Synthesis of indoxylic acid esters by rhodium-catalyzed carbene n-h insertion and thermal cyclization

Article abstract of DOI:10.1071/CH14116

Reaction between diethyl diazomalonate and a range of N-alkylanilines in the presence of a catalytic amount of rhodium(ii) acetate dimer afforded carbene N-H insertion to produce anilinomalonates in modest-to-good yields. Upon heating to a high temperatur

Full text of DOI:10.1071/CH14116

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem. 2014, 67, 1211–1216
Full Paper
http://dx.doi.org/10.1071/CH14116
Synthesis of Indoxylic Acid Esters by Rhodium-catalyzed
Carbene N–H Insertion and Thermal Cyclization
A
A B
,
Mark A. Honey and Christopher J. Moody
A
School of Chemistry, University of Nottingham, University Park,
Nottingham NG7 2RD, UK.
B
Corresponding author. Email: c.j.moody@nottingham.ac.uk
Reaction between diethyl diazomalonate and a range of N-alkylanilines in the presence of a catalytic amount of rhodium(II)
acetate dimer afforded carbene N–H insertion to produce anilinomalonates in modest-to-good yields. Upon heating to a
high temperature for a short time, the anilinomalonates underwent thermal cyclization to indoxylic acid esters.
Manuscript received: 5 March 2014.
Manuscript accepted: 26 March 2014.
Published online: 8 May 2014.
Introduction
biochemistry and histochemistry for monitoring glycosidase
enzyme activity.[4,5] We now report a simple new route to
synthesizing indoxyl acid esters from anilines that employs
carbene N–H insertion as a key step.
3-Indolinones, also known as indoxyls, are air-sensitive deri-
vatives of indole. The parent indoxyl undergoes the well-known
oxidative dimerization to give the blue dye indigo, together with
the isomeric indorubicin as a by-product (Fig. 1).[1] Natural
indigo, obtained from the plants Indigofera tinctoria and Isatis
tinctoria, is formed via hydrolysis of indoxyl glycosides, such as
indicane, followed by oxidation.[2] Other indoxyls, including
adrenolutin, are metabolites of adrenaline,[3] whereas indoxyl
acid esters (that exist exclusively in the 3-hydroxyindole tau-
tomer) are pivotal intermediates in the synthesis of substituted
indoxyl glycosides, which are important reagents in
Results and Discussion
The most general route to indoxyl acid esters involves
the intermediacy of N-(2-carboxyphenyl)glycine derivatives,
obtained from the corresponding anthranilic acids (Scheme 1,
Route A).[4,5] Although this is a relatively straightforward route,
it can involve additional steps if the anthranilic acid is com-
mercially unavailable. In contrast, our route involves readily
accessible anilines as starting reagent, transforming into anili-
nomalonate derivatives, as outlined in Scheme 1, Route B. It was
expected that the required anilinomalonates would be produced
in a single-step method, involving carbene N–H insertion
reactions of the corresponding anilines.
Thermal reaction of aniline with a diazocarbonyl com-
pound, ethyl diazoacetate, was first described by Curtius over
100 years ago.[6] However, currently, the reaction is invariably
carried out in the presence of a metal catalyst, based on Yates
seminal report on copper-catalyzed decomposition of diazo-
acetophenone in the presence of aniline to give a-anilinoaceto-
phenone in 33 % yield.[7] The N–H insertion reaction between
anilines and diazocarbonyl compounds is now a standard reac-
tion of carbene and metal carbene intermediates,[8,9] and is
catalyzed by a range of transition metal complexes, including
copper,[10–13] rhodium,[14–17] rhenium,[18] and ruthenium.[19] In
our laboratory, we have used a rhodium-catalyzed carbene
insertion reaction in the N–H bond of N-alkylanilines as a key
step in a modified Bischler synthesis method for the preparation
of indoles.[20–23] In continuation to this study and studies
involving N–H insertion chemistry,[24–29] we now report the
application of N–H insertion reactions for the synthesis of
indoxyls.
indorubicin
The desired anilinomalonates were prepared by N–H inser-
tion of the rhodium carbene derived from diethyl diazomalonate
and a range of anilines 1 (Table 1). Two methods were used, both
Fig. 1. Derivatives of 3-indolinone (indoxyl).
