PTC-promoted Japp-Klingmann reaction for the synthesis of indole derivatives

Article abstract of DOI:10.1081/SCC-200057274

Indole derivatives have been efficiently synthesized from ethyl 2-phenylhy-drazono-5-phthalimido-pentanoate and its derivatives, which were obtained by Japp-Klingmann reaction under phase-transfer catalytic (PTC) conditions. Several different phase-transf

Full text of DOI:10.1081/SCC-200057274

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PTC‐Promoted Japp–Klingmann
Reaction for the Synthesis of
Indole Derivatives
Wei He a , Bang‐Le Zhang a , Zhong‐Jie Li b &
Sheng‐Yong Zhang a
a Department of Chemistry, Fourth Military Medical
University, Xi'an, Shaanxi, China
b Department of Chemistry, Northwest University,
Xi'an, Shaanxi, China
Version of record first published: 16 Aug 2006.
To cite this article: Wei He, Bang‐Le Zhang, Zhong‐Jie Li & Sheng‐Yong Zhang (2005):
PTC‐Promoted Japp–Klingmann Reaction for the Synthesis of Indole Derivatives,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 35:10, 1359-1368
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Synthetic Communicationsw, 35: 1359–1368, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200057274
PTC-Promoted Japp–Klingmann Reaction
for the Synthesis of Indole Derivatives
Wei He and Bang-Le Zhang
Department of Chemistry, Fourth Military Medical University, Xi’an,
Shaanxi, China
Zhong-Jie Li
Department of Chemistry, Northwest University, Xi’an, Shaanxi, China
Sheng-Yong Zhang
Department of Chemistry, Fourth Military Medical University, Xi’an,
Shaanxi, China
Abstract: Indole derivatives have been efficiently synthesized from ethyl 2-phenylhy-
drazono-5-phthalimido-pentanoate and its derivatives, which were obtained by Japp–
Klingmann reaction under phase-transfer catalytic (PTC) conditions. Several different
phase-transfer catalysts were investigated and dimethyldioctadecyl ammonium
chloride (DMDOA) was found to promote this reaction efficiently. Using DMDOA
as the PTC, aryl hydrazones were obtained in yields of 90%. The pure aryl hydrazones
were then efficiently cyclized to indole derivatives in yields of more than 80%.
Keywords: Aryl hydrazones, Fischer indolization, Japp–Klingmann reaction, phase-
transfer catalysts
INTRODUCTION
Indole is an important structural element in peptides and antibiotics as well as
in indole alkaloids, which are frequently found in various classes of pharma-
cologically active compounds. Replacement of the indole by other
heterocycles is often accompanied by loss of the desired biological
Received in Japan November 30, 2004
Address correspondence to Sheng-Yong Zhang, Department of Chemistry,
Fourth Military Medical University, Xi’an, Shaanxi, 710032, China. Tel.: þ86-29-
83376945; Fax: þ86-29-83253816; E-mail: syzhang@fmmu.edu.cn
1359

1360
W. He et al.
activity.[1] The important biological activity of indoles in natural products has
led to a continued strong interest in the practical synthesis of the indole
nucleus. Numerous indole syntheses have been described in the literature.[2]
Among the diverse and creative approaches that have been discovered, the
Fischer indole synthesis via Japp–Klingmann reaction plays an important
role as it provides a versatile and convergent route to a wide variety of
indole derivatives.[3] Despite being quite versatile, the Fischer indole
synthesis via Japp–Klingmann reaction often suffers from cumbersome
manipulations and low to moderate yields.[4]
Phase-transfer catalysis (PTC) is one of the most important and useful
methods in synthetic organic chemistry because of its preparative advantages,
such as simple reaction procedures, mild conditions, inexpensive and environ-
mentally friendly reagents, atom economy, and the ease in scaling the
reaction.[5] As a general technique for catalyzing reactions, PTC has been
quite successfully used in a wide range of reactions, such as SN2 type alky-
lations using C-, O-, S- and N-nucleophiles,[6] dehydrohalogenations,[7] oxi-
dations and epoxidations,[8] O-acylations,[9] etherification reactions,[10] aldol
condensations,[11] and isomerizations.[12] To the best of our knowledge, no
Japp–Klingmann reaction promoted by PTC has been reported previously.
