Conformation and atropisomeric properties of indometacin derivatives

Article abstract of DOI:10.1002/chem.201300064

The stereochemistry around the N-benzoylated indole moiety of indometacin was studied by restricting the rotation about the N-C7′ and/or C7′-C1′ bond. In the 2′,6′-disubstituted ones, an atropisomeric property was found and the atropoisomers were separate

Full text of DOI:10.1002/chem.201300064

DOI: 10.1002/chem.201300064
Conformation and Atropisomeric Properties of Indometacin Derivatives
Shintaro Wakamatsu,[a] Yuka Takahashi,[a] Hidetsugu Tabata,[a] Tetsuta Oshitari,[a]
Norihiko Tani,[a] Isao Azumaya,[b] Yukiteru Katsumoto,[c] Takeyuki Tanaka,[d]
Shinzo Hosoi,[e] Hideaki Natsugari,[a] and Hideyo Takahashi*[a]
Abstract: The stereochemistry around
the N-benzoylated indole moiety of in-
dometacin was studied by restricting
Their biological abilities to inhibit cy-
clooxygenase-1 (COX-1) and cyclooxy-
genase-2 (COX-2) were examined.
Only the aR-isomer showed specific in-
hibition of COX-1, and COX-2 was not
inhibited by either atropisomer. Con-
formational analysis in NMR studies
and X-ray crystallography, and CD
spectra in combination with calcula-
tions were utilized to elucidate the bio-
active conformations.
À
the rotation about the N C7’ and/or
À
C7’ C1’ bond. In the 2’,6’-disubstituted
Keywords: chirality · conformation-
al analysis · drug design · nitrogen
heterocycles · stereochemistry
ones, an atropisomeric property was
found and the atropoisomers were sep-
arated and isolated as stable forms.
Introduction
Indometacin is one of the most well-known non-steroidal
anti-inflammatory drugs (NSAIDs). Its clinical use involves
difficulty because it inhibits two isoforms of cyclooxygenase
(COX-1 and COX-2) with little specificity, leading to serious
side effects such as gastrointestinal bleeding and ulcera-
tion.[1] Therefore COX-1/2 selective indometacin analogues
have been explored with the expectation of the development
of a new generation of NSAIDs.[2] For the design of new in-
dometacin analogues, the bioactive conformations com-
plexed with COX-1/2 gave useful information. In 1996, the
group of Loll and Gravito proposed that indometacin inter-
acts with COX-1 in two possible binding modes correspond-
ing to the trans or cis form.[3] Independently, another group
Figure 1. a) Conformations traditionally used for indometacin.
b) 2’-Chloro-6’-iodo-substituted indometacin derivative 1.
[a] S. Wakamatsu, Y. Takahashi, Dr. H. Tabata, Dr. T. Oshitari, N. Tani,
Prof. Dr. H. Natsugari, Prof. Dr. H. Takahashi
School of Pharmaceutical Sciences
Teikyo University, 2-11-1 Kaga
Itabashi-ku, Tokyo 173-8605 (Japan)
E-mail: hide-tak@pharm.teikyo-u.ac.jp
reported that indometacin adopts a cis conformation in the
complex with COX-2 (Figure 1a).[4]
Since then, trans/cis conformations of indometacin have
drawn much attention as key features for drug design.[5]
However, a close look at the X-ray crystallographic analysis
of indometacin revealed that the indole ring and benzoyl
moiety are twisted with each other.[6] Therefore, the term
“cis/trans” associated with images of the planar structure
may cause misunderstanding. It should be realized that the
[b] Prof. Dr. I. Azumaya
Faculty of Pharmaceutical Sciences, Kagawa Campus
Tokushima Bunri University, 1314-1 Shido, Sanuki
Kagawa 769-2193 (Japan)
[c] Dr. Y. Katsumoto
Department of Chemistry, Graduate School of Science
Hiroshima University, Higashi-Hiroshima
Hiroshima 739-8256 (Japan)
2
2
À
À
N-benzoyl moiety has two sp –sp axes (N 7’ bond and C7’
C1’ bond), which provide numerous conformations of indo-
metacin. To elucidate the active conformation, restriction of
[d] Dr. T. Tanaka
Integrated Center of Science, Ehime University, 3-5-7 Tarumi
Matsuyama, Ehime 790-8566 (Japan)
[e] Dr. S. Hosoi
À
À
the rotation about the N C7’ bond and C7’ C1’ bond
should be helpful. In the course of our study, we introduced
Pharmaceutical Manufacturing Chemistry
Kyoto Pharmaceutical University, 1 Shichono-cho, Misasagi
Yamashina-ku, Kyoto 607-8412, (Japan)
substituents at C2’ and C6’ in benzoyl and succeeded in elic-
[7]
À
iting atropisomerism about the C7’ C1’ bond (Figure 1b).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300064.
The isolation of each enantiomer of 1 (aR, aS) with high
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FULL PAPER
stereochemical stability confirmed that the rotation about
7.14 ppm. Meanwhile, H7 of 3 is observed at d=6.90 ppm.
