An efficient synthesis of Ecopladib

Article abstract of DOI:10.1016/j.tet.2008.06.045

An efficient synthesis of Ecopladib, an indole inhibitor of cytosolic phospholipase A₂α, is described. A new reaction involving indole C3 reductive alkylation using an acetal in the absence of water and a novel transformation of the C2 methyl t

Full text of DOI:10.1016/j.tet.2008.06.045

Tetrahedron 64 (2008) 7871–7876
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An efficient synthesis of Ecopladib
,
a
a
b
Wei Li a , Jianchang Li , Dianne DeVincentis , Tarek S. Mansour
*
a Departments of Chemical and Screening Sciences, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, United States
b Departments of Chemical and Screening Sciences, Wyeth Research, 401 Middletown Road, Pearl River, NY 10965, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 April 2008
Received in revised form 6 June 2008
Accepted 12 June 2008
Available online 14 June 2008
An efficient synthesis of Ecopladib, an indole inhibitor of cytosolic phospholipase A2a, is described. A
new reaction involving indole C3 reductive alkylation using an acetal in the absence of water and a novel
transformation of the C2 methyl to an aldehyde via dimethyl sulfoxide-mediated oxygen-transfer re-
action are used in the present synthesis, which dramatically increased the synthetic efficiency.
Ó 2008 Elsevier Ltd. All rights reserved.
This paper is dedicated with respect to the
memory of Hassan Elokdah and Ronald L.
Magolda.
1. Introduction
carry out the O-alkylation of 6 using K2CO3 in DMF near reflux.2b
Under these conditions, the reaction required 2–3 days at one mole
Cytosolic phospholipase A2a (cPLA2a) catalyzes the selective
release of arachidonic acid to initiate the production of leukotri-
enes, prostaglandins, thromboxanes and the downstream genera-
tion of platelet-activating factor (PAF).1 As part of a program at
Wyeth directed toward the development of orally active small
molecule inhibitors for this enzyme, Ecopladib 1 (Fig. 1) was ad-
vanced to clinical trials.2 We report herein an efficient synthesis of
1 developed to support the preclinical studies.
Ecopladib 1 is a tetrasubstituted indole derivative. The indole
scaffold is common for known cPLA2a inhibitors, such as com-
pounds 2a–c,3 and offers a pharmacophore with favorable prop-
erties and viability for derivatization.
scale, and a large excess of K2CO3 was added in portions to drive the
reaction to completion. Alternative procedures were investigated to
improve the reaction. The best results were obtained using Cs2CO3
in DMSO at 95 ꢀC for 5 h, furnishing 7 in 90% yield.
The procedures reported for indole C3 reductive alkylation are
based on nucleophilic addition of the indole C3 carbon to an al-
dehyde in the presence of TFA and triethylsilane (TES).4 TFA is used
to activate the carbonyl through protonation for the formation of
intermediate 8c (Scheme 3). Elimination of water from 8c under
acidic conditions sets the stage for ionic hydrogenation5 to generate
the desired product 8 (Schemes 2 and 3).
2.1. The one-pot acetal–indole reductive alkylation
2. Results and discussion
For our synthesis, it would be advantageous to use acetal 7 di-
rectly for the alkylation. This objective should be achieved by ad-
dition of water to the reaction medium to generate 7c in situ via
acid hydrolysis of 7. Indeed, treatment of 7 and indole 5 with TFA/
The proposed synthesis of 1 consisted of three stepwise stages
(Scheme 1):2 the C3 alkylation of the commercially available 5-
chloro-2-methylindole 5 to form 4, the transformation of the 2-
methyl group to the corresponding aldehyde 3, and the final stage
including C2 homologation of 3 to the corresponding C2-ethyl-
amine for the final derivatization to 1. Installation of the N-benz-
hydryl group would be optional at various points in the synthesis.
The exploration and development of new reaction protocols were
emphasized in this synthesis.
Among available literature protocols for indole C3 alkylations,
reductive alkylation appeared the most attractive. For this appli-
cation, preparation of the alkylation precursor 7 was required
(Scheme 2). Initially, a common literature protocol was utilized to
HO2C
O
CO2H
C11H23
CO2H
Cl
CO2Me
Cl
O
N
X
N
H
N
Cl
O
O
S
O
N
O
O
HOOC
2a X = F
2b X = H
C10H21
1
2c
* Corresponding author. Tel.: þ1 617 665 5625; fax: þ1 617 499 1017.
E-mail address: weili@wyeth.com (W. Li).