In our pursuit of an efficient synthesis of melatonin,[13] we found that the
intermediate aryl hydrazone 4c could be easily obtained as a fine solid rather
than viscous oil in near quantitative yields when using a PTC in the reaction.
These results encouraged us to investigate the scope and effect of PTC in the
Japp–Klingmann reaction for Fischer indole synthesis. In this article, we
report systematically a convenient and practical synthesis of aryl hydrazones
and the corresponding indole derivatives in good to excellent yield under PTC
conditions.
RESULTS AND DISCUSSION
The indole derivatives could be prepared as indicated in Scheme 1. At first,
commercially available aryl amines 1 were diazotized and reacted under
alkaline conditions with ethyl 2-acetyl-5-phthalimidopentanote 3 using
PTC-promoted Japp–Klingmann reaction to form the ring-opened aryl hydra-
zones 4. These aryl hydrazones were then cyclized and converted into the
corresponding indole derivatives 5 by treatment with hydrochloric acid in
ethanol.
In previously reported Japp–klingmann reactions,[4] the solvents are
EtOH/H2O (10:1) and it is often difficult to separate pure aryl hydrazones.
Previous procedures required large volumes of CH2Cl2 or benzene[14] to
[4]
extract the product after the reaction mixture was diluted with a large
amount of water at the end of the reaction. Despite this, dark viscous
reaction products were obtained, which were difficult to purify. In our exper-
iment, the ratio of H2O to EtOH was increased to 1:1 and the phase-transfer

PTC-Promoted Japp–Klingmann Reaction
1361
Scheme 1. Synthesis of the indole derivatives.
catalysts were added to improve the reaction process. After considerable study
of the effect of PTC, it was discovered that addition of a suitable PTC to the
reaction could significantly improve the reaction profile, producing pure crys-
talline aryl hydrazones 4 rather than viscous oils in near quantitative yields.
The effect of PTC is shown in Table 1. Of the PTCs investigated, quaternary
ammonium salts were found to be superior to polyethylene glycol in this
reaction, and the long chain quaternary ammonium salts were superior to
the short ones. Dimethyldioctadecyl ammonium chloride (DMDOA) was
optimal, affording aryl hydrazones 4c as pure product in 98% yield by
simple filtration process.
Table 1. Japp–Klingmann reaction under different phase-transfer catalysts
Aryl hydrazones 4c
(R ¼ p-OCH3)
Yield
(%)
Mp of crude
product
PTC
no PTC
PEG 400
PEG 1000
PEG 6000
TEBA
Dark red oil
—
82
86
87
90
96
93
99
—
Dark red oil and semisolid
Dark red oil and semisolid
Semisolid
,658C
,658C
,658C
,708C
74–768C
73–768C
76–778C
Semisolid
Dark solid
TMHA
TBAB
DMDOA
Dark solid
Light yellow crystal
PEG: polyethylene glycol; TEBA: triethyl benzyl ammonium chloride; TMHA:
trimethylhexadecyl ammonium bromine; TBAB: tetrabutylammonium bromide;
DMDOA: dimethyldioctadecyl ammonium chloride.

1362
W. He et al.
To expand the scope of the methodology, the reaction of aryl diazonium
salts with other substituent groups were investigated. The generality of the
process using DMDOA as PTC in the Japp–Klingmann reaction was demon-
strated with a wide variety of aryl amines bearing ortho, meta, and para sub-
stituents. The results are shown in Table 2. Interestingly, aryl hydrazones
bearing either electron-withdrawing or electron-donating substituent groups
can be prepared from corresponding aryl amines and easily be isolated in
excellent yields as fine solids, which then led to the efficient formation of sub-
stituted indoles. Here we should mentioned that the reaction mixture of 4f
should be kept overnight to get a crystalline product, whereas in other
cases, the fine solid products can be derived directly from the reaction
mixture. The aryl hydrazones 4a–h and indole derivatives 5a–h are known
compounds, although some have only been partially characterized. Here
we fully characterize all the hydrazones and indoles by melting point, IR,
1H NMR, and elemental analysis. Compounds 4j and 5j are new
compounds, which were also fully characterized.