This upfield shift is due to the shielding effect of the ben-
zene ring, meaning that the benzoyl ring adopts a cis-like
conformation with respect to the indole (Figure 2). The op-
posite H7-shift observed in 2 and 3 indicates that N-benzoy-
lated indole without a 2-methyl group adopts an intrinsically
trans-like conformation and that the 2-methyl-substituted N-
À
the C7’ C1’ axis is fully restricted by substituents at C2’ and
À
C6’, even though the N C7’ axis can allow rotation. This
atropisomerism serves as evidence of the rotational restric-
À
tion of the C7’ C1’ axis. The interesting independent behav-
ior of these two axes in solution led us to investigate further
details of the rotational restriction about the two axes allow-
ing isolation of the stable conformation. In this study,
adding a significant data to the precedent one, we evaluated
whether the substituents at the 2-position of the indole
moiety and 2’- and/or 6’-position of the benzoyl moiety may
benzoylated indole adopts
a
cis-like conformation
(Figure 2). It is obvious that steric hindrance caused by the
À
substituent at the 2-position of indole mainly affects the N
C7’ axis, which regulates the cis/trans-like conformation. In
indometacin, a 2-methyl-substituted N-benzoylated indole
derivative, H7 is observed at d=6.90 ppm, and thus its con-
formation should be cis-like, similar to 3. In addition, NOE
of indometacin seen between H7 and H2’ (1.29%) and be-
tween 2-CH3 and H2’ (0.70%) indicates that its conforma-
tion is a rather cis-like one. We may therefore conclude that
the characteristic resonance of H7 of the indole unit gives
good information on the cis/trans-like conformation regulat-
À
À
restrict rotation about the N C7’ and C7’ C1’ axes due to
steric or electronic effects. We discuss the conformations of
1
these indometacin analogues utilizing H NMR spectrosco-
py, X-ray crystallography, and circular dichroism (CD) in
combination with calculations.
Results and Discussion
À
ed by the N C7’ axis of N-benzoylated indole derivatives.
First, we investigated the conformation of N-benzoylindoles
in solution (Figure 2). Indometacin and related compounds
We next examined the steric or electronic effects of the
substituents at the 2-position of the indole and/or C2’ and
C6’ of the benzoyl moiety. We synthesized various indome-
tacin derivatives 4–6 and presumed their conformations
mainly based on the H7-shift mentioned above (Table 1,
Scheme 1).[10]
Table 1. H7 chemical shifts[a] of indometacin analogues 4–6.
4
X1
d [ppm]
5
X2
d [ppm]
6
X1
X2 d [ppm]
[b]
a
b
c
d
e
CH3
6.90
6.57
6.43
a
b
c
d
e
CH3 6.96
CF3 7.02
a
b
c
d
e
CH2Cl
CH2OH Cl 6.05
CH2Cl
CH2OH
CHO
Cl 6.45
CH2Cl
CH2OH
CH2OTBS 6.77
CHO 7.37
Cl
Br
I
7.19
7.21
7.14
I
I
I
6.45
5.91
6.99
[a] Recorded at 238C in CDCl3 with TMS as internal reference. [b] Indo-
metacin methyl ester.
Figure 2. Conformational analysis based on the 1H NMR spectra of indo-
metacin and its analogues 2 and 3.
For all of these compounds, only one set of resonances
1
(cis- or trans-like) was observed in the H NMR spectrum.[11]
In compounds 4a–d, H7 is observed at d=6.43–6.90 ppm,
which confirms that the compounds with bulkier substitutes
at C2 adopt a cis-like conformation as mentioned above. On
the other hand, in compounds 5a–e, H7 is observed at d=
6.96–7.21 ppm. Such a downfield shift supports that the com-
pounds with substitutes at C2’ of the benzoyl group adopt a
trans-like conformation.[12] It was found that substitution at
the C2’ position of the benzoyl group also affects the rota-
1
(2,[8] 3[9]) were characterized by using H NMR spectroscopy
with CDCl3 as a solvent, which showed the characteristic
resonances for H7 of indole units.
Whereas H7 in 5-methoxyindole (the mother compound
of 2) is observed at d=7.38 ppm, H7 in 2 is observed at d=
8.40 ppm. This downfield shift is caused by a deshielding
effect of the carbonyl group of the benzoyl moiety, meaning
that the benzoyl ring adopts a trans-like conformation with
respect to the indole. In the case of 5-methoxy-2-methylin-
dole (the mother compound of 3), H7 is observed at d=
À
tion of the N C7’ axis. In compounds 6a–d, H7 is observed
at d=5.91–6.45 ppm, which confirms that the compounds
with bulkier substitutes at both C2 and C2’ adopt a cis-like
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H. Takahashi et al.
Figure 3. Structure of 5e determined by using X-ray crystallographic
analysis.
Scheme 2. Synthesis of derivatives 7–9: a) KHMDS, ArCOCl, THF, RT,
2 h, 22% for 7, 28% for 8, 45% for 9.
Scheme 1. Synthesis of indometacin derivatives 4–6: a) NCS, BPO, CCl4,
heat at reflux, 2.5 h, 70% for 4b, 70% for 6a, 81% for 6c; b) AgNO3,
THF/H2O, RT, 25 min, 64% for 4c, 66% for 6b, 42% for 6d;
c) TBSOTf, 2,6-lutidine, CH2Cl2, 08C, 10 min, 78%; d) NCS, BPO, CCl4,
heat at reflux, 5 h, 63% for 4e, 13% for 6e.
sets of resonances corresponding to cis- and trans-like con-
formations are observed in the H NMR spectrum (cis-like/
1
trans-like=1:1.4–2.0). We assigned the cis/trans comforma-
tions using a combination of the H7 shift as mentioned
above and the NOESY spectrum of 1 reported in a previous
paper.[7] Because the rotational barrier of the N C7’ axis is
À
conformation. It is interesting that a different downfield
shift was observed in 4e and 6e with a formyl group at C2.
The apparent trans-like conformation is due to carbonyl
electronic repulsion of the benzoyl group away from the
formyl group at C2. It seems reasonable to assume that the
cis- or trans-like conformation of indometacin and related
compounds 2–6 mentioned above is typical in solution and
the H7 shift may provide a clue to determining the rotation
less than that required for the isolation of each conformer at
room temperature, compounds 7–9 were observed as one
peak on non-chiral HPLC at ambient temperature.
However, each was observed as two separate peaks when
analyzed in HPLC on a chiral column (CHIRALPAK IB) at
room temperature, indicating that they exist as racemates of
the atropisomers. It is clear that steric hindrance caused by
substituents at C2’ and C6’ forms a greater rotational barrier
À
of the N C7’ axis.