Journal compilation Ó CSIRO 2014
www.publish.csiro.au/journals/ajc

1212
M. A. Honey and C. J. Moody
involving rhodium(II) acetate dimer as catalyst (2 mol-%),
and entailed either heating the reaction mixture to reflux in
toluene for 1.5–2.0 h or heating to 808C in dichloromethane in a
sealed tube in a focussed microwave reactor. This gave a range
of anilinomalonates 2 in modest-to-good yields (53–82 %)
(Table 1).
There are only three reports on the cyclization of anilinoma-
lonates to indoxyl acid esters, typically generating poor yields.
For example, heating diethyl anilinomalonate to 260–2658C
under water aspirator vacuum produced ethyl 3-hydroxyindole-
2-carboxylate in 40 % yield.[30] Likewise, an N-substituted
derivative of dimethyl anilinomalonate only cyclized in 17 %
yield upon heating,[31] although in the third report, in an
approach to adrenolutin derivatives, the key cyclization step
was reported to proceed in good yield upon brief heating
(10 min) in paraffin at 240–2458C.[3] To this effect, we focussed
on heating the anilinomalonates 2 to a relatively high tempera-
ture for a short time using microwave irradiation. A representa-
tive range of diethyl anilinomalonates 2, incorporating both
electron-donating and -withdrawing substituents, were heated in
a focussed microwave reactor to a temperature set at 2508C.
Although the cyclized product was sometimes isolated, yields
varied considerably. Upon analysis of the microwave absorption
trace for the duration of the reaction, it became evident that
the maximum temperature attained in each sample was incon-
sistent. In an attempt to overcome this problem, 0.5 mL of
solvent N-methylpyrrolidone was added and the reaction was
repeated, but with no improvement. Likewise, the addition of
acid catalysts, such as Amberlyst 15Ò and boron trifluoride
etherate, to the reaction mixture did not induce cyclization.
Because of the highly inconsistent results obtained under
microwave irradiation conditions, we reverted to traditional
heating. When the anilinomalonates were heated under vacuum
to 2658C for 15 min, the desired ethyl 3-hydroxyindole-2-
carboxylates were isolated (Table 1).
A
B
Scheme 1. Synthesis routes of indoxyl acid esters.
Table 1. Rhodium-catalyzed carbene N–H insertion reactions and thermal cyclization reactions
cat. RhII
toluene
reflux
265ЊC
under vacuum
15 min
Compounds 1/2
X
R
Yield of
Compounds 3
X
Yield of
compounds 2 [%]
compounds 3 [%]
a
b
c
d
e
f
2-Br
Me
68A
69
53
58
76
82
71
71
75
75
a
7-Br
35
2-MeO
3-Br
Me
Me
4-Br
Me
b
c
5-Br
77
74
43
55
4-Cl
Me
PMBB
5-Cl
4-Cl
d
e
5-Cl
g
h
i
4-MeO
4-Me
Me
5-MeO
Me
4-NO2
4-CO2Me
Me
j
Me
f
5-CO2Me
62
AReaction was carried out in dichloromethane at 808C in a microwave reactor (300 W, 20 min).
BPMB ¼ p-methoxybenzyl.

Indoxylic Acid Esters
1213
The reaction was compatible with a range of substituents
located at varying positions in the aromatic ring, and moderate-
to-good yields of 3-hydroxyindole esters were obtained. In an
attempt to achieve a one-pot synthesis of 3-hydroxyindoles,
4-chloro-N-methylaniline (1e), diethyl 2-diazomalonate, and
rhodium(II) acetate in toluene were heated to 1108C for 2 h.
The reaction mixture was then cooled to room temperature
and the solvent was removed. The residue was then heated to
2658C for 15 min under vacuum to produce 3-hydroxyindole
(3c) in 33 % yield. As the combined yield of 3c obtained via
two separate reactions was higher than that obtained via the
one-pot reaction (i.e. 56 % vs 33 %), the one-pot approach was
not pursued.
4-Chloro-N-(4-methoxyphenyl)methylaniline (1f)
To 4-chloroaniline (1.02 g, 8.00 mmol) and para-methoxy-
benzaldehyde (1.09 g, 8.00 mmol, 1 eq.) in tetrahydrofuran
(10 mL) was added glacial acetic acid (0.46 mL, 8.00 mmol,
1 eq.). The reaction mixture was sealed and heated to 658C for
1 h. The solution was then cooled to room temperature and
sodium borohydride (0.45 g, 12.00 mmol, 1.5 eq.) was added.