Analogues of the aryl hydrazone 4 in Ishii et al.’s paper[15] have Z,E-
isomers via Japp–Klingmann reaction and the ratio of two isomers is about
1:1. In our case, each substance we used only got a single product via
Japp–Klingmann reaction because there was only one spot on thin-layer
chromatography (TLC). The geometrical structure of the aryl hydrazone 4
should be Z-isomer, established by the infrared spectrum (IR) and the
nuclear magnetic resonance spectrum (1H NMR).
In conclusion, a general, efficient method for the synthesis of indole
derivatives through PTC-promoted Japp–Klingmann reaction has been
demonstrated. The procedure is general with respect to both the electron-
withdrawing and electron-donating substituted aryl amines and the method
is superior to other previously reported methods with regard to its simplicity
Table 2. Fischer indole synthesis via Japp–Klingmann reaction promoted by
DMDOA
Yield
(%)
Yield
(%)
Entry
Substrate (R¼)
Aryl hydrazone 4
Indole 5
1
2
H
4a
4b
4c
4d
4e
4f
97
98
98
98
94
99
95
99
99
98
5a[4a]
5b[4a]
5c[4c]
5d[14]
5e[4e]
5f[4a]
5g[4f]
5h[4a]
5i
82
87
86
88
85
83
80
85
83
86
p-CH3
p-OCH3
p-OCH2Ph
m-OCH2Ph
p-NO2
o-NO2
p-Cl
3
4
5
6
7
4g
4h
4i
8
9
10
p-Br
p-COCH3
4j
5j

PTC-Promoted Japp–Klingmann Reaction
1363
and efficiency, and avoidance of toxic solvents and complicated work up
procedures. It is therefore an environmentally friendly methodology
amenable for scaling.
EXPERIMENTAL
Melting points were measured on a XRC-1 melting apparatus and are uncor-
rected. Infrared spectra were recorded with KBr disks on a PE-938G
Spectrometer. NMR spectra were recorded on a Varian INOVA 400 MHz
spectrometer in CDCl3 solutions and tetramethylsilane was used as the
internal standard (d1/4 0 ppm). Element analyses were obtained using a
Foss-Heraeus Vario EL instrument.
Ethyl 2-acetyl-5-phthalimidopentanote 3 was synthesized using phase-
transfer catalysis as we have previously reported.[13] All other solvents and
chemicals were obtained from commercial sources and were used without
further purification unless otherwise stated.
Typical Procedure
Preparation of Aryl Diazonium Salts 2
The substituted aryl amine 1 (0.01 mol) was added to a mixture of water
(6 mL) and ethanol (4 mL). A solution of NaNO2 (0.69 g, 0.01 mol) in concen-
trated HCl (37%, 2 mL, 0.05 mol) was added dropwise to the mixture and
temperature was maintained at 0–58C for 0.5 h. This produced the solution
of aryl diazonium salts 2.
Preparation of 2-Phenylhydrazono-5-Phthalimido-Pentanoic Acid Ethyl
Ester and Its Derivatives 4a–j
Ethyl 2-acetyl-5-phthalimidopentanote 3 (3.17 g, 0.01 mol) was dissolved in
ethanol (20 mL). The phase-transfer catalysts (0.05 g) were added to the
.
solution. A solution of NaOAc 3H2O (6.24 g, 0.048 mol) in water (20 mL)
was added and the mixture was cooled down to 08C. The aforementioned
alcohol–water solution of aryl diazonium salts 2 was added to the mixture
and stirred at a temperature of 08C for 1 h. The temperature was then
gradually raised to 258C and the reaction mixture was stirred for 3 h. The
resulting solid was filtered and then washed with a small amount of ethanol
to yield pure yellow crystals of compounds 4a–j.
4a (R¼H): yield 97%; mp 67.5–68.58C; IR (KBr) n (cm21): 3470
(m, N–H); 1770, 1710 (s, C55O); 1605 (w, C55N); 1H NMR d: 12.06
(s, 1H, N–H); 8.20–7.80 (m, 4H, Ar–H); 7.30–7.13 (m, 5H, Ar0 –H); 4.30
(q, 2H, CH3CꢀH2O–); 3.80 (t, 2H, –NCꢀH2CH2CH2–); 2.61 (t, 2H,

1364
W. He et al.
–N55C–CꢀH2CH2–); 2.04 (m, 2H, –CH2CꢀH2CH2–); 1.22 (t, 3H,
–OCH2CꢀH3); Anal. calcd. for C21H21N3O4: C, 66.48; H, 5.58; N, 11.08.