Figure 1. cPLA2a indole inhibitors.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.045

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W. Li et al. / Tetrahedron 64 (2008) 7871–7876
ROOC
ROOC
O
O
Cl
Cl
Cl
1
CHO
N
N
N
H
R1
R1
5
3
4
Scheme 1. Retrosynthetic analysis.
intermediate, the O-alkyl oxonium 7b and indicated that there are
two different pathways in the C3 alkylation between the acetal and
aldehyde. To the best of our knowledge, this is the first example of
an acetal being directly employed in an indole C3 reductive alkyl-
ation under anhydrous conditions and the absence of water may
render acetals potentially more useful. We are currently in-
vestigating its synthetic implications.
The test run protocol followed a procedure developed for the
indole/aldehyde conditions with a typical concentration of 0.1 M of
5 in dichloromethane and an average yield of 60%.4 The low con-
centration limited the synthetic efficiency of our preparation. Thus,
modifying the protocol to increase throughput was crucial. It was
found that the reaction gave better yields at higher concentrations.
The optimal conditions involved conducting the reaction at room
temperature with a concentration of 1 mol of 5 in 1.3 L of
dichloromethane, which afforded 8 in 88% yield. This was a 10-fold
increase over the indole concentration reported in the literature4
and seemed to be the limitda 15-fold concentration resulted in
a reduced yield (71%).
Since high concentrations and large scale often bring un-
predictable events to reactions, the reaction was further tested
on one mole scale in a 5 L flask (165.6 g of 5, 0.96 L of DCM).
After the addition of TFA, a temperature increase from 25 to
29 ꢀC was observed. In our previous smaller scale reactions, no
exotherm had been detected. In addition, in contrast to the
earlier studies under dilute conditions, a white solid slowly
precipitated out of the reaction medium. The white solid, upon
analysis, turned out to be the desired product 8 with 99.2%
R2OOC
OEt
OEt
EtO
OH
O
Br
OEt
O
Cs2CO3,
DMSO
TFA/TES
5
Cl
90%
88%
N
O
OMe
O
OMe
R1
6
7
8a: R1 = H, R2 = H
8: R1 = H, R2 = Me
9: R1 = CHPh2, R2 = Me
NaH, DMF
Ph2CHBr
Scheme 2. Synthesis of compound 9.
H
OEt
H
OEt
H
O
O
O
O
OEt
H2O
TFA
-EtOH
7
Pathway
B
COOMe
COOMe
COOMe
7a
7b
7c
5
H+
MeOOC
5
Pathway
A
MeOOC
TFA/[H]
-EtOH
O
O
EtO
HO
TFA/[H]
-H2O
Cl
Cl
purity. Therefore, isolation and purification of
8 became
N
8b
N
8c
straightforward. simple filtration of the reaction mixture
A
8
afforded 8 as a white powder in 61% yield for the first crop. The
rest of the product in the filtrate was easily recovered through
recrystallization (CH2Cl2/CH3OH) to get an additional 27% yield.
The ease of isolation, high yield, and the superior quality of the
product rendered this procedure as the best protocol for the
indole C3 reductive alkylation.
Scheme 3. Active intermediate 7b in the indole C3 alkylation.
TES/water resulted in the desired product 8 in good yield, which
also suggests that aldehyde 7c is generated under the aqueous
acidic conditions6 during the course of the reaction.
However, benzoic acid byproduct 8a (Scheme 2) was detected
following the alkylation, contaminating the desired product 8. The
byproduct 8a could be generated from hydrolysis of the desired
methyl ester 8 under the reaction conditions or from the hydrolysis
of 7, with the resulting acid carried on to 8a in the C3 alkylation.
Nonetheless, this outcome led us to question the function of water
in the reaction. Based on the proposed reaction mechanism
(Scheme 3), the presence of water might not be necessary if indole
5 could capture the active intermediate 7b (pathway A), which has
been widely accepted as the first step of acetal hydrolysis under
acidic conditions.7 In this case, the reductive alkylation would then
be accomplished without going through the generation of aldehyde
7c (pathway B), a step that requires the presence of water.
Several unique features of this acetal–indole reductive alkyl-
ation are worth further discussion. First, this is a multi-step cascade
reaction initiated by a Friedel–Crafts alkylation8 on an indole aro-
matic ring via an active oxonium intermediate generated by re-
action of the acetal and TFA under anhydrous conditions. This is the
first example successfully employing an acetal for the regio-selec-
tive indole C3 alkylation. Second, the Friedel–Crafts alkylation did
not stop after the alkylation, rather proceeded to subsequent in situ
reduction of the resulting 3-alkoxymethylindole intermediate (8b)
through ionic hydrogenation.9 Therefore, the novelty of the water-
free reductive alkylation conditions lies in the ability to conduct
both the Friedel–Crafts reaction and subsequent Si–H reduction in
one-pot simultaneously.