The reaction mixture was re-sealed and stirred at room tem-
perature for 48 h. The solution was neutralized with aqueous
sodium hydroxide and the organic material was extracted in
dichloromethane. The solvent was removed under reduced
pressure and the colourless solid was purified over a silica car-
tridge (100 g) using a solvent system of 0–100 % ethyl acetate in
cyclohexane over a period of 40 min. The title compound 1f was
isolated as a fluffy colourless solid (1.35 g, 68 %), mp 75–768C
(lit. 78–818C[33]). nmax (neat)/cmꢀ1 3410, 1595, 1495, 1476,
1401, 1308, 1246, 1173, 1028. dH (CDCl3, 400 MHz) 7.28 (2H,
d, J 8.8, ArH), 7.12 (2H, d, J 8.8, ArH), 6.89 (2H, d, J 8.8, ArH),
6.56 (2H, J 8.8, ArH), 4.24 (2H, d, J 4.2, CH2), 3.98 (1H, br s,
NH), 3.82 (3H, s, OMe). dC (CDCl3, 100 MHz) 158.9 (C), 146.7
(C), 130.9 (C), 129.0 (CH), 128.7 (CH), 122.0 (C), 114.1 (CH),
113.9 (CH), 55.3 (Me), 47.8 (CH2).
In conclusion, we have developed a simple, two-step route to
synthesizing indoxyl acid esters from anilines using rhodium-
catalyzed carbene N–H insertion followed by thermal cycliza-
tion of intermediate anilinomalonates.
Experimental
General Procedures
Commercially available reagents were used throughout without
purification unless otherwise stated. Light petroleum refers to
the fraction with bp 40–608C. Ether refers to diethyl ether.
Analytical thin layer chromatography was carried out on
aluminium-backed plates coated with silica gel, and visualized
under UV light at 254 and/or 360 nm. Column chromato-
graphy was carried out on silica gel cartridges (50 mm silica)
with a Jones Chromatography Flashmaster II automated
system. Fully characterized compounds are chromatographi-
cally homogeneous. Infrared spectra were recorded in the range
4000–600 cmꢀ1. NMR spectra were recorded on Bruker
instruments at 300, 400, and 500 MHz (1H frequencies) and
75, 100, and 125 MHz (13C frequencies). Chemical shifts are
reported in ppm and are referenced to residual H in the deuter-
ated solvent as the internal standard. In the 13C NMR spectra,
signals corresponding to CH, CH2, and CH3 groups were
assigned from the distortionless enhancement by polarization
transfer (DEPT) spectra. High- and low-resolution mass spectra
were recorded on a Bruker Microtof time-of-flight mass spec-
trometer. Microwave reactions were carried out in a CEM
DiscoverTM S-class (300 W) microwave reactor with an infrared
temperature sensor.
Diethyl 2-[N-(2-Bromophenyl)-N-methylamino]
propanedioate (2a)
To 2-bromo-N-methylaniline (223 mg, 1.20 mmol) and diethyl
diazopropanedioate (246 mg, 1.32 mmol, 1.1 eq.) in dichloro-
methane (4 mL) was added rhodium(II) acetate dimer (2 mol-%).
The reaction vessel was sealed and the reaction mixture heated
in a focussed microwave reactor (300 W) to 808C for 20 min.
The solution was allowed to cool to room temperature and the
solvent was removed under reduced pressure. The residue was
purified over silica using a solvent system of 15 % ethyl acetate
in light petroleum to give the title compound 2a as a colourless
oil (281 mg, 68 %). nmax (CHCl3)/cmꢀ1 2941, 1733, 1587, 1476,
1445, 1305, 1258, 1178, 1115, 1028. dH (CDCl3, 400 MHz) 7.57
(1H, dt, J 7.6, 0.9, ArH), 7.29–7.27 (2H, m, ArH), 6.95 (1H, ddd,
J 8.0, 5.8, 3.0, ArH), 4.84 (1H, s, CH(CO2Et)2), 4.31–4.25 (4H,
m, CH2CH3), 3.05 (3H, s, NMe), 1.32 (6H, t, J 7.1, CH2CH3). dC
(CDCl3,100 MHz) 167.5 (C), 149.3 (C), 133.8 (CH), 127.9
(CH), 124.9 (CH), 123.6 (CH), 119.1 (C), 68.6 (CH), 61.5
(CH2), 36.5 (Me), 14.2 (Me). Found: MþNaþ 366.0315.