Found C, 66.51; H, 5.60; N, 11.11.
4b (p-CH3): yield 98%; mp 91.0–92.08C; IR (KBr) n (cm21): 3465
1
(m, N–H); 1769, 1745, 1711 (s, C55O); 1604(w, –C55N–); H NMRd:
7.89–7.69 (m, 4H, Ar–H); 7.20–7.45 (m, 4H, Ar0 –H); 4.21 (q, 2H,
CH3CꢀH2O–); 3.57 (t, 2H, –NCꢀH2CH2CH2–); 2.08 (t, 2H,
–N55C–CꢀH2CH2CH2–); 1.79 (m, 2H, –CH2CꢀH2CH2–); 1.29 (t, 3H,
–OCH2CꢀH3); Anal. calcd. for C22H23N3O4: C, 67.16; H, 5.89; N, 10.68.
Found C, 67.21; H, 5.90; N, 10.63.
4c (p-OCH3): yield 98%; mp 76.0–77.08C; IR (KBr) n (cm21): 3463
(m, N–H); 1769, 1745, 1711 (s, C55O); 1604 (w, –C55N–); 1H
NMR d: 7.83–7.63 (m, 4H, Ar–H); 7.09 (m, 4H, Ar0 –H); 4.16 (q, 2H,
CH3CꢀH2O–); 3.82 (s, 3H, –OCH3); 3.57 (t, 2H, –NCꢀH2CH2CH2–); 2.08
(t, 2H, –N55C–CꢀH2CH2CH2–); 1.27 (m, 2H, –CH2CꢀH2CH2–); 1.10
(t, 3H, –OCH2CꢀH3); Anal. calcd. for C22H23N3O5: C, 64.54; H, 5.66;
N, 10.26. Found C, 64.51; H, 5.64; N, 10.21.
4d (R¼p-OCH2Ph): yield 98%; mp 86.0–87.08C; IR (KBr) n (cm21):
1
3463 (m, N–H); 1769, 1745, 1711 (s, C55O); 1604 (w, –C55N–); H NMR
d: 12.04 (s, 1H, N–H); 7.82–7.68 (m, 4H, Ar–H); 7.50–7.11 (m, 9H,
Ar0 –H); 5.00 (s, 2H, phCH2O); 4.43 (q, 2H, CH3CꢀH2O–); 4.01
(t, 2H, –NCꢀH2CH2CH2–); 3.44 (t, 2H, –NCH2CH2CH2ꢀ –); 1.57 (m, 2H,
–CH2CꢀH2CH2–); 1.43 (t, 3H, –OCH2CꢀH3); Anal. calcd. for
C28H27N3O5: C, 68.26; H, 5.61; N, 8.65. Found C, 68.21; H, 5.67; N, 8.61.
4e (R¼m-OCH2Ph): yield 94%; mp 135.0–136.08C; n (cm21): 3451
(m, N–H); 1769, 1745, 1711 (s, C55O); 1610 (w, –C55N–); 1H NMR
d:11.35 (s, 1H, N–H); 7.78–7.68 (m, 4H, Ar–H); 7.50–7.01 (m, 9H,
Ar0 –H); 5.11 (s, 2H, phCH2O); 4.37(q, 2H, CH3CꢀH2O–); 3.95
(t, 2H, –NCꢀH2CH2CH2–); 3.38 (t, 2H, –NCH2CH2CH2ꢀ –); 1.61 (m, 2H,
–CH2CꢀH2CH2–); 1.32 (t, 3H, –OCH2CꢀH3); Anal. calcd. for
C28H27N3O5: C, 68.26; H, 5.61; N, 8.65. Found C, 68.23; H, 5.57; N, 8.71.
4f (R ¼ p-NO2): yield 99%; mp 176.0–177.08C; IR (KBr) n: 3442
1
(m, N–H); 1768, 1750, 1700 (s, C55O); 1604 (w, –C55N–); H NMR d:
8.20–7.80 (m, 4H, Ar–H); 7.65–7.20 (m, 4H, Ar0 –H); 4.2 (q,
2H, CH3CꢀH2O–); 3.8 (t, 2H, –NCꢀH2CH2CH2–); 2.08 (t, 2H,
–N55C–CꢀH2CH2CH2-); 1.6 (m, 2H, –CH2CꢀH2CH2–); 1.32 (t, 3H,
–OCH2CꢀH3); Anal. calcd. for C21H20N4O6: C, 59.43; H, 4.75; N, 13.20.
