vivo studies at relevant molecular targets.

Full text of DOI:10.1016/j.tet.2012.08.044

Tetrahedron 68 (2012) 10049e10058
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Straightforward protocol for the efficient synthesis of varied N1-acylated (aza)
indole 2-/3-alkanoic acids and esters: optimization and scale-up
,
a,
*
Andy J. Liedtke a, Kwangho Kim b, Donald F. Stec b, Gary A. Sulikowski b , Lawrence J. Marnett
*
a A.B. Hancock Jr. Memorial Laboratory for Cancer Research, Departments of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Center in Molecular
Toxicology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
b Departments of Chemistry and Biochemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37235, USA
a r t i c l e i n f o
a b s t r a c t
A library of approximately 40 N1-acylated (aza)indole alkanoic esters and acids was prepared employing
a microwave-assisted approach. The optimized synthetic route allows for parallel synthesis, variation of
the indole substitution pattern, and high overall yield. Additionally, the procedure has been scaled up to
yield multi-gram amounts of preferred indole compounds, e.g.: 20-des-methyl indomethacin 2. The re-
ported compounds were designed as biomedical tools for primary and secondary in vitro and in vivo
studies at relevant molecular targets.
Article history:
Received 23 June 2012
Received in revised form 12 August 2012
Accepted 15 August 2012
Available online 28 August 2012
Keywords:
Heterocyles
Ó 2012 Elsevier Ltd. All rights reserved.
Indoles
(20-Des-methyl) indomethacin
Microwave synthesis
Synthesis scale-up
1. Introduction
N-Acylated indole acetic acids are drawing continued attention
due to their wide-ranging pharmacological activities.1e5 For exam-
ple, indomethacin (INDO, 1, Fig. 1), a traditional non-steroidal anti-
inflammatory drug (NSAID), is a potent, time-dependent inhibitor of
cyclooxygenases (COX-1 and COX-2) with a long history of clinical
use in human subjects.6 It promotes anti-inflammatory, anti-pyretic,
and analgesic activities, but also contributes to severe stomach irri-
tation and ulcers due to secondary pharmacodynamic effects.7,8
Recently, 1 and some of its derivatives have been shown to hold
interesting and potentially useful ‘off-target’ activities, e.g., regula-
tion of Th2-mediated asthma and other allergic diseases or chemo-
prevention of tumors by addressing targets different from COX.9e14
Of these INDO derivatives, those that do not (strongly) interfere
with arachidonic acid (AA) metabolism, have greater potential to be
valuable drug candidates because of their presumably lower gas-
trointestinal toxicity. Very recently we have probed 20-des-methyl
indomethacin (20-DM-INDO, 2, Fig. 1),15 a structurally edited version
of 1, which exhibits drastically reduced inhibitory potency against
both COX enzymes and reduced gastric toxicity relative to 1 in
C57BL6 mice.16,10 To further probe the effects of indoles related to 1
and 2, we required rapid production of iterative series of N-acyl in-
dole alkanoic acids and esters in good overall yield.
Fig. 1. Structure of indomethacin derivatives.
In the present manuscript we report a very efficient indoliza-
tion/acylation approach toward N-substituted (aza)indole com-
pounds and we describe the successful scale-up of the synthesis of
two prototype indole analogues.
2. Results and discussion
2.1. Small-scale approach
We accomplished a robust synthetic routine and generated
a series of novel INDO (1) analogues 18e31 (Tables 2 and 3) with
individual compounds emerging in milligram or multi-gram
quantities and good overall yield (>55%). The general reaction
* Corresponding authors. Tel.: þ1 615 343 4155; fax: þ1 615 343 6361 (G.A.S); tel.:
þ1615 343 7329; fax: þ1615 343 7534 (L.J.M); e-mail addresses: gary.a.sulikowski@
vanderbilt.edu (G.A. Sulikowski), larry.marnett@vanderbilt.edu (L.J. Marnett).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.08.044

10050
A.J. Liedtke et al. / Tetrahedron 68 (2012) 10049e10058
sequence leading to indoles 18 through 31, followed three simple
steps: (a) Fischer indolization of substituted phenylhydrazine hy-
drochlorides condensed with selected ketoacids/esters, (b) base-
catalyzed indole N1-acylation reactions (SN2 substitutions) with
different acid chlorides, and (c) ester hydrolysis of the intermediate
methyl or cleavage of allyl N-acyl indole alkanoates in the presence
of a metal organic catalyst. Structural modifications with respect to
1 (and 2) were made at the C2, C3, C5, COOH, and N1-position of the
indole ring. Previous procedures using similar synthetic strategies
have not been reported on large-scale and oftentimes proceed in
low overall yield.
and ease of removal. Utilization of tBuONa in THF or DMAP/Et3N in
DCM as reaction medium facilitated indole N-acylation with select
aryl acid chlorides. Final ester cleavage was done in 1,2-DCE with
trimethyltin hydroxide24 (methyl esters) or in THF using Pd(PPh3)4/
morpholine as catalyst complex (allyl esters). Concurrent
N-deacylation was not observed with these expedient procedures,
which clearly privileges them over standard saponification
methods with metal alkaline hydroxide/water. We also investigated
the synthesis under microwave irradiation for numerous com-
pounds with a view to speed up reaction rates and increase isolable
yields.
Several creative methods for assembly of N1-substituted indole
compounds have been reported. These include one-pot Stille cou-
plings of N-acyl-2-iodoanilines,17 catalytic dehydrogenative N1-
couplings of indoles with primary alcohols,18 distinct indolization
reactions with cyclic enol ethers and enol lactones,19 and variations
of the Fischer Indole synthesis.20
In the refined standard procedure of Yamamoto for compound 1
(Scheme 1),21,22 an arylhydrazone precursor 4 is benzoylated at the
N1-position to give the N1,N1-disubstituted hydrazine 5. Typically,
commercial hydrazine hydrochloride starting materials 3 need to
be deprotonated prior to reaction. The intermediate 5 is then hy-
drolyzed with hydrogen chloride to give the hydrazine hydro-
chloride salt 6, which is cyclized in the final reaction step with
levulinic acid to afford 1.23 The synthesis of 20-des-methyl INDO 2
has been conducted accordingly with the exception that succinic
semialdehyde was used for the ring-closure.
Scheme 2. Esterification of (20-aza-/20-des-methyl) indole-30-acetic acids.
2.1.1. Preparation of different indole methyl alkanoates. Initially, we
generated a set of 10 different C2/C3/C5-substituted (aza)indole in-
termediates. The structures, specific conditions, and yields are
summarized in Table 1. Detailed experimental data can be also
found in Supplementary data.
Table 1
Preparation of different (aza)indole alkanoic acid ester precursors
#
X
Y
R1
R2
R3
Method Yielda (%)
9a
9b
9c
9d
9e
14
C
C
C
C
C
C
C
C
C
C
C
C
OMe CH2C(O)OMe
OMe CH2C(O)OMe
Me
H
Me
Me
H
A1
A1
B2
B2
B2b
>99
85
84
76
86
F
F
F
F
CH2C(O)OMe
CH2CH2C(O)OMe
CH2C(O)OMe
Me
Scheme 1. Yamamoto’s procedure for the synthesis of (20-des-methyl) indomethacin;
R¼CH3 or H.
CH2CH2C(O)OMe B2
46
15a
15b
C
C
C
C
OMe
B1
90
99
Isolated product yields are often unsatisfactory using this liter-
ature procedure due to multiple reaction steps, the formation of by-
products, and the requirement for extensive purification of in-
termediates.19 The early insertion of the N1-acyl moiety in the re-
action sequence is another limitation of this entry, which involves
the addition and subsequent displacement of an ethylidene pro-
tection group (N2). Therefore, in order to vary the N-acyl sub-
stituent for a series of indole analogues 18e21 (Table 2), each
derivative needed to be constructed individually. To overcome this
limitation and enhance the flexibility toward the introduction of
multiple substituents in the indole scaffold, we pursued a strategy
(Scheme 2) that has not been intensively investigated for the serial
production of substituted indoles because it has proven to be rather
uneconomical, especially for larger scales. This strategy employs
indolization first followed by late-stage N1-substitution and release
of the carboxylic acid under optimized reaction conditions. Cycli-
zation reactions of arylhydrazines with different ketoacids/esters
were conducted in AcOH or refluxing methanol/H2SO4. We used
methyl or allyl esters for our small-scale and large-scale reactions,
respectively, because of their stability to the reaction conditions
F
B2
10
17
C
N
N
C
H
CH2C(O)OMe
d
A2
Other
77
60
OMe CH2C(O)OMe
H
Reagents and conditions: [method A1]: BOPeCl, triethylamine, CH2Cl2, MeOH, rt,
overnight; [method A2]: MeOH, H2SO4, reflux, overnight; [method B1]: arylhy-
drazine HCl, ketoacid ester, AcOH, 80 ꢀC, 3 h; [method B2]: arylhydrazine HCl,
ketoacid or ketoacid ester, MeOH, H2SO4, microwave, 120 ꢀC, 10 min.
a
Isolated yield.