C14H1879BrNO4þNaþ requires 366.0317.
Diethyl Diazopropanedioate
Diethyl 2-[N-(2-Methoxyphenyl)-N-methylamino]
propanedioate (2b)
To diethyl malonate (4.0 g, 25.0 mmol) in acetonitrile (200 mL)
at 08C was added 4-acetamidobenzenesulfonyl azide (7.2 g,
30.0 mmol). Triethylamine (7.0 mL, 49.9 mmol) was added
dropwise to the stirred reaction mixture. The reaction mixture
was allowed to warm to room temperature and stirred for 16 h.
The solvent was removed under reduced pressure and the
yellow–white residue was triturated with chloroform. The
solution was filtered and the filtrate was concentrated under
reduced pressure. The residue was purified over a silica car-
tridge (100 g) using a solvent system of 0–50 % ethyl acetate in
cyclohexane over a period of 20 min. The title compound was
isolated as a yellow oil (3.2 g, 70 %). nmax (neat)/cmꢀ1 2985,
2134, 1757, 1733, 1688, 1467, 1448, 1395, 1371, 1313, 1266,
1197, 1170, 1073, 1016. dH (CDCl3, 400 MHz) 4.31 (4H, q,
J 7.0, OCH2CH3), 1.32 (6H, t, J 7.2, OCH2CH3). dC (CDCl3,
100 MHz) 161.1 (C), 61.6 (CH2), 14.3 (Me); diazo carbon was
not observed. Data are consistent with the literature.[32]
To 2-methoxy-N-methylaniline (137 mg, 1.00 mmol) and
diethyl diazopropanedioate (242 mg, 1.30 mmol) in toluene
(3 mL) under an atmosphere of nitrogen was added rhodium(II)
acetate dimer (9 mg, 0.02 mmol), and the mixture was heated to
1108C for 2 h. The reaction mixture was cooled to room tem-
perature and the solvent was removed under reduced pressure.
The residue was purified over a silica cartridge (20 g) using a
solvent system of 0–50 % ethyl acetate in cyclohexane over a
period of 20 min. The title compound 2b was isolated as a col-
ourless oil (203 mg, 69 %). nmax (neat)/cmꢀ1 2981, 1732, 1595,
1502, 1458, 1368, 1295, 1260, 1235, 1206, 1173, 1152, 1132,
1101, 1025. dH (CDCl3, 400 MHz) 7.05 (1H, dd, J 7.8, 1.8, ArH),
7.00–6.89 (2H, m, ArH), 6.85 (1H, dd, J 7.8, 1.5, ArH), 5.07 (1H,
s, CH(CO2Et)2), 4.30–4.23 (4H, m, OCH2CH3), 3.84 (3H, s,
NMe), 3.02 (3H, s, OMe), 1.29 (6H, t, J 7.2, OCH2CH3). dC
(CDCl3, 100 MHz) 168.4 (C), 151.5 (C), 139.9 (C), 122.7 (CH),

1214
M. A. Honey and C. J. Moody
120.9 (CH), 119.7 (CH), 111.5 (CH), 67.6 (CH), 61.3 (CH2),
55.5 (Me), 35.9 (Me), 14.2 (Me). Found: MþHþ 296.1486.
C15H21NO5þHþ requires 296.1498.
requires C 56.1, H 6.1, N 4.7 %. Found: MþHþ 300.0996.
C14H1835ClNO4þHþ requires 300.1003.
Diethyl 2-[N-(4-Chlorophenyl)-N-(4-methoxybenzyl)
amino]propanedioate (2f)
Diethyl 2-[N-(3-Bromophenyl)-N-methylamino]
propanedioate (2c)
To 4-chloro-N-(4-methoxybenzyl)aniline (37 mg, 0.15 mmol)
and diethyl diazopropanedioate (34 mg, 0.18 mmol, 1.2 eq.) in
toluene (1 mL) was added rhodium(II) acetate dimer (2 mol-%).