Found C, 59.40; H, 4.70; N, 13.21.
4g (R ¼ o-NO2): yield 95%; mp: 106–1078C; IR (KBr) n: 3442
1
(m, N–H); 1768, 1750, 1700 (s, C55O); 1604 (w, –C55N–); H NMR d:
11.19 (s, 1H, N–H); 7.8–7.72 (m, 4H, Ar–H); 7.68–7.30 (m, 4H, Ar0 –H);
4.26 (q, 2H, CH3CꢀH2O–); 3.72 (t, 2H, –NCꢀH2CH2CH2–); 2.28 (t, 2H,
–N55C–CꢀH2CH2CH2–); 1.87 (m, 2H, –CH2CꢀH2CH2–); 1.28 (t, 3H,
–OCH2CꢀH3); Anal. calcd. for C21H20N4O6:C, 59.43; H, 4.75; N, 13.20.
Found C, 59.39; H, 4.77; N, 13.17.

PTC-Promoted Japp–Klingmann Reaction
1365
4h (R ¼ p -Cl):yield 99%; mp 147.0–148.08C; IR (KBr) n (cm21): 3452
1
(m, N–H); 1747, 1710 (s, C55O); 1604 (w, C55N); H NMR d: 8.00–7.8
(m, 4H, Ar–H); 7.66–7.20 (m, 4H, Ar0 –H); 4.2 (q, 2H, CH3CꢀH2O–); 3.70
(t, 2H, –NCꢀH2CH2CH2–); 2.2 (t, 2H, –N55C–CꢀH2CH2–); 1.8 (m, 2H,
–CH2CꢀH2CH2–); 1.25 (t, 3H, –OCH2CꢀH3); Anal. calcd. for
C21H20ClN3O4:C, 60.95; H, 4.87; N, 10.15. Found C, 60.91; H, 4.90; N, 10.12.
4i (R ¼ p-Br): yield 99%; mp 90.0–91.08C; IR (KBr)n(cm21): 3457
1
(m, N–H); 1751, 1710 (s, C55O); 1604 (w, –C55N–); H NMRd:12.06
(s, 1H, N–H); 7.81–7.70 (m, 4H, Ar–H); 7.61–7.50 (m, 4H, Ar0 –H); 4.26
(q, 2H, CH3CꢀH2O–); 3.67 (t, 2H, –NCꢀH2CH2CH2–); 2.26 (t, 2H,
–N55C–CꢀH2CH2–); 1.80 (m, 2H, –CH2CꢀH2CH2–); 1.26 (t, 3H,
–OCH2CꢀH3); Anal. calcd. for C21H20BrN3O4: C, 55.03; H, 4.40; N, 9.17.
Found C, 55.01; H, 4.40; N, 9.12.
4j (R ¼ p -COCH3): yield 98%; mp 101.0–102.08C; IR (KBr) n (cm21):
3463 (m, N–H); 1769, 1745, 1711 (s, C55O); 1604 (w, –C55N–);
1H NMR d: 12.23 (s, 1H, N–H); 8.08–7.71 (m, 4H, Ar–H); 7.82–7.70
(m, 4H, Ar0 –H); 4. 27 (q, 2H, CH3CꢀH2O–); 3.69 (t, 2H, –NCꢀH2CH2CH2–);
2.66 (s, 3H, CH3CO); 2.21 (t, 2H, –N55C–CꢀH2CH2CH2–); 1.80 (m, 2H,
–CH2CꢀH2CH2–); 1.27 (t, 3H, –OCH2CꢀH3); Anal. calcd. for C23H23N3O5:
C, 65.55; H, 5.50; N, 9.97. Found C, 65.51; H, 5.47; N, 10.01.
