An efficient and practical synthesis of N,N-diethyl-7-indolyloxyacetamide via 7-hydroxyindole

Article abstract of DOI:10.1081/SCC-120015783

An efficient and practical synthesis of N, N-diethyl-7-indolyloxyacetamide (1) from 3-hydroxy-2-nitrotoluene (4) via 7-hydroxyindole (2) is described. Treatment of 3-benzyloxy-2-nitrotoluene (5) obtained from 4 with DMF dimethyl acetal and pyrrolidine afforded the (E)-2-nitro-β-pyrrolidinostyrene 6, which can be readily converted into the 2-nitrophenylacetaldehyde semicarbazone 7 without isolation of 6. Hydrogenation of 7 over Pd/C, followed by reaction of the resulting 2 with 2-chloro-N, N-diethylacetamide produced 1 in good yield.

Full text of DOI:10.1081/SCC-120015783

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An Efficient and Practical Synthesis of N , N -Diethyl-7-
indolyloxyacetamide via 7-Hydroxyindole
a
a
a
Hiroshi Harada , Akihito Fujii & Shiro Kato
a
Medicinal Chemistry Group, Chemistry Research Laboratories, Dainippon Pharmaceutical
Co., Ltd., Enoki, Suita, Osaka, Japan
Published online: 17 Aug 2006.
To cite this article: Hiroshi Harada , Akihito Fujii & Shiro Kato (2003) An Efficient and Practical Synthesis of N , N -Diethyl-7-
indolyloxyacetamide via 7-Hydroxyindole, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 33:3, 507-514, DOI: 10.1081/SCC-120015783
To link to this article: http://dx.doi.org/10.1081/SCC-120015783
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 3, pp. 507–514, 2003
An Efficient and Practical Synthesis of
N,N-Diethyl-7-indolyloxyacetamide
via 7-Hydroxyindole
Hiroshi Harada,* Akihito Fujii, and Shiro Kato
Medicinal Chemistry Group, Chemistry Research Laboratories,
Dainippon Pharmaceutical Co., Ltd., Enoki, Suita, Osaka, Japan
ABSTRACT
An efficient and practical synthesis of N,N-diethyl-7-indolyloxyacet-
amide (1) from 3-hydroxy-2-nitrotoluene (4) via 7-hydroxyindole (2)
is described. Treatment of 3-benzyloxy-2-nitrotoluene (5) obtained
from 4 with DMF dimethyl acetal and pyrrolidine afforded the
(
E )-2-nitro-b-pyrrolidinostyrene 6, which canbe readily co nv erted
into the 2-nitrophenylacetaldehyde semicarbazone 7 without isola-
tionof 6. Hydrogenation of 7 over Pd/C, followed by reactionof
the resulting 2 with 2-chloro-N,N-diethylacetamide produced 1 in
good yield.
*
Correspondence: Hiroshi Harada, Medicinal Chemistry Group, Chemistry
Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Enoki 33-94,
Suita, Osaka 564-0053, Japan; Fax: 81-6 6338-7656; E-mail: hiroshi-harada@
dainippon-pharm.co.jp.
5
07
DOI: 10.1081/SCC-120015783
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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5
08
Harada, Fujii, and Kato
Figure 1.
N,N-Diethyl-7-indolyloxyacetamide (1), a key intermediate of AJ-
9
677 which is a potent and selective adrenalin b receptor agonist devel-
3
[1,2]
oped inour laboratories,
was easily derived from 7-hydroxyindole (2),
which in turn can be obtained from protected 7-hydroxyindole such as 7-
benzyloxyindole (3, Fig. 1). Inorder to produce 1 ona large scale, an
efficient and practical synthetic method of 3 was essential. To our knowl-
edge, there are only few reports on the synthesis of protected 7-hydro-
xyindoles except 7-methoxyindole. 7-Benzyloxyindole (3), which is a
protected 7-hydroxyindole, is usually prepared from 2-nitrophenol by
[3]
Gassman’s method or from 3-hydroxy-2-nitrotoluene by Witkop’s
[4]
method. In addition, Bartoli and Palmieri reported a novel and short
synthetic route to 7-substituted indoles containing 7-trimethylsilyloxyin-
dole. In this route, reaction of 2-substituted nitrobenzenes with 3 molar
ꢁ
equivalents of vinylmagnesium bromide at ꢀ40 C directly gives the
corresponding 7-substituted indoles in poor to moderate yield (in the
[
case of 7-trimethylsilyloxyindole, the yield was 41%). 7-Benzyloxyin-
5]
dole (3) and 7-benzhydryloxyindole were also prepared by Bartoli’s
6]
[
method in13% a dn 57% yield, respectively.
Recently, Murakami
et al. reported a new method for the synthesis of indoles with electron-
withdrawing oxygenated substituents at the 7-position e.g., 7-( p-
toluenesulfonyloxy)indole, which can be converted into 7-hydroxyindole
(2), via Fischer indolization of 2-( p-toluenesulfonyloxy)phenylhydra-
zones. However, Gassman’s, Witkop’s, and Murakami’s methods
[7]
Scheme 1. Substituted indole synthesis by Leimgruber and Batcho’s method.