The reaction mixture was sealed and heated to 1108C for 2 h. The
reaction mixture was allowed to cool to room temperature and
the solvent was removed under reduced pressure. The residue
was purified over silica using a solvent system of 20 % ethyl
acetate in light petroleum. The title compound 2f was isolated as
a yellow solid (50 mg, 82 %), mp 86–888C. nmax (CHCl3)/cmꢀ1
2939, 1737, 1612, 1599, 1512, 1500, 1464, 1370, 1303, 1246,
1175, 1101, 1034. dH (CDCl3, 400 MHz) 7.23 (2H, d, J 8.7,
ArH), 7.12 (2H, d, J 9.1, ArH), 6.84 (2H, d, J 8.7, ArH), 6.70
(2H, d, J 9.1, ArH), 5.11 (1H, s, CHCO2Et), 4.62 (2H, s, CH2Ar),
4.23–4.12 (4H, m, CH2CH3), 3.79 (3H, s, OMe), 1.22 (6H, t,
J 7.2, CH2CH3). dC (CDCl3, 100 MHz) 167.5 (C), 158.6 (C),
146.9 (C), 130.2 (C), 128.9 (CH), 127.8 (CH), 124.1 (C), 116.0
(CH), 113.8 (CH), 66.4 (CH), 62.0 (CH2), 55.2 (Me), 53.6
(CH2), 14.0 (Me).
To 3-bromo-N-methylaniline (186 mg, 1.00 mmol) and diethyl
diazopropanedioate (242 mg, 1.30 mmol) in toluene (3 mL)
under an atmosphere of nitrogen was added rhodium(II) acetate
dimer (9 mg, 0.02 mmol). The reaction mixture was heated to
1108C for 2 h. The reaction mixture was allowed to cool to room
temperature and the solvent was removed under reduced pres-
sure. The residue was purified over a silica cartridge (20 g) using
a solvent system of 0–50 % ethyl acetate in cyclohexane over a
period of 20 min. The title compound 2c was isolated as a col-
ourless oil (182 mg, 53 %). nmax (neat)/cmꢀ1 2982, 1735, 1592,
1560, 1489, 1446, 1367, 1300, 1217, 1175, 1158, 1117, 1096,
1025. dH (CDCl3, 400 MHz) 7.09 (1H, t, J 8.5, ArH), 6.94–6.92
(2H, m, ArH), 6.71 (1H, d, J 8.5, ArH), 5.06 (1H, s, CH
(CO2Et)2), 4.29 (4H, q, J 7.0, OCH2CH3), 3.05 (3H, s, NMe),
1.31 (6H, t, J 7.2, OCH2CH3). dC (CDCl3, 100 MHz) 167.2 (C),
150.2 (C), 130.4 (CH), 123.4 (C), 121.4 (CH), 116.4 (CH), 111.8
(CH), 65.7 (CH), 62.0 (CH2), 35.9 (Me), 14.1 (Me). Found:
C 48.8, H 5.1, N 4.0. C14H18BrNO4 requires C 48.9, H 5.3,
N 4.1 %. Found: MþHþ 344.0483. C14H1879BrNO4þHþ
requires 344.0497.
Diethyl 2-[N-(4-Methoxyphenyl)-N-methylamino]
propanedioate (2g)
To 4-methoxy-N-methylaniline (137 mg, 1.00 mmol) and
diethyl diazopropanedioate (242 mg, 1.30 mmol, 1.3 eq.) in
toluene (3 mL) under an atmosphere of nitrogen was added
rhodium(II) acetate dimer (2 mol-%). The reaction mixture was
sealed and heated to 1108C for 2 h. The solution was cooled to
room temperature and the solvent was removed under reduced
pressure. The residue was purified over a silica cartridge (20 g)
using a solvent system of 0–50 % ethyl acetate in cyclohexane
over a period of 20 min to give the title compound 2g as a yellow
oil (209 mg, 71 %). nmax (neat)/cmꢀ1 2983, 1734, 1512, 1465,
1446, 1369, 1298, 1241, 1176, 1156, 1112, 1028. dH (CDCl3,
400 MHz) 6.86–6.80 (4H, m, ArH), 4.99 (1H, s, CH(CO2Et)2),
4.27 (4H, q, J 7.2, CH2CH3), 3.77 (3H, s, NMe), 3.03 (3H, s,
OMe), 1.29 (6H, t, J 7.2, CH2CH3). dC (CDCl3, 100 MHz) 167.8
(C), 153.0 (C), 143.6 (C), 116.0 (CH), 114.6 (CH), 67.3 (CH),
61.7 (CH2), 55.7 (Me), 36.2 (Me), 14.1 (Me). The compound
was previously reported,[34] but with no characterization data.