We next examined the C7’ C1’ axis in indometacin deriv-
À
À
À
to the C7’ C1’ axis than to the N C7’ axis. It should be
noted that each cis- and trans-like conformation of N-ben-
zoylated indole derivatives 7–9 exists as racemates of the aR
and aS isomers (Figure 4).
atives. Unfortunately, separation analysis of compounds 2–6
by using chiral HPLC provides only one peak at room tem-
perature, which means that the atropisomeric property aris-
À
ing from the C7’ C1’ axis does not exist in these com-
pounds. However, the single-crystal X-ray analysis of com-
The enantiomers of compounds 7–9 were successfully iso-
lated by using preparative chiral HPLC (CHIRALPAK IB).
The isolated atropisomers have opposite [a]D values: 7A
(with shorter retention time in HPLC) as 96.4% ee showed
[a]2D0 =À32.5 (c=0.2, CHCl3) and 7B (with longer retention
time in HPLC) as 98.5% ee showed [a]2D0 = +31.7 (c=0.2,
CHCl3), 8 A (with shorter retention time in HPLC) as
98.8% ee showed [a]D20 =À28.6 (c=0.2, CHCl3) and 8B
(with longer retention time in HPLC) as 95.8% ee showed
[a]2D0 = +24.6 (c=0.2, CHCl3), and 9 A (with shorter reten-
tion time in HPLC) as 99.9% ee showed [a]2D0 =À26.1 (c=
0.2, CHCl3) and 9B (with longer retention time in HPLC)
pound 5e gave meaningful information. The dihedral angle
À
À
À
(F) C6’ C1’ C7’ O of 61.88 in compound 5e confirmed
that the benzene ring is orthogonal to the indole ring
(Figure 3). This geometry convinced us that even a mono-
substituent at C2’ of benzoyl can essentially affect the rota-
À
tion of the C7’ C1’ axis, although the rotational barrier is
less than required for the isolation of each enantiomer.
We therefore focused on the C2’- and C6’-disubstituted
derivatives 7–9, which were synthesized as shown in
Scheme 2. In all of these compounds, as well as in 1, two
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Indometacin Derivatives
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Table 2. In vitro cyclooxygenase assay of 1 (racemate and atropisomers).
IC50 [mm]
COX-1
[a]2D2 (CHCl3)
COX-2
1 (racemate)
(À)-1
13.4Æ3.4
>200
>500
>500
>500
3.50Æ0.41
À21.2 (c=0.13, 96% ee)
+20.4 (c=0.10, 94% ee)
(+)-1
15.6Æ1.8
indometacin
0.106Æ0.042
(15.6Æ1.8) mm. The other (À)-enantiomer showed no inhibi-
tory activity at a concentration of 200 mm (Table 2).[7,14]
The results clearly indicate that COX-1 recognizes the
stereochemistry of the axial chirality arising from the
Figure 4. Conformers including atropisomers of the N-benzoylated indole
derivatives 7–9.
À
C7’ C1’ axis. Initially, efforts to obtain the absolute configu-
ration of these atropisomers by X-ray crystallography were
not successful. Therefore the stereochemical information on
them was obtained by circular dichroism (CD) in combina-
tion with calculations.
as 99.9% ee showed [a]D20 = +18.8 (c=0.2, CHCl3). We also
examined the stereochemical stability of the enantiomers
and found that it was estimated to be high. The higher ster-
eochemical stability with a DG° value[13] of 109 kJmolÀ1 for
8A and 8B (X=CH3), and 111 kJmolÀ1 for 7A and 7B
(X=Br), compared with 105 kJmolÀ1 for 9A and 9B (X=
Cl) may be explained largely because of the steric bulkiness
(van der Waals radius) of the methyl (2.0 ꢁ) and Br
(1.85 ꢁ) versus Cl (1.75 ꢁ). Also, some type of electronic
A conformational search by using molecular mechanical
calculation (CONFLEX-MMFF94s) in vacuo for cis/trans
conformers yielded 32 conformers for each enantiomer
(aS-1, aR-1). All conformers were then fully optimized by
using DFT at the B3LYP/6-31G(d) level with the
LANL2DZ basis sets for iodine, affording only eight con-
formers [cis-aS-1 (1), cis-aS-1 (2), cis-aR-1 (1), cis-aR-1 (2),
trans-aS-1 (1), trans-aS-1 (2), trans-aR-1 (1), trans-aR-1 (2)]
lying in a range of 2 kJmolÀ1 (Figure 5). Based on those real
energy minima (no imaginary frequencies) for these con-
formers, the energy values with the zero-point energy cor-
rection were calculated. The relative energies and their con-
formational distributions are given in Table 3.
À
effect may affect the rotational barrier of the C7’ C1’ axis
by controlling the electronic density on the benzene ring.
We next examined the relationship with axial chirality
and biological activity. The racemate of 1 or its enantiomers
did not show COX-2 inhibitory activity at a concentration of
500 mm. However, it was found that the (+)-enantiomer of 1
shows potent activity against COX-1 with an IC50 value of
Figure 5. Low-energy conformers of aS-1 and aR-1, as was calculated by DFT methods.
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H. Takahashi et al.
Table 3. Conformational analysis of 1.
After some time, we fortunately succeeded in obtaining
(À)-1 as a single crystal.[7] On the basis of X-ray analysis,[7]
(À)-1 was also assigned to be aS, and hence the bioactive
atropisomer (+)-1 is aR. It should be noted that the assign-
ments of the configurations of 1 based on the calculated CD
spectra agree with those obtained by using X-ray analysis.