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N,N-Diethyl-7-indolyloxyacetamide
509
have the disadvantage of being multi-step routes with a low overall yield.
In addition, Bartoli’s method requires low temperature and chromato-
graphic purification.
Leimgruber and Batcho reported an efficient and novel indole synth-
esis based on the condensation of 2-nitrotoluene with N,N-dimethylfor-
mamide (DMF) dimethyl acetal, followed by reductionof the resulting
[
8]
(
were synthesized by this method.
E )-2-nitro-b-dimethylaminostyrene (Sch. 1). Many substituted indoles
[8,9]
Inthe reactionof 2- ni trotolue ne
derivatives with DMF dimethyl acetal, additionof anami ne such as
pyrrolidine or triethylamine was found to be effective in facilitating the
[10]
enamine formation. Onthe other hand, attempts to apply this method
to the preparation of indoles having bulky or electron-donating group
resulted in only limited success. In general, the unsuccessful preparations
were due to less reactive (E)-2-nitro-b-dimethylaminostyrenes. Kruse
resolved this difficult problem by pivotal modificationinwhich the very
insoluble phenylacetaldehyde semicarbazone derivatives are prepared
from the (E)-2-nitro-b-dimethylaminostyrenes by treatment with acidic
aqueous semicarbazide. Indole derivatives such as 4-methoxyindole and
4-benzyloxyindole were obtained in good yield by reducing the corre-
sponding phenylacetaldehyde semicarbazones (modified Leimgruber
[
11]
and Batcho’s method).
However, the preparationof 3, which canbe
converted into 2, by the modified Leimgruber and Batcho’s method has
so far not been reported. In this study, we examined the preparation
of 3, a protected 7-hydroxyindole, using the modified Leimgruber and
Batcho’s method.
Treatment of the commercially available 3-hydroxy-2-nitrotoluene
4) with benzyl bromide in the presence of potassium carbonate gave
-benzyloxy-2-nitrotoluene (5) inquat ni tative yield. Crude 5 thus
(
3
obtained was used in the next reaction without further purification.
Reactionof crude 5 with 2.0 molar equivalents of DMF dimethyl
acetal and pyrrolidine in refluxing DMF for 5 h, followed by treatment
of the resulting (E)-3-benzyloxy-2-nitro-b-pyrrolidinostyrene (6) with
semicarbazide hydrochloride and aqueous HCl solution produced the
very insoluble 3-benzyloxy-2-nitrophenylacetaldehyde semicarbazone
(
7) as a pale yellow powder in74% yield from the starti ng 4. When1.1
molar equivalents of DMF dimethyl acetal was used, complete reaction
of 5 needed 18 h. Reduction of the isolated 7 with Fe inthe prese nc e
of ammonium chloride in aqueous ethyl alcohol afforded 7-
benzyloxyindole (3) ingood yield. Hydroge na tionof
oncarbonproduced the desired 7-hydroxyi dn ole (
3 over palladium
2). Although the
reductionof the ( E )-2-nitro-b-dimethylaminostyrenes having a benzyl-