Found: MþHþ 296.1489. C15H21NO5þHþ requires 296.1498.
Diethyl 2-[N-(4-Bromophenyl)-N-methylamino]
propanedioate (2d)
To 4-bromo-N-methylaniline (223 mg, 1.20 mmol) and diethyl
diazopropanedioate (246 mg, 1.32 mmol, 1.1 eq.) in toluene
(2 mL) was added rhodium(II) acetate dimer (2 mol-%). The
reaction vessel was sealed and heated to 1108C for 1.5 h. The
solvent was removed under reduced pressure and the residue
purified over a silica cartridge (20 g) using a solvent system of
0–50 % ethyl acetate in cyclohexane over a period of 20 min.
The title compound 2d was isolated as a pale yellow oil (240 mg,
58 %). nmax (neat)/cmꢀ1 2982, 1735, 1591, 1495, 1366, 1603,
1273, 1216, 1174, 1158, 1113, 1026. dH (CDCl3, 400 MHz) 7.34
(2H, d, J 9.0, ArH), 6.68 (2H, d, J 9.0, ArH), 5.04 (1 H, s, CH
(CO2Et)2), 4.28 (4H, q, J 7.2, CH2CH3), 3.04 (3H, s, NMe), 1.30
(6H, t, J 7.2, CH2CH3). dC (CDCl3, 100 MHz) 167.3 (C), 148.0
(C), 131.9 (CH), 115.1 (CH), 110.73 (C), 66.0 (CH), 62.0 (CH2),
36.0 (Me), 14.1 (Me). Found: C 49.0, H 5.1, N 4.0.
C14H18BrNO4 requires C 48.9, H 5.3, N 4.1 %. Found: MþHþ
344.0486. C14H1879BrNO4þHþ requires 344.0497.
Diethyl 2-[N-Methyl-N-(4-methylphenyl)amino]
propanedioate (2h)
Diethyl 2-[N-(4-Chlorophenyl)-N-methylamino]
propanedioate (2e)
To N,4-dimethylaniline (145 mg, 1.20 mmol) and diethyl dia-
zopropanedioate (246 mg, 1.32 mmol) in toluene (2 mL) was
added rhodium(II) acetate dimer (11 mg, 0.02 mmol). The
reaction vessel was sealed and heated to 1108C for 1.5 h.
The solvent was removed under reduced pressure and the resi-
due purified over a silica cartridge (20 g) using a solvent system
of 0–50 % ethyl acetate in cyclohexane over a period of 20 min.
The title compound 2h was isolated as a light opaque oil
(238 mg, 71 %). nmax (CHCl3)/cmꢀ1 2982, 1735, 1617, 1519,
1447, 1366, 1302, 1275, 1205, 1156, 1112, 1027. dH (CDCl3,
400 MHz) 7.07 (2H, d, J 8.6, ArH), 6.74 (2H, d, J 8.6, ArH), 5.08
(1H, s, CH(CO2Et)2), 4.27 (4H, q, J 7.2, OCH2CH3), 3.05 (3H, s,
NMe), 2.26 (3H, s, PhCH3), 1.30 (6H, t, J 7.2, OCH2CH3). dC
(CDCl3, 100 MHz) 167.8 (C), 146.9 (C), 129.7 (CH), 127.9 (C),
113.8 (CH), 66.4 (CH), 61.7 (CH2), 35.8 (Me), 20.3 (Me), 14.1
(Me). Found: MþHþ 280.1543. C15H22NO4þHþ requires
280.1549.
To 4-chloro-N-methylaniline (100 mg, 0.71 mmol) and diethyl
diazopropanedioate (158 mg, 0.85 mmol, 1.2 eq.) in toluene
(1 mL) was added rhodium(II) acetate dimer (2 mol-%). The
reaction vessel was sealed and heated to 1108C for 1.5 h.
The solvent was removed under reduced pressure and the resi-
due purified over a silica cartridge (20 g) using a solvent system
of 0–50 % ethyl acetate in cyclohexane over a period of 20 min.