However, the calculated cis preferential formation shown in
Table 3 differed from the trans preferential one confirmed
by 1H NMR spectra, resulting
Conformer
DE [kJmolÀ1
]
Boltzmann factor
cis-aS-1 (1)
0.000
1.000
1.000
cis-aR-1 (1)
cis-aS-1 (2)
0.000
0.07879
0.07879
1.397
1.371
1.613
0.9687
0.9687
0.5752
0.5691
0.5352
0.5218
cis-aR-1 (2)
trans-aS-1 (1)
trans-aR-1 (1)
trans-aS-1 (2)
trans-aR-1 (2)
1.550
in an underestimation of the
importance of the cis/trans ratio
in the geometric optimization
of 1. Furthermore, conforma-
tional analysis using X-ray crys-
tallography showed that (À)-1
crystallized only in the cis form
(Figure 7), which was not iden-
tical to the results in the
1H NMR analysis. Although
this discrepancy needs further
consideration, it seems reasona-
ble to say that the twisted con-
formation including atropiso-
Figure 7. Structure of (À)-1 de-
À
merism arising from the C7’
termined by using X-ray crys-
C1’ axis in 1 might hamper the
binding to COX-2 (Table 2).
We presume that the restriction
À
tallographic analysis.[7]
À
of the rotation about the C7’ C1’ axis instead of the N C7’
axis might be informative for the design of COX-1/2-selec-
tive drugs.
Conclusion
The introduction of substituents at the 2-position of the
indole moiety and 2’- and/or the 6’-position of the benzoyl
moiety succeeded in eliciting specific conformations through
À
the restriction of the rotation about the N C7’ axis and
À
C7’ C1’ axis. The characteristic resonance for H7 of the
1
indole unit in H NMR spectra serves as a clue to the cis/
trans-like formation of indometacin derivatives. It was also
revealed that atropisomers of 2’,6’-disubstituted derivatives
exist with high stereochemical stability and can be separated
and isolated by chiral HPLC. It is noteworthy that this new
Figure 6. a) Calculated CD spectra of aR-1 (red, averaged) and aS-1
(blue, averaged). b) Experimental UV and CD spectra of (+)-1 (red) and
(À)-1 (blue).
À
chirality occurs by fixing of the C7’ C1’ axis alone, and
À
hence, the other N C7’ axis independently rotates to form
The CD calculations for the conformers were then con-
ducted with the same level of calculation. The calculated
CD spectra, weighted based on the Boltzmann factor of
both aS and aR enantiomers, are shown in Figure 6, along
with the experimental CD of (À)-1 and (+)-1 in EtOH,
which were symmetrical to the x axis for the antipodal pairs,
indicating that the two isomers are enantiomeric to each
other in solution. The weighted CD spectra for the aS/aR
enantiomer of 1 are in good accordance with the experimen-
tal ones for (À)/(+)-1, respectively. Therefore, we presumed
that (À)-1 can be assigned as aS and (+)-1 as aR.
an equilibrium between cis- and trans-like conformations in
each enantiomer. For the determination of the configuration
of the bioactive atropisomer (+)-1, the calculated CD spec-
trum, which is in good accordance with the experimental
one, was strongly supportive of the structure determined by
X-ray crystallographic analysis. The atropisomeric property
À
arising from the C7’ C1’ axis may be useful in the develop-
ment of next-generation NSAIDs.
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Indometacin Derivatives
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(3H, s), 4.82 (2H, s), 6.65 (1H, dd, J=2.4, 9.0 Hz), 6.77 (1H, d, J=
9.0 Hz), 6.93 (1H, d, J=2.4 Hz), 7.39 (2H, d, J=8.3 Hz), 7.63 ppm (2H,
d, J=8.3 Hz); 13C NMR (100 MHz, CDCl3): d=À5.5, 18.3, 25.8, 30.3,
52.2, 55.8, 56.5, 101.6, 112.8, 113.0, 114.6, 128.9, 129.9, 131.1, 131.4, 133.5,
Experimental Section
General experimental procedures: All reactions sensitive to air or mois-
ture were conducted under an argon atmosphere. Materials were ob-
tained from commercial suppliers. All anhydrous solvents were purified
following standard methods. Melting points were determined on a Yana-
gimoto micro melting point apparatus and were uncorrected. The NMR
spectra (1H, 13C) were determined on a JEOL 600 MHz (ECP-600) or
400 MHz (AL-400) spectrometer at 238C, using CDCl3 (with TMS for
1H NMR spectroscopy and CDCl3 for 13C NMR spectroscopy as the inter-
nal reference) solution, unless otherwise noted. Chemical shifts are given
in parts per million (ppm) downfield from tetramethylsilane as an inter-
nal standard, and coupling constants (J) are reported in Hertz (Hz).
Splitting patterns are abbreviated as follows: singlet (s), doublet (d), and
triplet (t). High-resolution mass spectra (HRMS) were obtained on
LCMS-IT-TOF (Shimadzu, Kyoto, Japan) for electrospray ionization
(ESI). Sodium trifluoroacetate (TFA-Na) was used as an internal stand-
ard for HRMS. Optical rotations were determined using a DIP-370 (Shi-
madzu, Kyoto, Japan) digital polarimeter in 100 mm cells and the sodium
D line (589 nm) at room temperature in the solvent and at the concentra-
tion indicated. Infrared (IR) spectra were recorded on a JASCO FT/IR-
410 spectrometer by using sodium chloride plates or potassium bromide
pellets. Absorbance frequencies were recorded in reciprocal centimeters
(cmÀ1). CD and UV spectra were recorded on a JASCO J-725. Analytical
138.0, 139.3, 155.7, 168.1, 171.1 ppm; IR (neat): n˜ =1740, 1691 cmÀ1
;
HRMS (ESI) m/z calcd for C26H32NO5SiCl: 524.1636 [M+Na]; found:
524.1623.
Compound 4e, methyl [1-(4-chlorobenzoyl)-2-formyl-5-methoxy-1H-
indol-3-yl]acetate: BPO (106.8 mg, 0.44 mmol) was added to a solution
of 4a (1.64 g, 4.41 mmol) and NCS (1.77 g, 13.2 mmol) in CCl4 (30 mL).