Conventional heating, 3 h instead of microwave.
b
Methyl esters 9a, and 9b of commercial 5-methoxy-2-
methylindole-3-acetic acid 7a, and 5-methoxyindole-3-acetic acid
7b were generated overnight at room temperature in yields >85%
using BOPeCl/triethylamine and methanol (Scheme 2).25

A.J. Liedtke et al. / Tetrahedron 68 (2012) 10049e10058
10051
The preparation of different C2/C3-substituted indole com-
pounds 9cee, 14, and 15 is summarized in Scheme 3. Substituted
arylhydrazine hydrochlorides 3 were directly subjected to reaction
with selected ketoacids or esters 11 through 13. Particularly, indole
compound 15a was generated in 90% yield under standard reaction
conditions (AcOH, 80 ꢀC, 3 h) using 4-methoxyphenyl hydrazine
hydrochloride 3a and methyl 4-ketocyclohexanecarboxylate. Next,
in order to allow investigation of the significance of a fluoro sub-
stitution at the indole 5-position, we pursued Fischer indole syn-
thesis of C2/C3-substituted indole analogues 9cee, 14, and 15b.
Whereas para-methoxylated phenylhydrazine hydrochloride 3a
(e.g., for compound 15a) readily dissolved in AcOH upon heating,
this was not the case for fluorinated starting material 3b (leaving
unreacted starting materials). Therefore, AcOH was replaced by
methanol/H2SO4 as solvent mixture for better solubility of the
fluorinated precursors. In this case, selected ‘ketoacids’ rather than
their low alkyl esters were employed in the reaction, as clean
COOH-esterification usually occurred alongside the ‘indole’ ring-
closure (compare Experimental section for 9c vs 9e). Reactions
were accelerated by microwave irradiation and ran approx. 50
times faster (5e10 min instead 3e6 h) than with conventional
heating affording consistently high and reproducible yields
(w80%). In many cases products precipitated upon pouring the
reaction mixture on crushed ice or could be extracted from the
resulting aqueous mixture, washed and obtained in acceptable
quality after removal of solvent in vacuo and trituration with
hexanes.
in the course of the Fischer indole synthesis. In the case of 11 (acetyl
or formyl tail end), the alkyl acid functionality was solely directed to
position 3 of the indole product, whereas reagents 12 (ethylcarbonyl
tail end) typically produce the alkyl acid functionality at position 2
(isolated products).26 Structure examples are given in Scheme 2 and
Table 1.26 Elongation of the alkyl chain in between the two functional
groups with respect to reagents 11 was tolerated and didn’t affect the
selectivity (e.g., 9d). On the contrary, the inclusion of one or more
extra methylene units into the terminal alkyl chain (beyond car-
bonyl) and/or extension of the alkyl spacer (between CO and COOH)
of 12 continuously yielded isomeric mixtures (C2/C3). Such com-
pounds are not part of the current work.
Poor regioselectivity is a general problem of Fischer indole re-
actions as evidenced in the use of unsymmetrical cyclic ketones.
Interestingly, there have been a few examples for the selective
cyclization of phenylhydrazones with, e.g., 3-ketocyclo-hex-
anecarboxylic acid or 5-aryldihydro-3(2H)-thiophenones.27,28 To
simplify matters in our present study we used symmetrical 4-
ketocyclohexanecarboxylic acid to produce indole derivatives 15a
(60-methoxy, see above) and 15b (60-fluoro) and to demonstrate the
later availability for use of similar intermediates in subsequent
N-acylation/ester cleavage reactions. In practice, indole derivative
15b could be isolated quantitatively after short reaction times using
microwave-aided synthesis.
In order to demonstrate the feasibility of additional heteroatoms
and to modify the hydrophilicity of the core skeletons, we also
produced a 2-aza (10) and a 4-aza indole-3-acetic acid methyl ester
analogue (17) (Schemes 2 and 4). The reaction for 10 was completed
in 77% yield according to a patent method starting from 2-(1H-
indazol-3-yl)acetic acid (14 h reflux in methanol/H2SO4).29 In this
case the originally attempted esterification with BOPeCl/methanol
did not succeed. Anotherliterature method allowed for the synthesis
of the 4-aza indole derivative 17.30,31 In contrast to the published
procedure, we adopted the reaction under microwave irradiation
with the respective methyl ester. Customized one-pot catalytic re-
duction/cyclization of a 3-cyano-3-(nitropyridin-2-yl)-methyl pro-
pionate precursor 16 in methanol using Pd/C and cyclohexadiene as
hydrogen source (10 min at 120 ꢀC) readily afforded 17 in 60% yield.
Scheme 3. Fischer cyclization reactions toward different indole 2-/3-alkylcarboxylic
acid methyl ester intermediates. Reagents and conditions: (a) AcOH, 80 ꢀC, 3h;
(b) MeOH/H2SO4, 5 min (microwave) to 3 h (conventional heating).
The same results were achieved when using ketoacids whose
carboxylic acid group had been esterified beforehand (see experi-
mental details for 9c). (Partial) re-esterification to the corre-
sponding methyl esters
9 even occurred when starting, for
example, with ethyl esters of 11 (data not shown). For compound
9d bearing an extended exocyclic alkyl chain on position C3 of the
indole, 4-F-phenylhydrazine hydrochloride was converted with 5-
oxohexanoic acid under the conditions described. Finally a 2-
propionic acid derivative was realized with indole 14, using 4-
oxohexanoic acid as cyclization reagent. In this case, however, the
desired product could be isolated only in 46% yield.
Not only did this reaction eliminate the need for an N-protection,
it also allowed the variation of all relevant substituents R1 through R3
as well as the length and position of the carboxyalkyl chain at the
indole framework within only one reaction step. Generally, linear
ketones 11 or 12 were of importance for the later configuration of the
carboxyalkyl substituted indoles. Certain ‘keto’ alkanoic acids/esters
provided high regioselectivity in the 3,3-sigmatropic rearrangement
Scheme 4. Synthesis of a 4-aza-indole-3-acetic acid ester analogue.
2.1.2. Substitution at nitrogen (N1). N-Substitution of indoles, 9 and
15, yielded a series of N-acyl indole methyl alkanoates, 18 and 19,
respectively (Table 2). Different benzoyl/aryl acid chlorides were
chosen as acylating reagents. However, direct N-acylation of an
indole nucleus is demanding and necessitates deprotonation of the
NeH center, as neutral indoles are non-nucleophilic at the nitrogen
atom. Due to the low acidity of the indole-N1, full deprotonation to
the reactive anion can be only realized under strong base catalysis
in (polar) aprotic solvents.
For the small-scale one-pot reactions on indole 9 we first tried
sodium hydride (powdered material) in DMF, though, with less

10052
A.J. Liedtke et al. / Tetrahedron 68 (2012) 10049e10058
Table 2
Synthesis of N-acyl methyl (aza)indole(cyclo)alkanoates
#
Y
R1
R2
R3
n
R4
Method Yielda (%)
18a
18b
18c
18d
18e
18f
18g
18h
18i
C
C
C
C
C
C
C
C
C
C
C
OMe CH2C(O)OMe
OMe CH2C(O)OMe
OMe CH2C(O)OMe
OMe CH2C(O)OMe
OMe CH2C(O)OMe
OMe CH2C(O)OMe
OMe CH2C(O)OMe
OMe CH2C(O)OMe
OMe CH2C(O)OMe
OMe CH2C(O)OMe
OMe CH2C(O)OMe
Me
Me
Me
Me
Me
Me
H
H
H
H
H
0
0
0
0
0
0
0
0
0
0
1
p-F
C2
C2
C2
C2
C2
C2
C1
C2
C2
C2
C1
25
32
33
57
42
32
18
22
13
29
(13)c
Scheme 5. N-Acylation and ester cleavage reactions.
m-CF3
p-CF3
p-Me
p-CH2Cl
p-OMe
p-Cl
instead of weighing moisture-sensitive solids; phase separation
after water quench). Reactions were run on
a small-scale
(80e100 mg each) under argon on a parallel synthesis apparatus.