To our delight, the test reaction of indole 5 with 7 worked
perfectly without water to afford 8 in high yield, while the
byproduct 8a was not detected. The reaction outcome supports our
hypothesis that the C3 alkylation could happen on an earlier active
Dialkylation10 and reduction of indole to indoline11 are possible
byproducts in indole C3 alkylations. Under the reaction conditions
here, byproducts such as 8d and 8e (Fig. 2) were not detected (by
HPLC/MS).

W. Li et al. / Tetrahedron 64 (2008) 7871–7876
7873
reaction mixture was filtered to remove the succinimide. The fil-
MeOOC
trate was concentrated to afford 10 as a thick oil.
Cl
HN
Cl
Cl
O
2.2. Formation of aldehyde via DMSO-mediated oxygen-
transfer
O
N
N
H
COOMe
H
Conversion of gem-dihalo compound 10 to aldehyde 11 was
carried out using the DMSO-mediated oxygen-transfer protocol
developed in our laboratory.12 Thus, DMSO was poured into the
concentrated filtrate with stirring, and the resulting solution was
poured into water. The solid that formed was filtered to afford the
desired aldehyde 11 (Scheme 4). This reaction is not only
straightforward (incorporating a reaction into a work-up opera-
tion), but also trims one step from the original synthetic sequence.
Prior to this discovery, the aldehyde 11 had been obtained2a via Agþ
mediated hydrolysis of the gem-dibromo species 10.13
8d
8e
Figure 2. Possible byproducts.
The indole N-alkylation of 8 was carried out using NaH in DMF
and benzhydryl bromide (Scheme 2). After completion, the reaction
mixture was slowly poured into water, and desired product 9
precipitated and was collected by filtration and used directly in the
subsequent bromination step.
Early attempts to prepare the monobrominated intermediate for
homologation at C2 failed due to the heavy contamination from
side products resulting from competitive dibromination. The ma-
nipulation of the C2 substituent therefore commenced with the
dibromination of 9, which was conducted using NBS (2 equiv) in
the presence of a radical initiator (Scheme 4). After completion, the
Sulfoxides have the ability to either accept or donate oxygen in
organic reactions, but the majority of synthetic applications are
associated with its oxygen-donating property, although exceptions
exist.14 One widely used reaction is the conversion of structurally
diverse alcohols into their corresponding carbonyl compounds by
DMSO in the presence of activating agents. In these reactions, the
original oxygen atom in DMSO is not directly donated to form the
carbonyl oxygen during the oxidative process, but rather is donated
to the activating agents.15 What we have described here is a unique
example in which the sulfoxide serves as a direct oxygen donor in
the absence of activating agents. It should also be pointed out that
unlike the Kornblum reaction,16 this is not an oxidative process: the
oxidation states of both starting material and product remain the
same. Therefore, this oxygen-transfer from sulfoxide occurs in
a non-oxidative reaction.
MeOOC
MeOOC
O
O
NBS
(PhCO)2O2
CCl4
Br
Br
Cl
Cl
DMSO
O
9
N
N
H
Mechanistically, the alkoxysulfonium species 11a17 (Fig. 3) ap-
pears to be the active intermediate, which undergoes a 1,2-elimi-
nation to give the desired aldehyde 11. However, the
alkoxysulfonium 11a was not detected when the reaction was
monitored by 1H NMR. This observation suggests that the dis-
placement of the first bromine atom is slow, and the 1,2-elimina-
tion occurs rapidly following the first displacement.
Ph
Ph
11
Ph
Ph
10
Scheme 4. Synthesis of compound 11.
Condensation of the aldehyde 11 and nitromethane in the
presence of ammonium acetate provided the desired nitroethene
12 as a pale yellow solid (Scheme 5, 61% overall yield from 8). The
choices for reduction of 12 to the ethylamine species 13 are very
limited due to the presence of the C5-chlorine and the methyl ester.
Hydride reducing agents such as LiAlH4 would reduce the methyl
ester, and hydrogenolysis would generate impurities from the re-
duction of the aromatic chlorine, or deprotection of the N-benz-
hydryl group. It appears that the Zn(Hg)/HCl reduction18 of nitro
olefin 12 is the only viable option for the preparation of 13. Indeed,
reduction of 12 by Zn/HCl afforded the desired ethylamine 13 as
a white powder.
MeOOC
11
10
O
Cl
O
S
Br
S
Br
Br
N
O
S
Br
Ph
11a
Figure 3. Oxygen-transfer from DMSO.
Ph
MeOOC
R1OOC
O
O
Cl
Zn (Hg)
MeNO2,
NH4OAc
NO2
Cl
NHR2
conc.
HCl
11
N
61%
N
72%
from 8
Ph
Ph
Ph
Ph
(3,4-Cl2Ph)CH2SO2Cl
Et3N, 100%
12
13: R1 = Me, R2 = H
14: R1 = Me, R2 =SO2CH2Ph(3,4-Cl)
1 : R1 = H, R2 = SO2CH2Ph(3,4-Cl)
NaO
H/H2
O (
95%
)
Scheme 5. Synthesis of Ecopladib (1).