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Harada, Fujii, and Kato
Scheme 2. (a) PhCH
pyrrolidine, DMF; (c) NH OCNHNH -HCl, HCl; (d) Fe, NH Cl, aq. EtOH;
2
Br, K
2
CO
3
, methyl ethyl ketone; (b) DMF dimethyl acetal,
2
2
4
(
e) Pd/C, H
2
; (f ) ClCH
2
CONEt
2 2 3
, KI, K CO , acetone.
[
8]
[10]
oxy group with Raney nickel,
titanium(III) chloride
Raney nickel/hydrazine,
has beenreported, reductionof 7 with these
and
[12]
reagents has not been examined. On the other hand, the reductive cycli-
zationof 7 to the indole ring using hydrogen with palladium on carbon as
a catalyst directly gave 2 in81% yield. As 2 was relatively instable, the
preparationof N,N-diethyl-7-indolyloxyacetamide (1) was performed
from 7 without isolationof 2; hydrogenation of 7 over palladium on
carbon, followed by reaction of the resulting 2 with 2-chloro-N,N-diethyl-
acetamide gave 1 in 87% yield. In a similar manner, 1 was obtained from
the isolated 2 in89% yield (Sch. 2).
In conclusion, N,N-diethyl-7-indolyloxyacetamide (1), ani nt ermedi-
ate inthe preparationof AJ-9677, was prepared from the pivotal i nt er-
mediate phenylacetaldehyde semicarbazone 7, which was inturnobtained
from the commercially available 2-nitro-3-hydoxytoluene (4), via 7-hydro-
xyindole (2). This synthetic route could be dispensed from chromato-
graphic purification and required neither low temperature nor expensive
reagents. These advantages, therefore, make this synthetic route of 1 prac-
tical to be operated onani nd ustrial scale.

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N,N-Diethyl-7-indolyloxyacetamide
EXPERIMENTAL SECTION
511
All melting points were determined on a Yanagimoto micromelting
point apparatus without correction. IR spectra were recorded on a
Shimadzu FTIR-8200PC spectrometer with KBr disks unless otherwise
stated. Atmospheric pressure chemical ionization mass spectra were
1
obtained on a Hitachi M-1000 spectrometer. H NMR spectra were
recorded ona VarianGemi ni -200 (200 MHz) or a JEOL JNM-LA 300
(
300 MHz) spectrometer using dilute solution in CDCl unless otherwise
3
stated. Chemical shifts are expressed as ꢀ (ppm) values from tetramethyl-
silane as an internal standard. The solvents were evaporated under reduced
pressure.
3-Benzyloxy-2-nitrophenylacetaldehyde Semicarbazone (7)
(1) A mixture of 3-hydroxy-2-nitrotoluene (4, 30.6 g, 0.20 mol),
K CO (27.6 g, 0.20 mol), benzyl bromide (34.2 g, 0.20 mol), and methyl
2
3
ethyl ketone (300 mL) was heated to reflux for 4 h and cooled to room
temperature. The reactionmixture was washed successively with water,
aqueous NaOH, water, and brine and dried over anhydrous MgSO . The
4
solvent was evaporated to give ca. 49 g of 3-benzyloxy-2-nitrotoluene (5)
as a pale yellow oil, which was used inthe ne xt step without further
1
purification. H NMR: 2.38 (3H, s), 5.15 (2H, s, CH Ph), 6.81–6.91
2
þ
(
2H, m), 7.20–7.39 (6H, m). MS; m/z, 244 (MH ).
(
2) A solutionof 5 (9.7 g, 40 mmol), pyrrolidine (6.6 mL, 80 mmol),
and DMF dimethyl acetal (10.6 mL, 80 mmol) in DMF (30 mL) was
heated to reflux for 5 h inargonatmosphere (the color of the reaction
mixture gradually changed from yellow to red). After the TLC indicated
that almost no starting material 5 remained, the reaction mixture was
ꢁ
cooled to ca. 5 C. The solution containing (E)-3-benzyloxy-2-nitro-b-
pyrrolidinostyrene (6) was diluted with diisopropyl ether (30 mL). A
small amount of the authentic crystalline 7 was seeded, and a solution
of semicarbazide hydrochloride (5.4 g, 48 mmol) in2N aqueous HCl
(
60 mL) was added in a one portion under ice-cooling (the inner
ꢁ
ꢁ
temperature raised from 7 C to 35 C, and the fine precipitates were
deposited). A mixture of water (10 mL) and diisopropyl ether (10 mL)
was added to the resulting unstirred reaction mixture, and the whole was
stirred at room temperature for 10 min. The precipitates were collected by
filtration, washed with water and diisopropyl ether, and dried to give
ꢁ
1
9
.8 g (74%) of 7 as a pale yellow solid, m.p. 184–185 C. H NMR