N-Acylation with different acid chlorides occurred best at tem-
peratures between 0 ꢀC and 25 ꢀC. Therefore, in a typical experi-
ment, we pipetted the base to an ice-cold stirred solution of the
indole in THF and after 20 min we added the acid chloride and let
the mixture react at ambient temperature until the starting ma-
terial was consumed or no further product formation could be
detected (usually overnight). Progress of the reactions was mon-
itored by LCMS and TLC. In most cases, one major product was
detected. By-products were predominantly unreacted or N-
deacylated/hydrolyzed indole starting materials and the carboxyl
counterparts of the applied benzoyl chlorides.
Isolated amounts of products with varied meta- and para-
substituted N-benzoyl moieties appeared to be better (24e57%),
when a 2-methyl group was present on the indole ring (18aef and
18meo) and were lower (13e29%) among the 2-des-methyl indole
analogues (18gek), except for 18q (42%). In compounds 18k and
18p the acyl substituent was ‘extended’ by an additional methylene
unit, which further reduced the percent yields [18k: 13% (impure)
and 18q: 4%, respectively]. A simple aliphatic N-propanoyl sub-
stituent was realized with indole acetic acid ester analogue 18l. C2/
C3-Cyclized indole intermediates, 12a and 12b could be substituted
on their nitrogens with a m-CF3- and p-Cl-benzoyl substituent in 24
and 14% yields, respectively (19a, 19b). Acylation of an N1,C2,C3-
unsubstituted 5-methoxyindole precursor using sodium tert-but-
oxide and p-Cl-benzoyl chloride afforded a mixture of three com-
pounds, two of which were isomers with the benzoyl moiety on
either position C3 (faint, not isolated) or N1 (20a, 25%). The other
isolated product 20b (8%) was analyzed to be an N1/C3-dibenzoy-
lated indole derivative. These reactions reflect the enhanced re-
activity of the unsubstituted indole 3-position upon hydrogen
abstraction at the nitrogen via the conjugated double-bond system
(conjugate-like substitution) and in turn the facilitated N1-depro-
tonation reaction by the 3-acyl ring substituent.
p-F
m-CF3
p-CF3
p-OMe
18j
18k
18l
C
OMe CH2C(O)OMe
H
0
C1
21
18m
18n
18o
18p
18q
C
C
C
C
C
F
F
F
F
F
CH2C(O)OMe
CH2C(O)OMe
CH2CH2C(O)OMe
CH2C(O)OMe
CH2C(O)OMe
Me
Me
Me
Me
H
0
0
0
1
0
p-Cl
m-CF3
p-Cl
p-Cl
p-Cl
C2
C2
C2
C2
C2
42
33
49
4
42
19a
19b
C
C
OMe
0
0
m-CF3
C2
C2
24
14
F
p-Cl
20a
20b
21
C
C
N
OMe
OMe
H
Me
Me
d
0
0
0
p-Cl
p-Cl
p-Cl
C2
C2
C2
25
8b
OMe CH2C(O)OMe
37
Reagents and conditions: [method C1]: NaH, DMF, acyl chloride, 0 ꢀC to rt, over-
t
night; [method C2]: BuONa, THF, acyl chloride, 0 ꢀC to rt, overnight.
a
The initial attempt to acylate a 2-propionic acid ester indole
derivative (e.g., 11) with 4-chlorobenzoyl chloride using similar
conditions failed and considerable amounts of starting material
were detected beside some undefined products by LCMS. Never-
theless, N-substitution of a comparable indole derivative was suc-
cessfully followed up later under larger scale and with optimized
reaction conditions (compound 30, see below).
Isolated yield.
b
Compound 20b emerged as one side product in the synthesis of 20a.
Compound after repeated chromatography only about 50% pure.
c
satisfying results due to several handling issues (e.g., with com-
pounds 18g, 18k or 18l). Then we switched to sodium tert-but-
oxide and used a 2 M commercial solution in THF to produce
a larger series of compounds 18e21 having different benzoyl (p-Cl,
p-CH2Cl, p-F, p-Me, p-OMe, m/p-CF3) and other acyl moieties
(Scheme 5, first step). Not only did we observe higher yields and
reproducibility with this base (yields ranging from 20 to 60% for
numerous analogues), but also total reaction processing and
workup were cleaner than with NaH/DMF (pipetting volumes
Lastly, compound 21 exemplifies an N1-benzoylated 2-aza-in-
dole acetic acid methyl ester emerging in 37% yield from the par-
allel routine described above.
2.1.3. Methyl ester cleavage. In order to obtain the free acid de-
rivatives 2, 22, 23, and 24 (Table 3) of the N-acylated indole

A.J. Liedtke et al. / Tetrahedron 68 (2012) 10049e10058
10053
Table 3
hydrolysis. Reactions normally ran to completion within
20e30 min (IPC by TLC and LCMS) and workup was quite simple, as
products could be extracted into dichloromethane after addition of
50% acetic acid. Residual Me3SnOH was removed with water or
brine; the organic layer was dried over Na2SO4, filtered, and con-
centrated. Flash chromatography on silica gel afforded the pure N-
acyl indole alkanoic acids 2, 22, and 23 quantitatively. As shown in
Table 3, this technique proved truly valuable in getting the selective
and high-yielding (76e99%) hydrolysis of methyl esters within the
sensitive substrates 18 and 19. Unfortunately, this procedure failed
with the 2-aza derivative 21 to obtain the corresponding free acid
derivative 24. The latter compound repeatedly decomposed into
several unidentified products, regardless of whether the reaction
was conducted with microwave or under conventional heating
conditions (60e80 ꢀC).
Synthesis of N-acyl indole(cyclo)alkanoic acids
#
Y
R1
R2
R3
H
R4
Method Yielda (%)
2
C
C
C
C
C
C
C
C
C
C
OMe CH2C(O)OH
OMe CH2C(O)OH
OMe CH2C(O)OH
OMe CH2C(O)OH
OMe CH2C(O)OH
OMe CH2C(O)OH
OMe CH2C(O)OH
OMe CH2C(O)OH
OMe CH2C(O)OH
OMe CH2C(O)OH
p-Cl
D
D
D
D
D
D
D
D
D
D
81
90
97
90
82
98
93b
76
96
99
22a
22b
22c
22d
22e
22f
22g
22h
22i
Me p-F
Me m-CF3
Me p-CF3
Me p-Me
Me p-CH2Cl
Me p-OMe
H
H
H
To extend this strategy to the large-scale synthesis of individual
N-acyl indole derivatives, we further optimized the reaction con-
ditions as described below, particularly with a view to improving
capacities of the N-acylation step.
p-F
m-CF3
p-CF3
2.2. Large-scale synthesis
New synthetic methodology was adopted for the scale-up to
multi-gram scale. Beside the efforts with N-substitution, the major
problematic step in the synthesis remained the final hydrolysis of
the ester in the presence of the N-acyl functional group. As men-
tioned above, the N-benzoyl bond is labile under basic conditions,
so it was hydrolyzed easily at normal hydrolysis condition for the
ester hydrolysis step.32 Therefore we considered using allyl,33,34
benzyl,35,36 and tert-butyl ester37 to overcome the side reaction
and allyl ester 26 was evaluated.
A large quantity of 2 was prepared from the commercially
available 2-(5-methoxy-1H-indol-3-yl)acetic acid 7b in three steps
starting with esterification with allyl bromide to afford allyl ester
25 in 75% yield (Scheme 6). Efficient acylation of 25 followed by
treatment with triethylamine and DMAP then gave N-benzoate 26
(92% yield). Subsequently, cleavage of the allyl ester was examined.