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W. Li et al. / Tetrahedron 64 (2008) 7871–7876
The remaining synthesis was accomplished in two steps. Re-
(300 mLꢁ2), and dried to give 153.56 g of white solid. The filtrate
was concentrated to 150 mL, and MeOH was added until no further
precipitation was observed. White solid (62.70 g) was obtained
after filtration as the second crop with equal quality. Further re-
covery of the desired product from the mother liquor by repeating
the same procedure described above afforded 4.14 g of desired
product. The combined yield of 8 was 220.40 g (88%). 1H NMR
action of the amine 13 with the corresponding sulfonyl chloride
furnished the desired sulfonamide 14, and the methyl ester was
hydrolyzed under standard saponification conditions to afford 1 as
a white powder.
3. Conclusions
(400 MHz, CDCl3):
d
2.42 (s, 3H), 3.15 (t, J¼7.0 Hz, 2H), 3.87 (s, 3H),
In conclusion, Ecopladib was synthesized in a three-stage, nine-
step process in 32% overall yield from indole 5. This process is
characterized by a novel C3 indole alkylation using acetal in the
absence of water and a unique oxygen-transfer reaction between
DMSO and a gem-dibromomethyl group for the transformation of
a methyl group to the corresponding aldehyde.
4.15 (t, J¼7.0 Hz, 2H), 6.81–6.91 (m, 2H), 7.07 (dd, J¼8.6, 2.0 Hz, 1H),
7.18 (d, J¼8.3 Hz, 1H), 7.50 (d, J¼2.0 Hz, 1H), 7.86 (s, 1H), 7.91–8.03
(m, 2H). 13C NMR (101 MHz, CDCl3):
d 11.9, 24.3, 51.9, 68.0, 107.6,
111.3, 114.0, 117.4, 121.3, 122.4, 125.1, 129.8, 131.6, 133.5, 133.9, 162.6,
167.0. HRMS (ES-MS) [(MþH)þ]: for C19H18ClNO3 344.1048. Found
344.1045.
4. Experimental section
4.1. General
4.4. Methyl 4-(2-(1-benzhydryl-5-chloro-2-methyl-1H-indol-
3-yl)ethoxy)benzoate (9)
To a 2 L three-necked r.b. flask containing a solution of methyl 4-
(2-(5-chloro-2-methyl-1H-indol-3-yl)ethoxy)benzoate (8) (68.76 g,
0.2 mol) in DMF (0.3 L) was added sodium hydride suspension
(9.90 g, 0.246 mol) slowly in portions. The temperature of the
resulting mixture rose to 40 ꢀC after completion of the addition. The
mixture was stirred for an additional 30 min. Bromodiphenyl-
methane (62.36 g, 0.239 mol) in 100 mL of DMF was added slowly,
and the reaction temperature was kept below 60 ꢀC by adjusting
the rate of addition. The reaction mixture was slowly poured into
1 L of stirred ice-water. The crude 9 precipitated as a pale yellow
solid and was used directly after filtration. 1H NMR (400 MHz,
All reagents and solvents were purchased from commercial
sources and used as received. All products were characterized by 1H
and 13C NMR, and MS if ionization was detectable. Mass spectrom-
eters used were the Micromass LCT (ESI or APCI) with an Agilent
1100 LC Pump (for LCMS). Gilson reversed-phase preparatory HPLC
(pump models of 331 and 332 and UV detector wave length:
254 nm) was used for separation with a Phenomenex Gemini col-
umn (5u C18 110A, 150ꢁ30 mm) gradient solvent program (solvent
A: H2O, solvent B: acetonitrile) from 10 to 50% solvent B for 10 min at
40 mL/min flow rate. NMRexperiments were performed on a Bruker
AVANCE 400 MHz spectrometer equipped with a 5 mm broadband
probe. The following abbreviations are used to designate the mul-
tiplicity: s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet.
13C NMR spectra were recorded with complete proton decoupling.
Chemical shifts are reported in parts per million with the solvent
CDCl3):
d
2.29 (s, 3H), 3.19 (t, J¼7.1 Hz, 2H), 3.88 (s, 3H), 4.17 (t,
J¼7.1 Hz, 2H), 6.54 (d, J¼8.8 Hz, 1H), 6.81 (dd, J¼8.8, 2.0 Hz, 1H),
6.83–6.90 (m, 3H), 7.03–7.13 (m, 4H), 7.28–7.34 (m, 6H), 7.51 (d,
J¼2.0 Hz, 1H), 7.89–8.02 (m, 2H). 13C NMR (101 MHz, CDCl3):
d 11.6,
24.7, 51.8, 62.7, 68.0, 107.9, 112.7, 114.1, 117.2, 120.9, 122.5, 124.9,
127.9, 128.2, 128.7, 129.6, 131.6, 134.8, 136.4, 139.0, 162.7, 166.9.