Preparation of Ethyl 3-(2-phthalimidoethyl) Indole-2-carboxylate and
its Derivatives 5a–i
Aryl hydrazone 4 (0.01 mol) was placed in a three-necked flask. A solution of
10% HCl-EtOH (24 mL) was added dropwise over a period of 0.5 h. The
solution was then heated at reflux for a period of 2 h, accompanied with
stirring throughout the whole process. After cooling, the solution was
filtered under reduced pressure. The solid residue was washed with
methanol, water, and methanol and then dried, producing the light yellow
solids 5a–i.
5a (R¼H): yield 82%; mp 190.0–191.08C; IR (KBr) n (cm21): 3500
1
(m, nN–H); 2941 (w, nC–H); 1772, 1740, 1722 (s, nC55O); H NMR d: 8.89
(s, N–H); 7.90–7.70 (m, 4H, Ar–H); 7.30–6.80 (m, 4H, Ar–H); 4.21
ꢀ
(q, 2H, –OꢀCH2CH3); 3.87 (t, 2H,ꢀ –CH2 CH2N–); 2.16 (t, 2H, –ꢀCH2
CH2CH2N–); 1.30 (t, 3H, –OCH2 CH3). Anal. calcd. for C21H18N2O4:
C, 69.60; H, 5.01; N, 7.73. Found C, 69.61; H, 5.00; N, 7.75.
5b (R¼5-CH3): yield 87%; mp 223.0–224.08; IR (KBr) n (cm21): IR:
3330 (NH), 1775, 1715, 1690 (s, nC55O); 1H NMR d: 8.73 (s, N–H);
7.98–7.66 (m, 4H, Ar–H); 7.20–6.45 (m, 3H, Ar–H); 4.40 (q, 2H,
ꢀ
–OꢀCH2CH3); 4.00 (t, 2H, –CH2 CH2N–); 3.43 (t, 2H, –ꢀCH2CH2N–);
ꢀ
2.33 (s, 3H, Ar–CH3); 1.46 (t, 3H, –OCH2 CH3). Anal. calcd. for
C22H20N2O4: C, 70.20; H, 5.36; N, 7.44. Found C, 70.28; H, 5.40; N, 7.39.
5c (R¼5-OCH3): yield 86%; mp 238.0–240.08C; IR (KBr)n(cm21): IR:
3330 (NH), 1775, 1715, 1690 (s, nC55O); 1H NMR d:10.1 (s, N–H); 8.10–7.70

1366
W. He et al.
(m, 3H, Ar–H);ꢀ7.20–6.80 (m, 4H, Ar–H); 4.20 (q, 2H, –OꢀCH2CH3); 3.90
(t, 2H,ꢀ –CH2 CH2N–); 3.20 (t, 2H, –ꢀCH2CH2N–); 1.30 (t, 3H,
–OCH2 CH3). Anal. calcd. for C22H20N2O5: C, 67.34; H, 5.14; N, 7.14.
Found C, 67.31; H, 5.16; N, 7.17.
5d (R¼5-OCH2Ph): yield 88%; mp 188.0–190.08C; IR (KBr) n (cm21):
3330 (NH), 1775, 1715, 1690 (s, n C55O); 1H NMR d: 8.07 (s, N–H);
7.80–7.68 (m, 4H, Ar–H); 7.55–7.02 (m, 8H, Ar–H); 5.03 (s, 2H,
ꢀ
PhCH2O); 4.26 (q, 2H, –OꢀCH2CH3); 3.78 (t, 2H, –CH2 CH2N–); 2.59
(t, 2H, –ꢀCH2CH2N–); 1.32 (t, 3H, –OCH2 CH3). Anal. calcd. for
ꢀ
C28H24N2O5: C, 71.78; H, 5.16; N, 5.98. Found C, 71.76; H, 5.14; N,
5.89.
5e (R¼6-OCH2Ph): yield 85%; mp 199–2018C; IR (KBr) n (cm21): 3330
1
(NH), 1780, 1720, 1680 (s, nC55O); H NMR d: 8.90 (s, N–H); 7.79–7.68
(m, 4H, Ar–H); 7.47–7.12 (m, 8H, Ar–H); 5.10 (s, 2H, PhCH2O); 4.18
ꢀ
(q, 2H, –OꢀCH2CH3); 3.84 (t, 2H, –CH2 CH2N–); 2.79 (t, 2H,
ꢀ
–ꢀCH2CH2N–); 1.28 (t, 3H, –OCH2 CH3). Anal. calcd. for C28H24N2O5:
C, 71.78; H, 5.16; N, 5.98. Found C, 71.80; H, 5.14; N, 5.90.