Optimal conditions employed tetrakis(triphenylphosphine) palla-
dium in combination with morpholine in THF to quantitatively
provide 2 without unwanted hydrolysis of the N-acyl group.38
22j
C
OMe CH2C(O)OH
H
D
94
22k
22l
22m
22n
C
C
C
C
F
F
F
F
CH2C(O)OH
CH2C(O)OH
CH2CH2C(O)OH Me p-Cl
Me p-Cl
Me m-CF3
D
D
D
D
87
95
95
78
CH2C(O)OH
H
p-Cl
m-CF3
Cl
23
24
C
OMe
D
D
98b
N
OMe CH2C(O)OH
d
No product
(decomposition)
Reagents and conditions: [method D]: trimethyltin hydroxide, 1,2-DCE, microwave,
130 ꢀC, 30 min.
a
Isolated yield.
b
Crude educts used; impurity of the starting material taken into account for the
calculation of the percent yield (see Supplementary data)!
compounds 18, 19, and 21, the methyl ester groups had to be
hydrolyzed. Different standard ‘saponification’ methods exist to
achieve this task, however, common drawbacks include elimi-
nation reactions induced by the aqueous-basic conditions.32 This
circumstance became particularly significant, as the N-acyl
bonds of our indole derivatives were perceptibly fragile toward
basic (and strong acidic) treatment and easily hydrolyzed to
liberate N-unsubstituted indole alkanoic acids. This was true for
numerous 2-des-methyl indole analogues and also for the ste-
rically more demanding 2-propionic acid derivatives (see be-
low), notwithstanding a limited number of literature instances
for successful ester saponification toward N-acyl 2-methylindole
acetic acids.20
We attempted a recently reported non-aqueous metal catalytic
method for the mild and selective hydrolysis of esters with trime-
thyltin hydroxide.24 It had been illustrated for many (complex)
aromatic and aliphatic systems that methyl, allyl, and benzyl esters
are hydrolyzed in quantitative yields using this reagent. For our
current study, we once more transferred the stated settings to
microwave conditions (for detailed parameters see Experimental
part) and consistently applied 5 equiv of Me3SnOH beside our
starting methyl esters in 1,2-dichloroethane for the expedited ester
Scheme 6. Large-scale synthesis of compound 2.
From the result of the synthesis for 2, allyl ester was projected
as an advanced intermediate in our synthesis so it was applied to
another large-scale synthesis of a 2-propionic acid derivative 30
en route to a more complex sulfonimide derivative (COOH bio-
isostere) 31 (Scheme 7).

10054
A.J. Liedtke et al. / Tetrahedron 68 (2012) 10049e10058
Indole 28 was not commercially available and therefore should
performed on precoated fluorescent silica gel 60 F254 plates (250
be prepared from succinyl chloride using Boger’s synthesis.39 Suc-
cinyl chloride was treated with ethyldichloroaluminum and allyl
alcohol in dichloromethane to provide allyl-4-oxohexanoate 27.
Fischer indolization of 27 with 4-methoxyphenyl hydrazine fol-
lowed by treatment with acetic acid then gave indole compound 28
in 71% yield. Acylation (87%) and ester cleavage (79%) produced
carboxylic acid, 30.15 Finally compound 31 was obtained by amide
coupling between methylsulfonylamine and acid 30 using CDI
coupling reagent (Scheme 7).
um) from Whatman (PartisilÒ LK6D, cat. no. 4865-821). Spots were
visualized under natural light, and UV illumination at
l
¼254 and
365 nm. Microwave reactions were performed in an automated
Biotage Initiator Eight Synthesizer. NMR spectra were recorded
with a Bruker AV-400 instrument with sample changer (BACS 60)
(400 MHz for 1H, 100 MHz for 13C) or a Bruker AV-300 system
(282 MHz for 19F) and calibrated with DMSO-d6 as solvent and TMS
as internal standard signal. Chemical shifts (d) are reported in parts
per million (ppm). Coupling constants (J) are given in hertz.
Low-resolution mass spectra were obtained on an Agilent 1200
series liquid chromatography e mass spectrometry (LCMS) system
with electrospray ionization. High-resolution mass spectra (HRMS)
were recorded on a Waters QTof-API-US Plus Acquity system with
ES as the ion source. Analytical high-pressure liquid chromatogra-
phy (HPLC) was performed on an Agilent 1200 analytical LCMS with
UV detection at 214 and 254 nm along with ELSD detection.
General methods are specified in Supplementary data. Compounds
9a, 9b, 10, and 17 were prepared according to literature
procedures.25,31,41,30
Synthesis of exemplified intermediates and target compounds:
4.2. Methyl 2-(5-fluoro-1H-indol-3-yl)acetate 9e
According to general procedure B_variant2 (conventional heat-
ing),
(4-fluorophenyl)hydrazine
hydrochloride
(100 mg,
0.62 mmol), 4-oxobutanoic acid (79 mg, 0.68 mmol), and 160
mL
H2SO4 in 2 mL methanol were refluxed for 3 h under argon to afford
110 mg (86%) of 9e as brownish viscous mass. C11H10FNO2,
Scheme 7. Large-scale synthesis of compounds 30 (free acid) and 31 (COOH
bioisostere).
Mr¼207.20; 1H NMR (400 MHz, DMSO-d6)
d: 3.60 (s, 3H), 3.72 (s,
2H), 6.91 (td, J¼2.6/9.2 Hz, 1H), 7.22 (dd, J¼2.4/10.0 Hz, 1H),
3. Conclusions
7.31e7.35 (m, 2H); 19F NMR (282 MHz, DMSO-d6)
d
: ꢁ123.52 (50-F);
LCMS (ESI) tR: 2.16 min (>99%, ELSD), m/z: 208.2 [MþH]þ; HRMS
(TOF, ESþ) C11H10FNO2 [MþH]þ calcd mass 208.0774, found
208.0772.
In summary, we have found that different INDO analogues, in-
cluding 20-des-methyl INDO 2 are efficiently prepared in a parallel
approach via their N-unsubstituted indole methyl-/allylalkanoate
intermediates starting from commercially available arylhydrazine
hydrochlorides and a variety of ketoacids/esters. Substituted phe-
nylhydrazine precursors were subjected to Fischer cyclization in
a one-pot procedure to provide respective indole products. The N-
unsubstituted indole alkanoic acid esters (optimally methyl or allyl
esters) were deprotonated and further elaborated by N-acylation
followed by aqueous-free ester cleavage in the presence of different
metal-based catalyst systems. Concomitant N-deacylation was not
observed with the applied technique. The synthetic strategy en-
abled assembly and variation of all relevant substituents within
only three reaction steps. Target compounds were readily formed
under optimized settings and could be isolated in good to high
overall yields and in acceptable analytical quality. The procedure
also allowed for scale-up to afford large amounts of selected
compounds of interest for further derivatization reactions and/or
direct use in in vitro and in vivo experiments. The range of indole
analogues will be evaluated for activity against peroxisome pro-
4.3. Methyl 2-(1H-indazol-3-yl)acetate 10
According to general procedure A_variant2, 2-(1H-indazol-3-
yl)acetic acid (300 mg, 1.70 mmol) was refluxed in methanol
(15 mL) for 14 h. The reaction mixture was worked up as de-
scribed to afford 250 mg (77%) of 10. C10H10N2O2, Mr¼190.20; 1H
NMR (400 MHz, DMSO-d6) d: 3.62 (s, 3H), 4.01 (s, 2H), 7.09 (td,
J¼0.8/7.4 Hz, 1H), 7.33 (td, J¼1.0/7.7 Hz, 1H), 7.48 (d, J¼8.4 Hz,
1H), 7.69 (d, J¼8.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6)
d:
33.04 (s, eCH2e), 52.17 (s, eOCH3), 110.49 (s, C70), 120.29 (s),
120.43 (s), 122.20 (s, C4a0), 126.40 (s, C60), 138.83 (s, C7a0), 141.20
(s, C30), 171.03 (s, pC]O); LCMS (ESI) tR: 1.65 min (>99%, UV254),
m/z: 191.2 [MþH]þ; HRMS (TOF, ESþ) C10H10N2O2 [MþH]þ calcd
mass 191.0821, found 191.0821.