HRMS (ES-MS) [(MþH)þ]: for C32H28ClNO3 510.1830. Found
510.1824. Anal. Calcd for C32H28ClNO3: C, 75.36; H, 5.53; N, 2.75.
Found: C, 75.69; H, 5.26; N, 2.63.
resonance as the internal standard (CDCl3: d 77.0 ppm).
4.2. Methyl 4-(2,2-diethoxyethoxy)benzoate (7)
A three-necked 5 L r.b. flask with an overhead mechanical stirrer
was charged with methyl 4-hydroxybenzoate (6) (169.10 g,
1.10 mol) and DMSO (2 L). After flushing with nitrogen for 30 min,
cesium carbonate (550.0 g, 1.69 mol) and bromoacetaldehyde
diethylacetal (222.90 g, 1.10 mol) were added. The resulting sus-
pension was heated at 95 ꢀC for 12 h under nitrogen. After com-
pletion of the reaction, the reaction mixture was poured into cold
water (3 L) and extracted with ethyl acetate (3 Lꢁ2). The organic
layers were combined and dried over MgSO4. Removal of the sol-
vent yielded the desired product 7 as a colorless oil (268.3 g, 90%
yield), which was directly used without further purification. 1H
4.5. Methyl 4-(2-(1-benzhydryl-5-chloro-2-formyl-1H-indol-
3-yl)ethoxy)benzoate (11)
To a solution of methyl 4-(2-(1-benzhydryl-5-chloro-2-methyl-
1H-indol-3-yl)ethoxy)benzoate (9) (114.84 g, 225 mmol) in CCl4
(900 mL) were added NBS (80.2 g, 450 mmol) and benzoylperoxide
(0.050 g). The resulting mixture was heated to reflux for 2.5 h. The
mixture was cooled to room temperature and filtered to remove the
succinimide. The filtrate was concentrated, and the crude product
10 (300.0 g) was obtained as a thick oil, which was dissolved in
DMSO (600 mL). The resulting solution was stirred at room tem-
perature for 30 min. An indication of the conversion of the dibro-
mide to above aldehyde is the smell of dimethyl sulfide. After
completion of the reaction, the reaction mixture was poured into
water (4 L). The resulting suspension was filtered. The filter cake
was washed with water. The product 11 (220.0 g) was used directly
NMR (400 MHz, CD2Cl2):
d 1.13–1.29 (m, 6H), 3.54–3.69 (m, 2H),
3.68–3.81 (m, 2H), 3.85 (s, 3H), 4.02 (d, J¼5.3 Hz, 2H), 4.81 (t,
J¼5.2 Hz, 1H), 6.85–7.08 (m, 2H), 7.87–8.08 (m, 2H).
4.3. Methyl 4-(2-(5-chloro-2-methyl-1H-indol-3-yl)ethoxy)
benzoate (8)
for the next step. 1H NMR (300 MHz, CDCl3):
d
3.58 (t, J¼6.6 Hz, 2H),
A three-necked 3 L r.b. flask was charged with the methyl 4-(2,2-
diethoxyethoxy)benzoate (7) (205.50 g, 0.758 mol), DCM (0.940 L),
and 5-chloro-2-methylindole (5) (122.57 g, 0.731 mol). To this so-
lution was added TFA (247.17 g, 2.168 mol), followed by triethyl-
silane (250.42 g, 2.32 mol). The solution turned red, and the reaction
temperature rose from 24 to 29 ꢀC within 1 h. Precipitation of
a white solid started after 3 h and the reaction mixture was stirred
at room temperature for an additional 24–48 h until TLC showed
completion of the reaction. The reaction mixture was filtered. The
filter cake was washed with MeOH (300 mLꢁ2) and hexane
3.90 (s, 3H), 4.19–4.50 (m, 2H), 6.69 (d, J¼9.2 Hz, 1H), 6.86 (d,
J¼8.9 Hz, 2H), 6.97–7.51 (m, 10H), 7.76 (d, J¼2.0 Hz, 1H), 7.97 (d,
J¼8.9 Hz, 2H), 8.23 (s, 1H), 10.22 (s, 1H). HRMS (ES-MS) [(MþH)þ]:
for C32H26ClNO4 524.1550. Found 524.1553.