After stirring for 5 h heated at reflux, the reaction was quenched with
H2O and extracted with CH2Cl2. The organic layer was dried over
Na2SO4. After evaporation in vacuo, the crude residue was purified by
silica gel column chromatography (Et2O/hexane, 1:2) to give 4e (1.07 g,
2.77 mmol, 63%) as a white solid. M.p. 1088C; 1H NMR (400 MHz,
CDCl3): d=3.72 (3H, s), 3.85 (3H, s), 4.14 (2H, s), 7.05 (2H, m), 7.37
(1H, d, J=9.0 Hz), 7.47 (2H, d, J=8.6 Hz), 7.68 (2H, d, J=8.6 Hz),
9.82 ppm (1H, s); 13C NMR (100 MHz, CDCl3): d=30.4, 52.7, 56.1, 102.3,
116.3, 119.7, 125.1, 129.7, 130.0, 131.7, 133.1, 133.9, 135.0, 140.8, 157.5,
168.1, 171.0, 182.7 ppm; IR (KBr): n˜ =1740, 1684 cmÀ1; HRMS (ESI) m/z
calcd for C20H16NO5Cl: 408.0609 [M+Na]; found: 408.0612.
Compound 6a, methyl [1-(2-chlorobenzoyl)-2-chloromethyl-5-methoxy-
1H-indol-3-yl]acetate: BPO (15 mg, 0.01 mmol) was added to a solution
of 5c (211 mg, 0.57 mmol) and NCS (227 mg, 1.7 mmol) in CCl4 (5 mL).
After stirring for 2.5 h with heating at reflux, the reaction was quenched
with H2O and extracted with CH2Cl2. The organic layer was dried over
Na2SO4. After evaporation in vacuo, the crude residue was purified by
silica gel column chromatography (Et2O/hexane, 1:1) to give 6a (162 mg,
0.40 mmol, 70%) as a colorless oil. 1H NMR (400 MHz, CDCl3): d=3.65
(3H, s), 3.72 (2H, s), 3.75 (3H, s), 5.01 (2H, s), 6.45 (1H, d, J=9.2 Hz),
6.61 (1H, dd, J=2.4, 9.2 Hz), 6.93 (1H, d, J=2.4 Hz), 7.42 ppm (4H, m);
13C NMR (100 MHz, CDCl3): d=29.8, 36.6, 52.4, 55.6, 102.0, 114.2, 114.6,
117.4, 127.2, 129.7, 129.9, 130.4, 130.6, 131.9, 132.3, 134.4, 135.1, 156.3,
165.8, 170.2; IR (neat): n˜ =1740, 1694 cmÀ1; HRMS (ESI) m/z calcd for
C20H17NO4Cl2: 428.0432 [M+Na]; found: 428.0441.
thin-layer chromatography was carried out using Merck silica gel 60 F254
Column chromatography was performed by using the silica gel Wakogel
.
C-300 (45–60 mm).
Compound 4b, methyl [1-(4-chlorobenzoyl)-2-chloromethyl-5-methoxy-
1H-indol-3-yl]acetate: Benzoyl peroxide (BPO; 4.8 mg, 0.02 mmol) was
added to
a solution of 4a (79 mg, 0.21 mmol) and NCS (56 mg,
0.42 mmol) in CCl4 (5 mL). After stirring for 2.5 h and heating at reflux,
the reaction was quenched with H2O and extracted with CH2Cl2. The or-
ganic layer was dried over Na2SO4. After evaporation in vacuo, the crude
residue was purified by silica gel column chromatography (Et2O/hexane,
1:1) to give 4b (60 mg, 0.15 mmol, 70%) as a colorless oil. Analytical
data: 1H NMR (400 MHz, CDCl3): d=3.73 (3H, s), 3.79 (2H, s), 3.84
(3H, s), 5.08 (2H, s), 6.57 (1H, d, J=8.8 Hz), 6.71 (1H, dd, J=2.4 Hz,
8.8 Hz), 7.02 (1H, d, J=2.4 Hz), 7.49 (2H, d, J=8.4 Hz), 7.72 (2H, d, J=
8.4 Hz); 13C NMR (100 MHz, CDCl3): d30.1, 35.6, 52.1, 55.7, 101.2, 111.5,
112.4, 114.8, 129.0, 129.2, 130.5, 131.0, 131.3, 133.8, 135.8, 139.1, 155.9,
168.1, 171.2 ppm; IR (neat): n˜ =1738, 1684 cmÀ1; HRMS (ESI): m/z calcd
for C20H17NO4Cl2 Na: 428.0427 [M+Na]; found: 428.0406.
Compound 6b, methyl [1-(2-chlorobenzoyl)-2-hydroxymethyl-5-methoxy-
1H-indol-3-yl]acetate: A solution of AgNO3 (5.0 mg, 0.03 mmol) in H2O
(1 mL) was added to a solution of 6a (11 mg, 0.03 mmol) in THF/H2O
(2:1, 1 mL) and stirred at room temperature for 1 h. The reaction was di-
luted with H2O and extracted with AcOEt. The organic layer was
washed with brine and dried over Na2SO4. After evaporation in vacuo,
the crude residue was purified by silica gel column chromatography
(EtOAc/hexane, 1:1) to give 6b (7.0 mg, 0.02 mmol, 66%) as a colorless
Compound 4c, methyl [1-(4-chlorobenzoyl)-2-hydroxymethyl-5-methoxy-
1H-indol-3-yl]acetate: A solution of AgNO3 (10.0 mg, 0.056 mmol) in
H2O (1 mL) was added to a solution of 4b (22.7 mg, 0.056 mmol) in
THF/H2O (2:1, 2 mL) and stirred at room temperature for 25 min. The
reaction was diluted with H2O and extracted with CHCl3. The organic
layer was washed with brine and dried over Na2SO4. After evaporation in
vacuo, the crude residue was purified by silica gel column chromatogra-
phy (EtOAc/hexane, 1:2) to give 4c (13.8 mg, 0.036 mmol, 64%) as a col-
1
oil. H NMR (400 MHz, CDCl3): d=3.67 (3H, s), 3.77 (5H, s), 4.87 (2H,
s), 6.05 (1H, d, J=9.2), 6.58 (1H, dd, J=2.4, 9.2 Hz), 6.98 (1H, d, J=
2.4 Hz), 7.52 ppm (4H, m); 13C NMR (100 MHz, CDCl3): d=30.0, 52.4,
55.4, 55.6, 102.4, 113.3, 114.4, 116.2, 127.5, 129.1, 129.7, 130.5, 131.1,
131.6, 132.3, 135.4, 138.6, 156.4, 170.0, 170.8 ppm; IR (neat): n˜ =3513,
2953, 1738, 1676 cmÀ1
; HRMS (ESI) m/z calcd for C20H18NO5Cl:
410.0766 [M+Na]; found: 410.0771.