liferator activated receptor g, induction of tumor cell apoptosis, and
4.4. Methyl 3-(5-fluoro-3-methyl-1H-indol-2-yl)propanoate 14
inhibition of aldo-keto reductase enyzmes.10,40
According to general procedure B_variant2, the title compound
was obtained from (4-fluorophenyl)hydrazine hydrochloride
(100 mg, 0.62 mmol), 4-oxohexanoic acid (88.8 g, 0.68 mmol), and
4. Experimental part
4.1. General
80 m
L H2SO4 in 3 mL methanol after 10 min at 120 ꢀC in 46% yield
(67 mg) as brownish viscous mass. C13H14FNO2, Mr¼235.25; 1H
All commercial reagents, solvents, and other materials were
used as received without further purification. Flash chromatogra-
phy was conducted on a Biotage SP1 automated flash chromatog-
raphy system equipped with a fixed wavelength UV detector
NMR (400 MHz, DMSO-d6)
d
: 2.12 (s, 3H), 2.66 (t, J¼8.0 Hz, 2H), 2.93
(t, J¼7.6 Hz, 2H), 3.58 (s, 3H), 6.80 (td, J¼2.8/9.2 Hz, 1H), 7.10 (dd,
J¼2.4/10.2 Hz, 1H), 7.20 (dd, J¼4.6/8.6 Hz, 1H), 10.74 (br s, 1H); 19F
NMR (282 MHz, DMSO-d6)
d
: ꢁ124.03 (d, 50-F); LCMS (ESI) tR:
(
l
¼254 nm) using prefabricated ‘Flash KP-SIL’ columns (size
2.58 min (>99%, UV220), m/z: 236.2 [MþH]þ; HRMS (TOF, ESþ)
C13H14FNO2 [MþH]þ calcd mass 236.1087, found 236.1085.
according to requirements). Thin-layer chromatography was

A.J. Liedtke et al. / Tetrahedron 68 (2012) 10049e10058
10055
4.5. Methyl 6-methoxy-2,3,4,9-tetrahydro-1H-carbazole-3-
carboxylate 15a
(td, J¼2.4/9.2 Hz, 1H), 7.08 (dd, J¼4.6/9.0 Hz, 1H), 7.39 (dd, J¼2.4/
9.2 Hz, 1H), 7.63e7.68 (m, 4H); LCMS (ESI) tR: 3.21 min (>95%,
ELSD), m/z: 374.3 [MþH]þ; HRMS (TOF, ESþ) C20H17ClFNO3 [MþH]þ
calcd mass 374.0959, found 374.0962.
According to general procedure B_variant1, the title compound
was obtained from (4-methoxyphenyl)hydrazine hydrochloride
(80.0 mg, 0.46 mmol) and methyl 4-oxocyclohexanecarboxylate
(85.9 mg, 0.55 mmol) in 0.5 mL glacial acetic acid after 3 h at
80 ꢀC in 90% yield (107 mg) as an off-white solid. C15H17NO3,
4.9. Methyl 6-methoxy-9-(3-(trifluoromethyl)benzoyl)-
2,3,4,9-tetrahydro-1H-carbazole-3-carboxylate 19a
Mr¼259.30; 1H NMR (400 MHz, DMSO-d6)
d
: 1.81e1.91 (m, 1H),
According to general procedure C_variant2, the title compound
was obtained from methyl 6-methoxy-2,3,4,9-tetrahydro-1H-car-
bazole-3-carboxylate (80 mg, 0.31 mmol), 3-(trifluoromethyl)
2.15e2.19 (m, 1H), 2.66e2.84 (m, 4H), 2.90 (dd, J¼4.6/14.2 Hz, 1H),
3.65 (s, 3H), 3.72 (s, 3H), 6.61 (dd, J¼2.4/8.8 Hz, 1H), 6.86 (d,
J¼2.4 Hz, 1H), 7.11 (d, J¼8.8 Hz, 1H), 10.51 (s, 1H); LCMS (ESI) tR:
2.27 min (>99%, ELSD), m/z: 260.2 [MþH]þ; HRMS (TOF, ESþ)
C15H17NO3 [MþH]þ calcd mass 260.1287, found 260.1285.
t
benzoyl chloride (77.2 mg, 0.37 mmol), and BuONa (2 M in THF,
185 mL, 0.37 mmol) in anhydrous THF (2.5 mL). The crude residue
was subjected to flash chromatography (SiO2, ethyl acetate/hexane
gradient) to afford the pure title compound in 24% yield (32 mg).
4.6. Methyl 2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)ace-
tate 17
C23H20F3NO4, Mr¼431.40; 1H NMR (400 MHz, DMSO-d6)
d:
1.70e1.80 (m, 1H), 2.03e2.07 (m, 1H), 2.47 (m, 2H, partly overlayed
by DMSO signal), 2.73e2.79 (m, 1H), 2.82e2.89 (m, 1H), 2.94 (dd,
J¼5.0/15.8 Hz, 1H), 3.65 (s, 3H), 3.77 (s, 3H), 6.73 (dd, J¼2.6/9.0 Hz,
1H), 7.04 (d, J¼2.4 Hz, 1H), 7.08 (d, J¼9.2 Hz, 1H), 7.79 (t, J¼8.0 Hz,
1H), 7.93 (d, J¼8.0 Hz, 1H), 7.99 (s, 1H), 8.04 (d, J¼8.0 Hz, 1H); 19F
A 2 mL microwave process vial with a stir bar was charged with
crude methyl 3-cyano-3-(6-methoxy-3-nitropyridin-2-yl)prop-
anoate 16 (50 mg, 0.19 mmol), 10% Pd/C (5 mol %, 20 mg,
0.01 mmol), and methanol (1.5 mL). An excess of 1,4-cyclohexadiene
(91 mg, 1.13 mmol) was added and the vessel flooded with argon,
capped, and heated under microwave conditions at 120 ꢀC for 5 min.
The reaction mixture was filtered through CeliteÒ and the solvent
was evaporated in vacuo. The crude material was purified by flash
chromatography (SiO2, ethyl acetate/hexane gradient) to yield the
product as greenish oil (25 mg, 60%). C11H12N2O3, Mr¼220.22; 1H
NMR (282 MHz, DMSO-d6)
d
: ꢁ59.41 (m-CF3); LCMS (ESI) tR:
0.95 min (>95%, UV254), m/z: 432.0 [MþH]þ; HRMS (TOF, ESþ)
C23H20F3NO4 [MþH]þ calcd mass 432.1423, found 432.1422.
4.10. Methyl 2-(1-(4-chlorobenzoyl)-1H-indazol-3-yl)acetate 21
According to general procedure C_variant2, methyl 2-(1H-
indazol-3-yl)acetate (80 mg, 0.42 mmol) was subjected to reaction
with 4-chlorobenzoyl chloride (88.3 mg, 0.50 mmol) (252 mL
NMR (400 MHz, DMSO-d6)
6.53 (d, J¼8.8 Hz, 1H), 7.38 (d, J¼2.8 Hz, 1H), 7.66 (d, J¼8.4 Hz, 1H),
11.01 (br s, 1H); 13C NMR (100 MHz, DMSO-d6)
: 29.41 (s, eCH2e),
d: 3.61 (s, 3H), 3.72 (s, 2H), 3.83 (s, 3H),
d
tBuONa). The crude product was purified by flash chromatography
(SiO2, ethyl acetate/hexane gradient) to afford 13.5 mg (52%) of the
title compound as bright yellow solid. The compound permanently
crystallized upon drying at high vacuum and storage at ꢁ20 ꢀC.
Yield: 51 mg (37%). C17H13ClN2O3, Mr¼328.75; 1H NMR (400 MHz,
51.86 (s, eC(O)OCH3), 52.83 (s, eOCH3),104.86 (s, C60),107.19 (s, C30),
122.78 (s, C20),124.60 (s, C7a0),126.80 (s, C70),141.29 (s, C3a0),159.16
(s, C50), 172.47 (s, pC]O); LCMS (ESI) tR: 0.69 min (>97%, UV220,
ELSD), m/z: 221.2 [MþH]þ; HRMS (TOF, ESþ) C11H12N2O3 [MþH]þ
calcd mass 221.0926, found 221.0926.
DMSO-d6)
d
: 3.65 (s, 3H), 4.16 (s, 2H), 7.50 (td, J¼0.8/7.6 Hz, 1H),
7.63e7.66 (m, 2H), 7.71 (td, J¼1.0/7.6 Hz, 1H), 7.91 (d, J¼8.0 Hz, 1H),
8.00e8.03 (m, 2H), 8.41 (d, J¼8.4 Hz, 1H); LCMS (ESI) tR: 2.80 min
(>99%, ELSD), m/z: 329.0 [MþH]þ; HRMS (TOF, ESþ) C17H13ClN2O3
[MþH]þ calcd mass 329.0693, found 329.0693.