4.6. (E)-Methyl 4-(2-(1-benzhydryl-5-chloro-2-(2-nitrovinyl)-
1H-indol-3-yl)ethoxy)benzoate (12)
The aldehyde 11 from the previous step (145 g, 0. 217 mol),
NH4OAc (170.6 g, 2.17 mol), and MeNO2 (1.8 L) were heated to

W. Li et al. / Tetrahedron 64 (2008) 7871–7876
7875
reflux for 4 h. After completion of the reaction, the solvent was
4.9. Ecopladib (1)
removed by evaporation under reduced pressure. The residue was
dissolved in 200 mL of DMF, and the resulting solution was poured
into water. The resulting suspension was filtered. The yellow filter
cake was washed with water and dried (187 g, crude). Re-
crystallization of the crude product from EtOAc yielded the desired
product with 94% purity, which was further purified by column
chromatography (eluting with 1–10% DCM/hexane) to afford pure
product (75.05 g, 61% for the last four steps) as a pale yellow solid.
To a solution of the methyl ester 13 (7.62 g,10 mmol) in inhibitor
free THF (150 mL) were added 2 N aq NaOH (15.0 mL, 30.0 mmol)
and MeOH (100 mL). The mixture was heated at 55 ꢀC until the
ester starting material was consumed. THF was removed and the
aqueous residue was acidified to pH 1 using 2 N HCl. The desired
product 1 precipitated as a white solid and was collected via fil-
tration (7.10 g, 95%). Mp 124–125 ꢀC. 1H NMR (400 MHz, DMSO-d6):
Mp 74–75 ꢀC. 1H NMR (400 MHz, CDCl3):
d
3.37 (t, J¼6.1 Hz, 2H),
d
2.97–3.06 (m, 2H), 3.06–3.14 (m, 2H), 3.17 (t, J¼6.7 Hz, 2H), 4.22 (t,
3.87 (m, 3H), 4.33 (t, J¼6.1 Hz, 2H), 6.82 (m, 3H), 7.06 (m, 6H), 7.34
(m, 6H), 7.57 (d, J¼13.6 Hz, 1H), 7.66 (d, J¼2.0 Hz, 1H), 7.95 (m, 2H),
J¼6.7 Hz, 2H), 4.35 (s, 2H), 6.46 (d, J¼8.8 Hz, 1H), 6.80 (dd, J¼8.8,
2.0 Hz, 1H), 6.91–7.00 (m, 2H), 7.04–7.14 (m, 5H), 7.26 (dd, J¼8.3,
2.0 Hz, 1H), 7.33–7.40 (m, 6H), 7.50 (t, 1H), 7.53 (d, J¼8.3 Hz, 1H),
8.02 (d, J¼13.4 Hz,1H). 13C NMR (101 MHz, CDCl3):
d 25.5, 51.9, 63.8,
67.6, 113.6, 114.0, 118.8, 119.3, 123.0, 125.6, 126.6, 127.5, 128.0, 128.5,
129.0, 129.0, 130.3, 131.7, 137.1, 137.6, 138.0, 162.1, 166.7. HRMS (ES-
MS) [(MþH)þ]: for C33H27ClN2O5 567.1681. Found 567.1680.
7.56 (d, J¼2.0 Hz, 1H), 7.67 (d, J¼2.3 Hz, 1H), 7.79–7.89 (m, 2H). 13
C
NMR (101 MHz, DMSO-d6):
d 23.8, 26.0, 42.6, 55.4, 61.4, 67.7, 109.1,
109.1, 113.1, 113.9, 122.6, 123.4, 127.6, 128.5, 129.2, 130.1, 130.6, 130.7,
130.7, 131.1, 131.2, 132.3, 134.1, 137.3, 138.8, 161.9, 166.7. HRMS (ES-
MS) [(MþH)þ]: for C39H33Cl3N2O5S 747.1249. Found 747.1241. Anal.
Calcd for C39H33Cl3N2O5S: C, 62.61; H, 4.45; N, 3.74. Found: C,
62.34; H, 4.28; N, 3.60.
4.7. Methyl 4-(2-(2-(2-aminoethyl)-1-benzhydryl-5-chloro-
1H-indol-3-yl)ethoxy)benzoate (13)
A three-necked 5 L r.b. flask containing a solution of the nitro
olefin 12 (35.0 g, 61.7 mmol) in THF (1450 mL) was charged with
concentrated HCl (175 mL) and the freshly prepared Zn(Hg) amal-
gam11 (186 g, 2.7 mol). Hydrogen release occurred immediately.
The reaction temperature rose from 20 to 52 ꢀC. Color of the re-
action mixture turned from yellow to pale green once the reaction
was complete (1–3 h, monitored by TLC). The reaction mixture was
poured into a mixture containing EtOAc (1.45 L) and concentrated
NH4OH (0.3 L) with efficient agitation for 20 min. The organic layer
was separated, washed with aq NH4OH (200 mL), satd NaHCO3
(500 mL), water (2000 mLꢁ4), and brine (500 mL), and dried over
MgSO4. Evaporation of the solvent afforded 34.5 g of crude product.