1
Compound 6c, methyl [2-chloromethyl-1-(2-iodobenzoyl)-5-methoxy-1H-
indol-3-yl]acetate: Compound 5e (27.1 mg, 0.059 mmol) was subjected to
reaction with NCS (7.8 mg, 0.059 mmol) and BPO (1.4 mg, 0.0059 mmol)
following the same procedure as that used for the synthesis of 6a descri-
bed above to afford the product 6c (23.5 mg, 0.047 mmol, 81%) as a col-
orless oil. H NMR (400 MHz, CDCl3): d=3.73 (3H, s), 3.82 (2H, s), 3.83
(3H, s), 3.93 (1H, brt, J=7.2), 4.79 (2H, d, J=7.2 Hz), 6.43 (1H, d, J=
9.2 Hz), 6.66 (1H, dd, J=2.4, 9.2 Hz), 7.00 (1H, d, J=2.4 Hz), 7.50 (2H,
d, J=8.8 Hz), 7.69 ppm (2H, d, J=8.8 Hz); 13C NMR (100 MHz, CDCl3):
d=30.0, 52.4, 55.0, 55.7, 102.0, 113.1, 115.2, 115.3, 128.3, 129.2, 130.0,
130.3, 130.6, 131.1, 133.0, 139.1, 139.6, 156.2, 168.9, 171.1 ppm; IR (neat):
n˜ =3503, 1736, 1672 cmÀ1; HRMS (ESI) m/z calcd for C20H18NO5ClNa
[M+Na]: 410.0766; found: 410.0773.
1
orless oil. H NMR (600 MHz, CDCl3): d=3.72 (3H, s), 3.79 (2H, s), 3.82
(3H, s), 5.05 (2H, d, J=3.6 Hz), 6.45 (1H, d, J=9.0 Hz), 6.69 (1H, dd,
J=2.4, 9.0 Hz), 7.00 (1H, d, J=2.4 Hz), 7.29 (1H, m), 7.50 (2H, m),
7.97 ppm (1H, d, J=7.8 Hz); 13C NMR (100 MHz, CDCl3): d=30.7, 35.9,
52.4, 55.7, 102.0, 113.1, 114.3, 115.2, 128.6, 128.9, 130.0, 132.3, 132.6,
136.0, 156.3, 167.9, 170.8 ppm; IR (neat): n˜ =1740, 1694 cmÀ1; HRMS
(ESI) m/z calcd for C20H17NO4ClI: 519.9789 [M+Na]; found: 519.9776.
Compound 4d, methyl [2-tert-butyldimethylsiloxymethyl-1-(4-chloroben-
zoyl)-5-methoxy-1H-indol-3-yl]acetate:
TBSOTf
(10.1 mg,
9 mL,
0.038 mmol) was added to a solution of 4c (7.4 mg, 0.019 mmol) and 2,6-
lutidine (4.5 mg, 5 mL, 0.042 mmol) in CH2Cl2 (1 mL) was added. After
stirring for 10 min at 08C, the reaction was quenched with H2O and ex-
tracted with CH2Cl2. The organic layer was washed with brine and dried
over Na2SO4. After evaporation in vacuo, the crude residue was purified
by silica gel column chromatography (EtOAc/hexane, 1:2) to give 4d
Compound 6d, methyl [2-hydroxymethyl-1-(2-iodobenzoyl)-5-methoxy-
1H-indol-3-yl]acetate: Compound 6c (19 mg, 0.038 mmol) was treated
with AgNO3 (6.4 mg, 0.038 mmol) following the same procedure as that
used for the synthesis of 6b described above to afford the product 6d
(7.5 mg, 0.015 mmol, 78%) as
a
colorless oil. 1H NMR (400 MHz,
(7.5 mg, 0.016 mmol, 42%) as
CDCl3): d=3.65 (3H, s), 3.74 (5H, s), 4.80 (2H, s), 5.91 (1H, d, J=
a
colorless oil. 1H NMR (400 MHz,
CDCl3): d=À0.10 (6H, s), 0.71 (9H, s), 3.63 (3H, s), 3.73 (2H, s), 3.77
Chem. Eur. J. 2013, 19, 7056 – 7063
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7061

H. Takahashi et al.
9.3 Hz), 6.51 (1H, dd, J=2.7, 9.3 Hz), 6.91 (1H, d, J=2.7 Hz), 7.24 (1H,
t, J=7.6 Hz), 7.41 (1H, d, J=7.6 Hz), 7.48 (1H, t, J=7.6 Hz), 7.89 ppm
(1H, d, J=7.6 Hz); 13C NMR (100 MHz, CDCl3): d=30.0, 52.4, 55.5,
55.6, 92.7, 102.3, 113.3, 114.8, 116.3, 128.8, 128.9, 129.7, 131.2, 132.2,
138.8, 140.1, 141.3, 156.4, 169.1, 170.8 ppm; IR (neat): n˜ =3507, 2951,
1736, 1672 cmÀ1; HRMS (ESI) m/z calcd for C20H18NO5Ina: 502.0122
[M+Na]; 502.0100.