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5
12
Harada, Fujii, and Kato
(
(
(
DMSO-d ): 3.46 (2H, d, J ¼ 6 Hz, ArCH ), 5.27 (2H, s, OCH ), 6.15
6
2
2
2H, s, NH ), 7.01 (1H, d, J ¼ 8 Hz), 7.16 (1H, t, J ¼ 6 Hz), 7.27–7.43
2
6H, m), 7.51 (1H, t, J ¼ 8 Hz), 9.98 (1H, s, NH). Anal. calcd. for
C H N O : C, 58.53; H, 4.92; N, 17.06. Found: C, 58.82; H, 4.99;
4
N, 16.76. MS; m/z, 329 (MH ). IR cm : 3460, 1699, 1529, 1367.
1
6
16
4
þ
ꢀ1
7-Benzyloxyindole (3)
To a mixture of ammonium chloride (1.1 g, 21 mmol), Fe (2.2 g,
9 mmol), water (20 mL), and EtOH (40 mL) was added portionwise 7
3.3 g, 10 mmol) at room temperature. The mixture was heated to reflux
3
(
for 1 h, after which it became homogeneous and then cooled to room
temperature. The insoluble materials precipitated were filtrated through
Celeit and washed with toluene. The filtrate was concentrated, diluted
with water, and extracted with toluene. The extract was washed succes-
sively with 10% aqueous HCl, water, and brine. To the organic solution
was added activated charcoal and anhydrous Na CO , and the whole was
2
3
filtered off. The filtrate was concentrated to a volume of toluene of ca.
3
7
mL. After additionof hexa ne (ca. 6 mL), the filtrate was seeded with
-benzyloxyindole (3) and left to stand at ambient temperature. The
resulting precipitates were collected by filtration, washed with hexane,
ꢁ
and dried to give 1.7 g (76%) of 3 as a pale browncrystal, m.p. 73 C
(
[4]
ꢁ
toluene/hexane) [lit. 67–68 C]. H NMR: 5.20 (2H, s, OCH ), 6.54 (1H,
2
1
t, J ¼ 3 Hz, indole 3-H), 6.71 (1H, d, J ¼ 7 Hz, indole 6-H), 7.02 (1H, t,
J ¼ 7 Hz, indole 5-H), 7.16 (1H, t, J ¼ 3 Hz, indole 2-H), 7.27 (1H, d,
J ¼ 7 Hz, indole 4-H), 7.32–7.52 (5H, m), 8.40 (1H, s, NH). Anal.
calcd. for C H NO: C, 80.69; H, 5.87; N, 6.27. Found: C, 80.75;
1
5
13
þ
ꢀ1
H, 6.03; N, 6.21. MS; m/z, 224 (MH ). IR cm : 3373, 1577, 1255,
072.
1
7-Hydroxyindole (2)
(1) Compound 3 (5.0 g, 22 mmol) was hydrogenated over 10% palla-
dium on carbon (0.5 g) in EtOH (50 mL) at ambient temperature under
atmospheric pressure to give 2.9 g (97%) of 2 as a pale purple crystal,
ꢁ
[4]
ꢁ
1
m.p. 95–96 C [lit. 100–100.5 C]. H NMR: 5.15 (1H, s, OH), 6.53 (1H,
t, J ¼ 3 Hz, indole 3-H), 6.55 (1H, d, J ¼ 8 Hz, indole 6-H), 6.94 (1H, t,
J ¼ 8 Hz, indole 5-H), 7.17 (1H, t, J ¼ 3 Hz, indole 2-H), 7.25 (1H, d,
ꢀ
1
J ¼ 8 Hz, indole 4-H), 8.38 (1H, s, NH). IR cm : 3423, 3408, 1580,