Purification by flash column chromatography (eluting with 0–5%
MeOH/DCM) afforded the pure product (24.03 g, 72%) as a pale
Acknowledgements
The authors thank Wyeth colleagues Katherine Lee, John
McKew, Steve Tam, and Andre Asselin for discussions on chemistry,
Charlie Wu for investigating the O-alkylation reactions, and Nelson
Huang, Walter Massefski, and Ning Pan for analytical support,
Nathan Fuller and Paul Morgan for assistance.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.06.045.
References and notes
yellow solid. Mp 121–122 ꢀC. 1H NMR (300 MHz, CDCl3):
d 2.81 (t,
J¼7.3 Hz, 2H), 2.98 (t, J¼7.4 Hz, 2H), 3.25 (t, J¼7.1 Hz, 2H), 3.88 (s,
3H), 4.22 (t, J¼7.0 Hz, 2H), 6.51 (d, J¼9.1 Hz, 1H), 6.8 (dd, J¼8.9,
2.1 Hz, 1H), 6.9 (d, J¼9.1 Hz, 2H), 6.9 (s, 1H), 7.03–7.18 (m, 4H), 7.28–
7.38 (m, 6H), 7.54 (d, J¼1.9 Hz, 1H), 7.96 (d, J¼9.1 Hz, 2H). 13C NMR
1. Clark, J. D.; Tam, S. Expert Opin. Ther. Pat. 2004, 14, 937.
2. (a) Lee, K. L.; Foley, M. A.; Chen, L.; Behnke, M. L.; Lovering, F. E.; Kirincich, S. J.;
Wang, W.; Shim, J.; Tam, S.; Shen, M. W. H.; Khor, S. P.; Xu, X.; Goodwin, D. G.;
Kamarao, M. K.; Nickerson-Nutter, C.; Donahue, F.; Ku, M. S.; Clark, J. D.;
McKew, J. C. J. Med. Chem. 2007, 50, 1380; (b) McKew, J. C.; Foley, M. A.; Thakker,
P.; Behnke, M. L.; Lovering, F. E.; Sum, F.-W.; Tam, S.; Wu, K.; Shen, M. W. H.;
Zhang, W.; Gonzalez, M.; Liu, S.; Mahadevan, A.; Sard, H.; Khor, S. P.; Clark, J. D.
J. Med. Chem. 2006, 49, 135.
(101 MHz, CDCl3):
d 24.9, 29.6, 42.3, 51.9, 62.5, 68.1, 109.2, 113.6,
114.1, 117.6, 121.3, 122.6, 125.1, 127.9, 128.1, 128.7, 129.5, 131.6, 134.8,
137.8, 139.0, 162.6, 166.9. HRMS (ES-MS) [(MþH)þ]: for
3. (a) Lehr, M.; Klimt, M.; Elfringhoff, A. S. Bioorg. Med. Chem. Lett. 2001, 11, 2569;
(b) Ludwig, J.; Bovens, S.; Brauch, C.; Elfringhoff, A. S.; Lehr, M. J. Med. Chem.
2006, 49, 2611.
C
33H31ClN2O3 539.2096. Found 539.2096.
4. (a) Mahadevan, A.; Sard, H.; Gonzalez, M.; McKew, J. C. Tetrahedron Lett. 2003,
44, 4589; (b) Appleton, J. E.; Dack, K. N.; Green, A. D.; Steele, J. Tetrahedron Lett.
1993, 34, 1529.
5. (a) Kursanov, D. N.; Parnes, Z. N.; Bassova, G. I.; Loim, N. M.; Zdanovich, V. I.
Tetrahedron 1967, 2235; (b) Kursanov, D. N.; Parnes, Z. N.; Loim, N. M. Synthesis
1974, 633.
4.8. Methyl 4-(2-(1-benzhydryl-5-chloro-2-(2-((3,4-
dichlorophenyl)methylsulfonamido)ethyl)-1H-indol-3-
yl)ethoxy)benzoate (14)
6. Selected recent references: (a) Duval, R. A.; Allmon, R. L.; Lever, J. R. J. Med.
Chem. 2007, 50, 2144; (b) Douelle, F.; Capes, A. S.; Greaney, M. F. Org. Lett. 2007,
9, 1931.
7. Smith, B. M.; March, J. Advanced Organic Chemistry, 5th ed.; John Wiley and
Sons: New York, NY, USA, 2001; p 466.
8. Cossy, J.; Lutz, F.; Alauuze, V.; Meyer, C. Synlett 2002, 45.
9. Zhou, H.; Liao, X.; Yin, W.; Ma, Y. J.; Cook, J. M. J. Org. Chem. 2006, 71, 251.
10. There are many reports on the formation of bis(indol-3-yl)methane derivatives
from indole and aldehyde under acidic conditions. (a) Lee, J. W.; Park, S. Y.; Cho,
B.; Kim, J. S. Tetrahedron Lett. 2007, 48, 2541; (b) Hagiwara, H.; Sekifuji, M.;
Hoshi, T.; Qiao, K.; Yokoyama, C. Synlett 2007, 1320.