5f (R¼5-NO2): yield 83%; mp 316.0–317.08C; IR (KBr) n (cm21): 3330
1
(NH), 1775, 1715, 1690 (s, nC55O); H NMR d: 12.3 (s, N–H); 8.53–7.14
(m, 3H, Ar–H); 8.1–7.7 (m, 4H, Ar–H); 4.23 (q, 2H, –OꢀCH2CH3); 3.87
ꢀ
(t, 2H,ꢀ –CH2 CH2N–); 3.36 (t, 2H, –ꢀCH2CH2N–); 1.35 (t, 3H,
–OCH2 CH3). Anal. calcd. for C21H17N3O6: C, 61.91; H, 4.21; N, 10.31.
Found C, 61.89; H, 4.22; N, 10.30.
5g (R¼7-NO2): yield 80%; mp 194–1958C; IR (KBr) n (cm21): IR: 3330
1
(NH), 1775, 1715, 1690 (s, nC55O); H NMR d: 13.83 (s, N–H); 7.80–7.68
(m, 4H, Ar–H); 8.03–7.62 (m, 3H, Ar–H); 4.37 (q, 2H, –OꢀCH2CH3);
ꢀ
3.85 (t,ꢀ 2H, –CH2 CH2N–); 2.71 (t, 2H, –ꢀCH2CH2N–); 1.38 (t, 3H,
–OCH2 CH3). Anal. calcd. for C21H17N3O6:C, 61.91; H, 4.21; N, 10.31.
Found C, 61.86; H, 4.27; N, 10.26.
5h (R¼5–Cl); yield 85%; mp 265.0–266.08C; IR (KBr) n (cm21): 3330
(NH2); 1760, 1700, 1675 (CO). 1H NMR d: 8.90 (s, N–H); 7.90–7.70 (m, 4H,
Ar–Hꢀ); 7.61–6.80 (m, 3H, Ar–H); 4.21 (q, 2H, –OꢀCH2CH3); 3.85 ꢀ(t, 2H,
–CH2 CH2N–); 3.30 (t, 2H, –ꢀCH2CH2N–); 1.30 (3t, 3H, –OCH2 CH3).
Anal. calcd. for C21H17ClN2O4: C, 63.56; H, 4.32; N, 7.06. Found C, 63.57;
H, 4.35; N, 7.08.
5i (R¼5-Br); yield 83%; mp 229.0–230.08C; IR (KBr) n (cm21): 3330
(NH); 1765, 1710, 1670 (CO). 1H NMR d: 8.82 (s, N–H); 7.87–7.70
(m, 4H, Ar–H); 7.30–6.93 (m, 3H, Ar–H); 4.26 (q, 2H, –OꢀCH2CH3);
ꢀ
3.80 (t,ꢀ 2H, –CH2 CH2N–); 2.61 (t, 2H, –ꢀCH2CH2N–); 1.32 (t, 3H,
–OCH2 CH3). Anal. calcd. for C21H17BrN2O4: C, 57.16; H, 3.88; N, 6.35.
Found C, 57.2; H, 3.92; N, 6.30.
5j (R¼5-COCH3): yield 86%; mp 184.0–185.08C; IR (KBr) n (cm21):
1
IR: 3330 (NH), 1775, 1715, 1690 (s, nC55O); H NMR d: 9.01 (s, N–H);
7.93–7.82 (m, 4H, Ar–H); 7.95–7.69 (m, 3H, Ar–H); 4.29 (q, 2H,
ꢀ
–OꢀCH2CH3); 4.04 (t, 2H, –CH2 CH2N–); 3.53 (t, 2H, –ꢀCH2CH2N–);

PTC-Promoted Japp–Klingmann Reaction
1367
ꢀ
2.56 (s, 3H, CH3CO); 1.25 (t, 3H, –OCH2 CH3). Anal. calcd. for C23H20N2O5: C,
68.31; H, 4.98; N, 6.93. Found C, 68.28; H, 4.94; N, 6.89.
ACKNOWLEDGMENT
The authors gratefully acknowledge Robert W. Baker of University of Sydney
for his valuable advice and encouraging discussions on this manuscript.
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