4.7. Methyl 2-(5-methoxy-2-methyl-1-(4-methylbenzoyl)-1H-
indol-3-yl)acetate 18d
According to general procedure C_variant2, the title compound
was obtained from methyl 2-(5-methoxy-2-methyl-1H-indol-3-yl)
4.11. 2-(1-(4-(Chloromethyl)benzoyl)-5-methoxy-2-methyl-
acetate (80 mg, 0.34 mmol), 4-methylbenzoyl chloride (63.6 mg,
1H-indol-3-yl)acetic acid 22e
t
0.41 mmol), and BuONa (2 M in THF, 206
m
L, 0.41 mmol) in anhy-
drous THF (2.5 mL). The crude residue was subjected to flash
chromatography (SiO2, ethyl acetate/hexane gradient) to afford the
pure title compound in 57% yield (68.5 mg). C21H21NO4, Mr¼351.40;
According to general procedure D, methyl 2-(1-(4-(chloromethyl)
benzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate (15 mg, 0.039
mmol) was subjected to reactionwith trimethyltin hydroxide (35 mg,
0.194 mmol) in 1,2-DCE (1 mL). The crude product was chromato-
graphed on a short silica gel column using 1:1 ethyl acetate/hexane
(0.5% AcOH) mixtures of increasing polarity as eluants to afford the
title compound quantitativelyas off-white solid. Yield: 14.1 mg (98%).
1H NMR (400 MHz, DMSO-d6)
d: 2.22 (s, 3H), 2.42 (s, 3H), 3.62
(s, 3H), 3.74 (s, 3H), 3.77 (s, 2H), 6.68 (dd, J¼2.6/9.0 Hz, 1H), 6.85
(d, J¼8.8 Hz, 1H), 7.01 (d, J¼2.4 Hz, 1H), 7.37 (d, J¼8.0 Hz, 2H), 7.54
(pseudo-d, J¼8.4 Hz, 2H); LCMS (ESI) tR: 2.74 min (>95%, ELSD),
m/z: 352.2 [MþH]þ; HRMS (TOF, ESþ) C21H21NO4 [MþH]þ calcd
mass 352.1549, found 352.1548.
C20H18ClNO4, Mr¼371.81; 1H NMR (400 MHz, DMSO-d6)
d: 2.19 (s,
3H), 3.65 (br s, 2H), 3.75 (s, 3H), 4.88 (s, 2H), 6.68 (dd, J¼2.4/9.2 Hz,
1H), 6.90 (d, J¼8.8 Hz, 1H), 7.02 (d, J¼2.4 Hz, 1H), 7.61e7.67 (m, 4H);
4.8. Methyl 3-(1-(4-chlorobenzoyl)-5-fluoro-2-methyl-1H-in-
13C NMR (125 MHz, DMSO-d6)
d: 13.34 (s), 29.93 (s), 45.23 (s), 55.72
dol-3-yl)propanoate 18o
(s),101.14 (s),111.68 (s),115.08 (s),128.79 (s, 2C),130.14 (s, 2C),130.41
(s), 130.85 (s), 135.38 (s), 136.27 (s), 142.26 (s), 156.02 (s), 168.79 (s),
176.3 (s), one signal invisible; LCMS (ESI) tR: 2.48 min (>99%, UV220,
UV254), m/z: 372.0 [MþH]þ; HRMS (TOF, ESþ) C20H18ClNO4 [MþH]þ
calcd mass 372.1003, found 372.1003.
According to general procedure C_variant2, the title compound
was obtained from methyl 3-(5-fluoro-2-methyl-1H-indol-3-yl)
propanoate (80 mg, 0.34 mmol), 4-chlorobenzoyl chloride
(71.4 mg, 0.41 mmol), and tBuONa (2 M in THF, 204
mL, 0.41 mmol)
in anhydrous THF (2.5 mL). The crude residue was subjected to flash
chromatography (SiO2, ethyl acetate/hexane gradient) to afford the
pure title compound as yellow oil in 49% yield (62 mg).
4.12. 2-(1-(4-Chlorobenzoyl)-5-fluoro-1H-indol-3-yl)acetic
acid 22n
C20H17ClFNO3, Mr¼373.81; 1H NMR (400 MHz, DMSO-d6)
d
: 2.19 (s,
According to general procedure D, methyl 2-(1-(4-chlorobenzoyl)-
5-fluoro-1H-indol-3-yl)acetate (15 mg, 0.043 mmol) was subjected to
3H), 2.59 (t, J¼7.4 Hz, 2H), 2.92 (t, J¼7.6 Hz, 2H), 3.56 (s, 3H), 6.94

10056
A.J. Liedtke et al. / Tetrahedron 68 (2012) 10049e10058
reaction with trimethyltin hydroxide (39 mg, 0.216 mmol) in 1,2-DCE
(1 mL). The crude product was chromatographed on a short silica gel
column using 1:1 ethyl acetate/hexane (0.5% AcOH) mixtures of in-
creasingpolarityas eluants toaffordthetitlecompound quantitatively
as off-white solid. Yield: 11.2 mg (78%). C17H11ClFNO3, Mr¼331.73; 1H
(200 mL), extracted with dichloromethane (3ꢂ150 mL), dried over
MgSO4, and concentrated in vacuo. The residue was purified by
column chromatography using Hex/EtOAc (gradient: 0e30% EtOAc)
to afford a yellow solid of allyl 2-(1-(4-chlorobenzoyl)-5-methoxy-
1H-indol-3-yl)acetate 26 (14.3 g, 92%). C21H18ClNO4, Mr¼383.82;
NMR (400 MHz, DMSO-d6)
d
: 3.66 (br s, 2H), 7.23 (td, J¼2.6/9.2 Hz,
1H NMR (400 MHz, CDCl3)
d 3.69 (s, 2H), 3.88 (s, 3H), 4.62 (d,
1H), 7.40e7.43(m, 2H), 7.65e7.69(m, 2H), 7.75e7.79(m, 2H), 8.28(dd,
J¼6.0 Hz, 2H), 5.23 (dd, J¼1.2, 10.4 Hz, 1H), 5.29 (dd, J¼1.2, 17.2 Hz,
1H), 5.95e5.84 (m, 1H), 7.01 (d, J¼7.6 Hz, 2H), 7.25 (s, 1H), 7.50 (d,
J¼8.4 Hz, 2H), 7.67 (d, J¼8.4 Hz, 2H), 8.28 (d, J¼10.0 Hz, 1H); 13C
J¼4.8/9.2 Hz, 1H); 13C NMR (125 MHz, DMSO-d6)
d: 30.62 (s), 104.99
(d, J¼24.3 Hz, 1C), 113.34 (d, J¼24.9 Hz, 1C), 113.92 (s), 117.76 (d,
J¼8.9 Hz, 1C), 127.35 (s), 129.08 (s, 2C), 130.57 (s, 2C), 131.38 (d,
J¼9.7 Hz,1C),132.37 (s),132.47 (s),138.58 (s),159.96 (d, J¼242 Hz,1C),
NMR (100 MHz, CDCl3) d: 30.97 (s), 55.70 (s), 65.74 (s), 101.93 (s),
113.76 (s), 114.68 (s), 117.39 (s), 118.69 (s), 126.31 (s), 128.92 (s, 2C),
130.50 (s, 2C), 130.73 (s), 131.43 (s), 131.78 (s), 132.85 (s), 138.15 (s),
156.89 (s), 166.96 (s), 170.25 (s); LCMS (ESI), single peak, tR:
0.92 min (>99%, UV, ELSD), m/z: 384.0 [MþH]þ; HRMS (TOF, ESþ)
C21H18ClNO4 [MþH]þ calcd mass 384.1003, found 384.1003.