139.4, 142.3}(Ar), 169.1 ppm (NC=O); IR (neat): n˜ =1686 cmÀ1; HRMS
(ESI) m/z calcd for C17H14NOI: 376.0193 [M+H]; found: 376.0192;
Compound (9) 1-(2-chloro-6-iodobenzoyl)-2-methyl-1H-indol: 2-Chloro-
6-iodobenzoyl chloride (644 mg, 2.3 mmol) was treated with 2-methylin-
dole (100 mg, 0.76 mmol) following the same procedure as that used for
the synthesis of 7 described above to afford the product 9 (134.4 mg,
0.34 mmol, 45% cis/trans, 1:1.9) as
a colorless oil. HPLC analysis:
eluent=hexane/iPrOH, 99:1. Flow rate: 0.5 mLminÀ1. 9A [with shorter
retention time (24.9 min) in HPLC using CHIRALPAK IB] [a]2D0 =À26.1
(c=0.2, CHCl3, 99.9% ee). 9B [with longer retention time (27.9 min) in
HPLC using CHIRALPAK IB] [a]2D0 = +18.8 (c=0.2, CHCl3, 99.9% ee).
Compound (6e), methyl [2-formyl-1-(2-iodobenzoyl)-5-methoxy-1H-
indol-3-yl]acetate: BPO (6.5 mg, 0.027 mmol) was added to a solution of
5e (124 mg, 0.27 mmol) and NCS (89.4 mg, 0.67 mmol) in CCl4 (8 mL)
was added. After stirring for 5 h while heating at reflux, the reaction was
quenched with H2O and extracted with CH2Cl2. The organic layer was
dried over Na2SO4. After evaporation in vacuo, the crude residue was pu-
rified by silica gel column chromatography (EtOAc/hexane, 1:2) to give
6e (17 mg, 0.036 mmol, 13%) as a colorless oil. 1H NMR (400 MHz,
CDCl3): d=3.72 (3H, s), 3.86 (3H, s), 4.14 (2H, s), 6.99 (2H, m), 7.04
(1H, m), 7.30 (1H, m), 7.51 (2H, m), 7.98 (1H, d, J=7.6 Hz), 9.97 ppm
(1H, s); 13C NMR (100 MHz, CDCl3): d=30.4, 52.4, 55.7, 93.1, 102.3,
116.0, 118.7, 128.4, 128.7, 129.6, 129.9, 130.1, 132.7, 140.4, 156.9, 167.8,
170.0, 183.1 ppm; IR (neat): n˜ =1738, 1686 cmÀ1. HRMS (ESI) m/z: calcd
for C20H16NO5I: 478.0151 [M+H]; 478.0165.
1
cis-9: H NMR (400 MHz, CDCl3): d=2.82 (3H, s, CH3), 6.08 (1H, d, J=
8.0 Hz, H7), 6.50 (1H, s, H3), 6.90 (1H, t, J=8.0, H6), 7.18 (1H, t, J=
8.0 Hz), 7.34 (1H, dd, J=1.2, 8.0 Hz, H5), 7.52 (2H, m), 7.85 ppm (1H,
d, J=8.0 Hz); 13C NMR (100 MHz, CDCl3): d=17.5 (CH3), {93.2, 110.5,
112.5, 119.5, 119.6, 120.8 124.5, 129.9, 130.5, 131.9, 135.3, 137.4, 139.5,
1
141.3}(Ar), 165.9 ppm (NC=O). trans-9: H NMR (400 MHz, CDCl3): d=
1.85 (3H, s, CH3), 6.38 (1H, s, H3), 7.11 (1H, t, J=8.0 Hz), 7.28 (1H, dd,
J=1.2, 8.0 Hz), 7.52 (3H, m, H4, H6, Ar), 7.81 (1H, d, J=8.0 Hz),
8.64 ppm (1H, d, J=8.0 Hz, H7); 13C NMR (100 MHz, CDCl3): d=15.7
(CH3), {93.8, 111.9, 117.2, 119.6, 120.2, 123.4, 124.7, 129.5, 131.7, 132.1,
137.7, 138.1, 137.7, 141.6}(Ar), 166.2 ppm (NC=O); IR (neat): n˜ =
1686 cmÀ1; HRMS (ESI) m/z calcd for C16H11NOClI: 395.9647 [M+H];
found: 395.9652.
Compound (7), 1-(2-bromo-6-iodobenzoyl)-2-methyl-1H-indol: KHMDS
(3.0 mL in 0.5m solution of toluene, 1.5 mmol) was added to a solution of
2-methylindole (100 mg, 0.76 mmol) in THF (2 mL) and stirred at room
temperature for 30 min. 2-Bromo-6-iodobenzoyl chloride (751 mg,
2.3 mmol) in THF (2 mL) was added to the mixture at room temperature.