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N,N-Diethyl-7-indolyloxyacetamide
513
1
489, 1315, 1244. 7-Hydroxyindole (2) was seemed to be instable in the
solution.
2) A mixture of 7 (4.9 g, 15 mmol), 10% palladium oncarbon(0.4 g),
(
and EtOH (50 mL) was stirred under an atmosphere of hydrogen with an
2
initial pressure of 3.0 kg/cm at ambient temperature for 2 h. After
absorptionof the theoretical amou nt of hydroge n, the catalyst was fil-
tered off and washed with EtOH. The filtrate was concentrated below
ꢁ
40 C in order to prevent coloration, and the residue was dissolved in
CHCl (50 mL) and 10% aqueous citric acid (20 mL). The organic layer
3
was separated and dried over anhydrous MgSO . The solvent was eva-
4
ꢁ
porated to give 1.6 g (80%) of 2 as a pale purple crystal, m.p. 95–96 C.
1
The H NMR and IR spectra of the compound obtained were identical to
those of the sample described above.
N,N-Diethyl-7-indolyloxyacetamide (1)
(
1) A stirred mixture of 2 (13.3 g, 0.10 mol), potassium carbonate
16.6 g, 0.12mol), potassium iodide (1.7g, 10mmol), 2-chloro-N,N-diethyl-
acetamide (16.5 g, 0.11 mol), and acetone (100 mL) was heated to reflux for
h and cooled to room temperature. The insoluble materials were filtered
(
3
off, and the filtrate was concentrated to dryness. The residue was dissolved
inCHCl 3 (200 mL) and water (100 mL), and the organic layer was sepa-
rated and dried over anhydrous MgSO . The solvent was evaporated, and
4
the residue was triturated with diisopropyl ether to give 22.0 g (89%) of
ꢁ
1
as a colorless crystal m.p. 123–124 C (toluene). H NMR: 1.16, 1.21
1
(
6
6
each 3H, t, J ¼ 7 Hz), 3.35, 3.43 (each 2H, q, J ¼ 7 Hz), 4.80 (2H, s),
.53 (1H, t, J ¼ 3 Hz, indole 3-H), 6.69 (1H, d, J ¼ 7 Hz, indole 6-H),
.99 (1H, t, J ¼ 7 Hz, indole 5-H), 7.21 (1H, t, J ¼ 3 Hz, indole 2-H), 7.32
(
1H, d, J ¼ 7 Hz, indole 4-H), 9.44 (1H, s, NH). Anal. calcd. for
14 18 2 2 2
C H N O ꢂ1/4H O: C, 67.04; H, 7.43; N, 11.17. Found: C, 67.28; H,
þ
ꢀ1
7
.26; N, 11.26. MS; m/z, 247 (MH ). IR cm : 3252, 1626, 1587, 1265, 1094.
(
2) Compound 7 (4.9 g, 15 mmol) was reduced catalytically over 10%
palladium oncarbon(0.4 g) inEtOH (50 mL) at ambie nt temperature
under medium pressure. After no further change of hydrogen was
observed, the catalyst was filtered off. The filtrate was concentrated to
dryness, and acetone (20 mL) was added to the oily residue containing the
ꢁ
solid. The mixture was cooled to ca. 5 C, and the solid was filtered off
and washed with acetone (10 mL). After addition of potassium carbonate
(2.5 g, 18 mmol), potassium iodide (0.2 g, 1.2 mmol), and 2-chloro-N,N-
diethylacetamide (2.7 g, 18 mmol) to the combined filtrate containing 2,

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Harada, Fujii, and Kato
the mixture was heated to reflux for 3 h and cooled to room temperature.
The insoluble materials were filtered off, and the filtrate was concentrated
to dryness. Water (100 mL) was added to the residue, and the resulting
mixture was stirred. The solid was collected by filtration, washed with
1
diisopropyl ether, and dried to 3.2 g (87%) of 1. The H NMR and IR
spectra of the compound obtained were identical to those of the sample
described above.
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3
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Tetrahedron 1998, 54, 45.
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0. Repke, D.B.; Ferguson, W.J. J. Heterocyclic Chem. 1982, 19, 845.
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Received inthe USA February 21, 2002