167.09 (s), 175.85 (s); 19F NMR (282 MHz, DMSO-d6)
LCMS (ESI) tR: 2.54 min (>99%, UV215, UV254, ELSD), m/z: 332.0
[MþH]þ; HRMS (TOF, ESþ) C17H11ClFNO3 [MþH]þ calcd mass
332.0490, found 332.0490.
d
: ꢁ116.72 (50-F);
4.13. 6-Methoxy-9-(3-(trifluoromethyl)benzoyl)-2,3,4,9-
tetrahydro-1H-carbazole-3-carboxylic acid 23
4.16. 2-(1-(4-Chlorobenzoyl)-5-methoxy-1H-indol-3-yl)acetic
acid 2
According to general procedure D, methyl 6-methoxy-9-(3-
(trifluoromethyl)benzoyl)-2,3,4,9-tetrahydro-1H-carbazole-3-
carboxylate (15 mg, 0.035 mmol; w60% pure) was subjected to
reaction with trimethyltin hydroxide (31 mg, 0.174 mmol) in 1,2-
DCE (1 mL). The crude product was chromatographed on a short
silica gel column using 1:1 ethyl acetate/hexane (0.5% AcOH)
mixtures of increasing polarity as eluants to afford the title com-
pound quantitatively as bright yellow solid. Yield: 8.5 mg (98%).
To a solution of allyl 2-(1-(4-chlorobenzoyl)-5-methoxy-1H-
indol-3-yl)acetate 3 (14.3 g, 37.3 mmol) in THF (200 mL) were
added morpholine (32.5 mL, 373 mmol) and Pd(PPh3)4 (2.3 g,
1.9 mmol) under argon at room temperature. Stirring was contin-
ued until LCMS analysis indicated starting material has dis-
appeared. The mixture was filtered and concentrated in vacuo. The
residue was redissolved in dichloromethane and acidified with 2 N
HCl (50 mL) to afford white solid 2 (10 g, 79%). C18H14ClNO4,
C22H18F3NO4, Mr¼417.38; 1H NMR (400 MHz, DMSO-d6)
d:
Mr¼343.76; 1H NMR (400 MHz, DMSO-d6)
d: 3.67 (s, 2H), 3.81 (s,
1.69e1.75 (m, 1H), 2.02e2.06 (m, 1H), w2.47 (m, 2H, partially
overlaid by DMSO signal), 2.71e2.74 (m, 2H), 2.89e2.92 (m, 1H),
3.78 (s, 3H), 6.73 (dd, J¼2.6/9.0 Hz, 1H), 7.03 (d, J¼2.4 Hz, 1H), 7.10
(d, J¼9.2 Hz, 1H), 7.78 (t, J¼7.8 Hz, 1H), 7.93 (d, J¼7.6 Hz, 1H), 7.99 (s,
3H), 6.99 (dd, J¼2.4/9.2 Hz, 1H), 7.12 (d, J¼2.4 Hz, 1H), 7.32 (s, 1H),
7.65e7.77 (m, 4H), 8.17 (d, J¼9.2 Hz, 1H); 13C NMR (100 MHz,
DMSO-d6) d: 30.15 (s), 55.47 (s), 102.70 (s), 113.05 (s), 115.70 (s),
116.70 (s), 126.84 (s), 128.82 (s, 2C), 129.99 (s), 130.69 (s, 2C), 131.87
(s), 133.00 (s), 136.57 (s), 156.30 (s), 166.60 (s), 171.97 (s); LCMS (ESI)
tR: 2.60 min (>99%, ELSD), m/z: 344.0 [MþH]þ; HRMS (TOF, ESþ)
C18H14ClNO4 [MþH]þ calcd mass 344.0690, found 344.0687.
1H), 8.03 (d, J¼7.6 Hz, 1H); 13C NMR (125 MHz, DMSO-d6)
d: 23.51
(s), 24.73 (s), 25.81 (s), 38.74 (s), 55.68 (s), 101.09 (s), 111.96 (s),
115.49 (s), 116.78 (s), 123.48 (d, J¼272 Hz, 1C), 126.18 (s), 128.81 (s),
129.34 (s), 130.63 (s), 130.95 (s), 131.37 (d, J¼29.0 Hz, 1C), 132.42 (s),
135.55 (s), 136.53 (s), 156.35 (s), 167.29 (s), 179.92 (s); 19F NMR
4.17. Allyl 4-oxohexanoate 27
(282 MHz, DMSO-d6)
d
: ꢁ59.38 (m-CF3); LCMS (ESI) tR: 2.74 min
(>99%, UV254, ELSD), m/z: 418.0 [MþH]þ; HRMS (TOF, ESþ)
C22H18F3NO4 [MþH]þ calcd mass 418.1266, found 418.1267.
Succinyl dichloride 4 (4.6 mL, 41.6 mmol) in dichloromethane
(200 mL) was cooled to ꢁ40 ꢀC and ethylaluminum dichloride
(50 mL, 50 mmol) was added at ꢁ40 ꢀC. The reaction mixture was
stirred at ꢁ40 ꢀC for 3.5 h and quenched with the addition of an-
hydrous allyl alcohol (100 mL). The reaction mixture was concen-
trated to dryness and redissolved in dichloromethane (100 mL).
The organic layer was washed with aqueous sodium potassium
tartrate (2ꢂ50 mL), water (50 mL), and saturated aqueous NaCl
(50 mL). The organic layer was dried over MgSO4, filtered, and
concentrated to provide pure allyl 4-oxohexanoate 27 (5.2 g, 73%).
4.14. Allyl 2-(5-methoxy-1H-indol-3-yl)acetate 25
To a solution of 2-(5-methoxy-1H-indol-3-yl)acetic acid 7b
(15.25 g, 74.3 mmol) in 250 mL of acetone was added 29 g of cesium
carbonate (89.2 mmol) and allyl bromide (7.1 mL, 81.74 mmol). The
reaction mixture was stirred at room temperature for 12 h. The
residual cesium carbonate was removed by filtration and solvent
was concentrated in vacuo. The residue was purified by column
chromatography using Hex/EtOAc (gradient: 0e30% EtOAc) to af-
ford allyl 2-(5-methoxy-1H-indol-3-yl)acetate 25 (13.6 g, 75%).
C9H14O3, Mr¼170.21; 1H NMR (400 MHz, CDCl3)
d
1.07 (t, J¼7.2 Hz,
3H), 2.47 (q, J¼7.2 Hz, 2H), 2.62 (t, J¼6.4 Hz, 2H), 2.73 (t, J¼6.4 Hz,
2H), 4.57 (d, J¼5.6 Hz, 2H), 5.23 (dd, J¼1.2, 10.4 Hz, 1H), 5.31 (dd,
J¼1.2, 18.0 Hz, 1H), 5.96e5.84 (m, 1H).
C14H15NO3, Mr¼245.27; 1H NMR (400 MHz, CDCl3)
d 3.8 (s, 2H), 3.89
(s, 3H), 4.64 (dt, J¼1.2, 5.7, 2H), 5.2 (dd, J¼1.2, 10.4, 1H), 5.32 (dd,
J¼1.5, 17.2, 1H), 6.0e5.90 (m, 1H), 6.89 (dd, J¼2.4, 8.8 Hz, 1H), 7.09
(d, J¼2.4 Hz, 1H), 7.17 (s, 1H), 7.26 (d, J¼8.8 Hz, 1H).