After stirring for 2 h at room temperature, the reaction was quenched
with H2O and extracted with AcOEt. The organic layer was washed with
saturated aqueous NaHCO3 and dried over Na2SO4. After evaporation in
vacuo, the residue was purified by silica gel column chromatography
(EtOAc/hexane, 1:3) to give 7 (73.2 mg, 0.17 mmol, 22%, cis/trans, 1:2.0)
as a colorless oil. HPLC analysis: eluent=hexane/iPrOH, 99:1; Flow
rate: 0.5 mLminÀ1. 7A [with shorter retention time (27.6 min) in HPLC
using CHIRALPAK IB; [a]2D0 =À32.5 (c=0.2, CHCl3, 96.4% ee). 7B
[with a longer retention time (29.9 min) in HPLC using CHIRALPAK
IB] [a]2D0 = +31.7 (c 0.2, CHCl3, 98.5% ee). cis-7: 1H NMR (400 MHz,
CDCl3): d=2.81 (3H, s, CH3), 6.08 (1H, d, J=8.0 Hz, H7), 6.50 (1H, s,
H3), 7.11 (1H, t, J=8.0 Hz), 7.36 (1H, dt, J=1.2, 8.0 Hz, H6), 7.46 (2H,
m, H4,H5), 7.69 (1H, dd, J=0.8, 8.0 Hz), 7.91 ppm (1H, dd, J=0.8,
8.0 Hz); 13C NMR (100 MHz, CDCl3): d=17.4 (CH3) {93.1, 110.4, 119.4,
119.8, 120.0, 123.3, 124.4, 130.3, 132.2, 132.9, 135.2, 137.3, 139.5,
Single-crystal X-ray analysis: Single-crystal X-ray diffraction data of the
crystals were collected on a CCD diffractometer with graphite mono-
chromated MoKa radiation. The data were collected at low temperature
(90 K) by using liquid nitrogen. The structure was solved by the direct
method SHELXS-97[15] and refined by full-matrix least-squares
SHELXL-97. The non-hydrogen atoms were refined anisotropically.
Crystal Data for 5e: C20H18O4NBr, Mr =416.26, MoKa (l=0.71073 ꢁ),
monoclinic, C2/c, colorless prism 0.10ꢂ0.05ꢂ0.05 mm, crystal dimensions
a=21.2964 (17) ꢁ, b=8.2148(7) ꢁ, c=21.8966 (18) ꢁ, a=908, b=
108.5550(10)8, g=908, T=90 K, Z=8, V=3631.6 (5) ꢁ3, Dcalcd
=
1.523 gcmÀ3, F000 =1696, GOF=1.021, Rint =0.0324, R1 =0.0346, wR2 =
0.0791. CCDC-918030 (5e) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_-
request/cif.
1
142.9}(Ar), 166.6 ppm (NC=O). trans-7: H NMR (400 MHz, CDCl3): d=
1.86 (3H, s, CH3), 6.40 (1H, s, H3), 7.04 (1H, t, J=8.0 Hz), 7.30 (1H, dd,
J=1.2, 7.6 Hz, H6), 7.46 (2H, m, H4, H5), 7.64 (1H, dd, J=1.2, 8.0 Hz),
7.91 (1H, dd, J=1.2, 8.0 Hz), 8.64 ppm (1H, d, J=7.6 Hz, H7); 13C NMR
(100 MHz, CDCl3): d=15.8 (CH3), {93.6, 111.8, 112.6, 117.2, 120.0, 123.3,
124.6, 129.8, 132.0, 132.4, 134.7, 138.0, 138.5, 143.2}(Ar), 166.9 ppm (NC=
O); IR (neat): 1683 cmÀ1; HRMS (ESI) m/z: calcd for C16H11NOBrI:
439.9141 [M+H]; found: 439.9137.
Acknowledgements
This work was supported in part by a Grant-in-Aid for Scientific Re-
search (C) (21590124) and a Grant-in-Aid for Young Scientists (B)
(21790025) from the Japan Society for the Promotion of Science.
Compound (8), 1-(2-iodo-6-methylbenzoyl)-2-methyl-1H-indol: 2-Iodo-6-
methylbenzoyl chloride (598 mg, 2.3 mmol) was subjected to treatment
with 2-methylindole (100 mg, 0.76 mmol) following the same procedure
as that used for the synthesis of 7 described above to afford the product
8 (79.8 mg, 0.21 mmol, 28%, cis/trans, 1:1.4) as a colorless oil. HPLC:
eluent=hexane/iPrOH, 99:1. Flow rate: 0.5 mLminÀ1. 8A [with shorter
retention time (23.3 min) in HPLC using CHIRALPAK IB] [a]2D0 =À28.6
(c=0.2, CHCl3, 98.8% ee). 8B [with longer retention time (24.8 min) in
HPLC using CHIRALPAK IB] [a]2D0 = +24.6 (c=0.2, CHCl3, 95.8% ee).
cis-8: 1H NMR (400 MHz, CDCl3): d=2.28 (3H, s, CH3), 2.82 (3H, s,
CH3), 5.96 (1H, d, J=8.4 Hz, H7), 6.49 (1H, s, H3), 6.85 (1H, t, J=
8.4 Hz, H6), 7.14 (1H, m), 7.30 (1H, m), 7.45 (2H, m, H4, H5), 7.68 ppm
(1H, d, J=8.0); 13C NMR (100 MHz, CDCl3): d=17.5 (CH3), 20.0 (CH3),
{92.7, 110.1, 112.7, 119.9, 124.2, 129.7 130.3, 130.5, 131.2, 135.5, 136.5,
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1
136.9, 137.2, 142.1}(Ar), 168.7 ppm (NC=O). trans-8: H NMR (400 MHz,
CDCl3): d=1.76 (3H, s, CH3), 2.28 (3H, s, CH3), 6.38 (1H, s, H3), 7.09
(2H, m), 7.26 (2H, m), 7.30 (1H, m), 7.70 (1H, m), 8.65 ppm (1H, d, J=
8.3 Hz, H7); 13C NMR (100 MHz, CDCl3): d=15.8 (CH3), 20.0 (CH3),
{93.4, 111.5, 117.3, 119.4, 123.2, 124.5, 130.0, 131.0, 135.1, 136.6, 137.0,
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7062
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Chem. Eur. J. 2013, 19, 7056 – 7063

Indometacin Derivatives
FULL PAPER
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[9] See the Supporting Information for the synthesis of 3.
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Although this phenomenon cannot be clearly explained at present,
the relatively weak IC50 values (on the order of 10 mm) may make it
difficult to differentiate clearly the potencies of 1 and (À)-1.
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Received: January 8, 2013
Published online: April 9, 2013
Chem. Eur. J. 2013, 19, 7056 – 7063
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7063