To a solution of the amine 13 from the previous step (5.39 g,
10 mmol) in CH2Cl2 (100 mL) were added (3,4-dichloro-
phenyl)methanesulfonyl chloride (3.1 g, 12 mmol) and triethyl-
amine (2.024 g, 20 mmol). The resulting suspension was stirred
until the amine was consumed. The mixture was washed with H2O
(80 mLꢁ2) and brine (50 mLꢁ2), dried, and concentrated to afford
the product (7.62 g, 100% yield) as white solid, which was directly
used in the next step. Mp 94–95 ꢀC. 1H NMR (400 MHz, CDCl3):
11. Lanzilotti, A. E.; Littell, R.; Fanshawe, W. J.; McKenzie, T. C.; Lovell, F. M. J. Org.
Chem. 1979, 44, 4809.
d
2.89 (m, 2H), 3.09 (t, 2H), 3.19 (t, J¼6.6 Hz, 2H), 3.86 (s, 3H), 3.92 (s,
12. Li, W.; Li, J.; DeVincentis, D.; Mansour, T. S. Tetrahedron Lett. 2004, 45, 1071. This
is the first large-scale synthetic application of this new reaction.
13. Shamblee, D. A.; Gillespie, J. S., Jr. J. Med. Chem. 1979, 22, 86.
14. For synthetic applications of DMSO not involving oxygen transfer or oxygen
donation, see: (a) Li, W.; Li, J.; Lin, M.; Wacharasindhu, S.; Tabei, K.; Mansour,
T. S. J. Org. Chem. 2007, 72, 6016; (b) Li, W.; Li, J.; Wan, Z.-K.; Wu, J.; Massefski,
W. Org. Lett. 2007, 9, 4607.
2H), 4.22 (t, J¼6.6 Hz, 2H), 4.32 (t, J¼6.2 Hz, 1H), 6.54 (d, J¼9.1 Hz,
1H), 6.82 (m, 3H), 6.90 (s, 1H), 6.98 (dd, J¼8.2, 2.2 Hz, 1H), 7.07 (dd,
J¼6.6, 2.8 Hz, 4H), 7.30 (m, 8H), 7.54 (d, J¼2.1 Hz, 1H), 7.94 (m, 2H).
13C NMR (101 MHz, CDCl3):
d 24.8, 27.5, 43.0, 51.9, 57.6, 60.4, 62.5,
68.0, 110.3, 113.7, 114.1, 117.8, 121.9, 122.7, 125.3, 128.1, 128.9, 129.2,
129.2, 129.7, 130.8, 131.6, 132.3, 132.9, 133.3, 135.1, 135.6, 138.9,
162.5, 166.8.
15. Selected literature: (a) Pfitzner, K. E.; Moffatt, J. G. J. Am. Chem. Soc. 1965, 87,
5661, 5670; (b) Albright, J. D.; Goldman, L. J. Am. Chem. Soc. 1967, 89, 2416;

7876
W. Li et al. / Tetrahedron 64 (2008) 7871–7876
(c) Parikh, J. R.; von Doering, W. J. Am. Chem. Soc. 1967, 89, 5505; (d) Corey, E. J.;
Kim, C. U. Tetrahedron Lett. 1973, 14, 919; (e) Omura, K.; Sharma, A.; Swern, D.
J. Org. Chem. 1976, 41, 957.
17. (a) Johnson, C. R.; Jones, M. P. J. Org. Chem.1967, 32, 2014; (b) Johnson, C. R.; Rigau,
J. J. J. Am. Chem. Soc. 1969, 91, 5398; (c) Khuddus, M. A.; Swern, D. J. Am. Chem. Soc.
1973, 95, 8393; (d) Zhang, J.; Saito, S.; Koizumi, T. J. Org. Chem. 1998, 63, 5265.
18. Claudi, F.; Di Stefano, A.; Napolitani, F.; Cingolani, G. M.; Giorgioni, G.; Fontenla,
J. A.; Montenegro, G. Y.; Rivas, M. E.; Rosa, E.; Michelotto, B.; Orlando, G.;
Brunetti, L. J. Med. Chem. 2000, 43, 599.
16. (a) Kornblum, N.; Powers, J. W.; Anderson, G. J.; Jones, W. J.; Larson, H. O.;
Levand, O.; Weaver, W. M. J. Am. Chem. Soc. 1957, 79, 6562; (b) Kornblum, N.;
Jones, W. J.; Anderson, G. J. J. Am. Chem. Soc. 1959, 81, 4113.