4.18. Allyl 3-(5-methoxy-3-methyl-1H-indol-2-yl)propanoate 28
To a mixture of (4-methoxyphenyl)hydrazine (10.4 g, 59.7 mmol)
and allyl 4-oxohexanoate 5 (10.2 g, 59.7 mmol) in 1,4-dioxane
(60 mL) was added acetic acid (30 mL) at room temperature. The
reaction mixture was heated at 80 ꢀC for 6 h then quenched with
saturated NaHCO3 (150 mL), extracted with EtOAc (3ꢂ60 mL), and
dried over MgSO4. The residue was purified by column chromatog-
raphy using Hex/EtOAc (gradient: 0e40% EtOAc) to afford brown oil
allyl 3-(5-methoxy-3-methyl-1H-indol-2-yl)propanoate 28 (11.6 g,
4.15. Allyl 2-(1-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl)
acetate 26
To a solution of allyl 2-(5-methoxy-1H-indol-3-yl)acetate 25
(10 g, 40.8 mmol) in dichloromethane (150 mL) were added trie-
thylamine (17.1 mL, 122. 4 mmol) and DMAP (4.9 g, 40.8 mmol) at
0 ꢀC. After stirring for 30 min, 4-chlorobenzoyl chloride (7.9 mL,
61.2 mmol) was added to the reaction mixture, which was allowed
to warm to room temperature and stirred for 12 h. The reaction
mixture was then quenched with saturated ammonium chloride
71%). C16H19NO3, Mr¼273.33; 1HNMR (400 MHz, CDCl3)
d 2.21 (s, 3H),
2.68 (t, J¼6.4 Hz, 2H), 3.03 (t, J¼6.4 Hz, 2H), 3.86 (s, 3H), 4.60 (d,
J¼7.2 Hz, 2H), 5.23 (dd, J¼1.2, 10.4 Hz, 1H), 5.29 (dd, J¼1.2, 17.2 Hz,

A.J. Liedtke et al. / Tetrahedron 68 (2012) 10049e10058
10057
1H), 5.95e5.83 (m, 1H), 6.78 (dd, J¼2.4, 8.8 Hz,1H), 6.93 (d, J¼2.4 Hz,
methanesulfonamide (1.97 g, 20.7 mmol) in dichloromethane
(94 mL) was treated with 1,10-carbonyldiimidazole (3.05 g,
18.8 mmol) and DBU (3.4 mL, 22.6 mmol) at 0 ꢀC. The reaction
mixture was stirred at room temperature for 4 h then quenched
with acetic acid (5 mL) and washed with brine (3ꢂ40 mL). The
organic layer was then dried over MgSO4 and the solvent was re-
moved in vacuo. The yellow solid 31 (5.6 g, 61%) was obtained after
column chromatography purification using Hex/EtOAc (gradient:
0e100% EtOAc with 0.5% of acetic acid). C21H21ClN2O5S, Mr¼170.21;
1H), 7.16 (d, J¼8.8 Hz,1H);13C NMR (100 MHz, CDCl3)
d: 8.43 (s), 20.91
(s), 34.09 (s), 55.95 (s), 65.47 (s),100.50 (s),106.91 (s),111.04 (s),111.08
(s), 118.54 (s), 129.32 (s), 130.39 (s), 131.85 (s), 134.45 (s), 153.73 (s),
173.45 (s); LCMS (ESI), single peak, tR: 0.79 min, m/z: 274.0 [MþH]þ;
HRMS (TOF, ESþ) C16H19NO3 [MþH]þ calcd mass 274.1443, found
274.1441.
4.19. Allyl 3-(1-(4-chlorobenzoyl)-5-methoxy-3-methyl-1H-
indol-2-yl)propanoate 29
1H NMR (400 MHz, CDCl3)
d
2.20 (s, 3H), 2.54 (dd, J¼7.2, 7.6 Hz, 2H),
3.10 (dd, J¼7.2, 7.6 Hz, 2H), 3.14 (s, 3H), 3.75 (s, 3H), 6.42 (d,
J¼9.2 Hz, 1H), 7.70e7.64 (m, 4H), 6.63 (dd, J¼2.4, 9.2 Hz, 1H), 7.01
To a solution of allyl 3-(5-methoxy-3-methyl-1H-indol-2-yl)
propanoate 28 (16 g, 61.8 mmol) in 1,2-dichloroethane (200 mL)
were added triethylamine (34.5 mL, 247.2 mmol) and DMAP
(7.55 g, 61.8 mmol) at 0 ꢀC. After stirring for 30 min, 4-
chlorobenzoyl chloride (19.7 mL, 154.6 mmol) was added to the
reaction mixture, which was allowed to stir for 12 h under reflux
condition. The reaction mixture was cooled down, quenched with
saturated ammonium chloride (200 mL), extracted with dichloro-
methane (3ꢂ150 mL), dried over MgSO4, and concentrated in
vacuo. The residue was purified by column chromatography using
Hex/EtOAc (gradient: 0e30% EtOAc) to afford brown oil of allyl 3-
(1-(4-chlorobenzoyl)-5-methoxy-3-methyl-1H-indol-2-yl)prop-
anoate 29 (22.2 g, 87%). C23H22ClNO4, Mr¼411.88; 1H NMR
(d, J¼2.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6)
d: 8.42 (s), 20.57
(s), 35.30 (s), 40.96 (s), 55.42 (s), 101.59 (s), 111.66 (s), 114.45 (s),
116.01 (s), 129.13 (s, 2C), 130.25 (s), 131.20 (s), 131.27 (s, 2C), 134.00
(s), 136.31 (s), 137.77 (s), 155.48 (s), 167.74 (s), 171.42 (s); LCMS (ESI),
single peak, 0.81 min, m/z: 449.08 [MþH]þ; HRMS (TOF, ESþ)
C21H21ClN2O5S [MþH]þ calcd mass 449.0938, found 449.0941.
Acknowledgements
The authors are grateful to the National Institutes of Health
(CA89450) and the National Foundation for Cancer Research for
financial support. We thank Dr. Matthew Mulder (Craig Lindsley
Group) for recording all high-resolution mass spectra and Christian
Wallen (2011 Vanderbilt REU Trainee) for the assistance with the
parallel syntheses of the fluorinated indole precursors. A.J.L. also
thanks the German Research Foundation (DFG) for obtaining a Re-
search Stipend (LI2019/1-1, Einzelprojekt).
(400 MHz, CDCl3)
d
2.24 (s, 3H), 2.69 (t, J¼7.6 Hz, 2H), 3.29 (t,
J¼7.6 Hz, 2H), 3.83 (s, 3H), 4.53 (d, J¼6.0 Hz, 2H), 5.18 (dd, J¼1.2,
10.4 Hz,1H), 5.25 (dd, J¼1.2,17.2 Hz,1H), 5.93e5.78 (m,1H), 6.44 (d,
J¼9.2 Hz, 1H), 6.59 (dd, J¼2.8, 8.4 Hz, 1H), 6.89 (d, J¼2.8 Hz, 1H),
7.46 (d, J¼8.4 Hz, 2H), 7.65 (d, J¼8.4 Hz, 2H); 13C NMR (100 MHz,
CDCl3) d: 8.67 (s), 21.67 (s), 34.14 (s), 55.65 (s), 65.18 (s), 101.38 (s),
111.48 (s), 114.78 (s), 116.38 (s), 118.28 (s), 129.10 (s, 2C), 129.33 (s),
130.76 (s), 131.15 (s, 2C), 131.66 (s), 131.84 (s), 132.06 (s), 133.88 (s),
136.71 (s), 139.15 (s), 155.77 (s), 168.13 (s), 172.23 (s); LCMS (ESI),
single peak, tR: 0.99 min, m/z: 412.0 [MþH]þ; HRMS (TOF, ESþ)
C23H22ClNO4 [MþH]þ calcd mass 412.1316, found 412.1320.
Supplementary data
Detailed synthetic procedures, routine spectroscopic and spec-
trometric data, and HPLC data, as well as exemplified 1H and 13C
NMR spectra of intermediates and final compounds are available.
Supplementary data associated with this article can be found in the
online version, at http://dx.doi.org/10.1016/j.tet.2012.08.044.
4.20. 3-(1-(4-Chlorobenzoyl)-5-methoxy-3-methyl-1H-indol-
2-yl)propanoic acid 30
References and notes
To a solution of allyl 3-(1-(4-chlorobenzoyl)-5-methoxy-3-
methyl-1H-indol-2-yl)propanoate 29 (11.1 g, 26.9 mmol) in THF
(200 mL) were added morpholine (23.0 mL, 269 mmol) and
Pd(PPh3)4 (1.67 g, 1.35 mmol) under argon at room temperature.
Stirring was continued until LCMS analysis indicated starting ma-
terial has disappeared. The mixture was filtered and concentrated
in vacuo. The residue was redissolved in dichloromethane, acidified
with 2 N HCl (50 mL), concentrated in vacuo, and purified by col-
umn chromatography using Hex/EtOAc (gradient: 0e100% EtOAc)
to afford yellow solid of 3-(1-(4-chlorobenzoyl)-5-methoxy-3-
methyl-1H-indol-2-yl)propanoic acid 30 (7.9 g, 79%). C20H18ClNO4,
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d: 8.40 (s), 21.24 (s), 33.74 (s), 55.42 (s), 101.55 (s), 111.58 (s), 114.38
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4.21. 3-(1-(4-Chlorobenzoyl)-5-methoxy-3-methyl-1H-indol-
2-yl)-N-(methylsulfonyl)propanamide 31
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