The title compound 2e was isolated as a very pale yellow oil
(160 mg, 76 %). nmax (neat)/cmꢀ1 2983, 1735, 1597, 1475, 1447,
1337, 1303, 1273, 1216, 1174, 1158, 1113, 1026. dH (CDCl3,
400 MHz) 7.20 (2H, d, J 9.2, ArH), 6.73 (2H, d, J 9.2, ArH), 5.04
(1H, s, CH(CO2Et)2), 4.28 (4H, q, J 7.2, CH2CH3), 1.30 (6H,
t, J 7.2, CH2CH3). dC (CDCl3, 100 MHz) 167.4 (C), 147.6 (C),
129.0 (CH), 123.6 (C), 114.7 (CH), 66.1 (CH), 62.0 (CH2), 36.0
(Me), 14.1 (Me). Found: C 55.8, H 5.8, N 4.6. C14H18ClNO4

Indoxylic Acid Esters
1215
Diethyl 2-[N-Methyl-N-(4-nitrophenyl)amino]
propanedioate (2i)
0–50 % ethyl acetate in cyclohexane over a period of 20 min to
give the title compound 3b as a very pale yellow solid (24 mg,
77 %), mp 115–1178C. nmax (CHCl3)/cmꢀ1 3332, 2938, 1736,
1665, 1608, 1567, 1539, 1495, 1470, 1439, 1370, 1339, 1273,
1194, 1148, 1111, 1051, 1019. dH (CDCl3, 400 MHz) 8.54 (1H,
s, OH), 7.89 (1H, d, J 2.0, H-4), 7.44 (1H, dd, J 8.9, 2.0, H-6),
7.15 (1H, d, J 8.9, H-7), 4.48 (2H, q, J 7.2, CH2CH3), 3.87 (3H, s,
NMe), 1.46 (3H, t, J 7.2, CH2CH3). dC (CDCl3, 100 MHz) 136.0
(C), 131.8 (C), 130.0 (CH), 122.6 (CH), 117.8 (C), 111.9 (C),
111.4 (CH), 110.3 (C), 77.2 (C), 60.9 (CH2), 31.9 (Me), 14.5
(Me). Found: C 48.3, H 4.0, N 4.6. C12H12BrNO3 requires
To N-methyl-4-nitroaniline (183 mg, 1.20 mmol) and diethyl
diazopropanedioate (246 mg, 1.32 mmol) in toluene (2 mL) was
added rhodium(II) acetate dimer (11 mg, 0.02 mmol). The
reaction vessel was sealed and heated to 1108C for 1.5 h.
The solvent was removed under reduced pressure and the resi-
due purified over a silica cartridge (20 g) using a solvent system
of 0–100 % ethyl acetate in cyclohexane over a period of 20 min.
The title compound 2i was isolated as a yellow oil (278 mg,
75 %). nmax (neat)/cmꢀ1 2983, 1736, 1594, 1504, 1386, 1368,
1322, 1295, 1224, 1200, 1177, 1105, 1023. dH (CDCl3,
400 MHz) 8.17 (2H, d, J 9.5, ArH), 6.77 (2H, d, J 9.5, ArH), 5.19
(1H, s, CH(CO2Et)2), 4.32 (4H, q, J 7.0, OCH2CH3), 3.17 (3H, s,
NMe), 1.33 (6H, t, J 7.2, OCH2CH3). dC (CDCl3, 100 MHz)
166.4 (C), 153.5 (C), 126.0 (CH), 111.7 (CH), 71.9 (C), 65.3
(CH), 62.5 (CH2), 36.5 (Me), 14.1 (Me). Found: C 53.6, H 5.7,
N 8.4. C14H18N2O6 requires C 54.2, H 5.8, N 9.0 %.
C
48.3,
H
4.1,
N
4.7 %. Found: MþNaþ 319.9894.
C12H1279BrNO3þNaþ requires 319.9898.
Ethyl 5-Chloro-3-hydroxy-1-methyl-
1H-indole-2-carboxylate (3c)
Diethyl 2-[N-(4-chlorophenyl)-N-methylamino]propanedioate
(2e) (34 mg, 0.11 mmol) was heated to 2658C under vacuum for
15 min. The crude product was cooled to room temperature and
purified over a silica cartridge (10 g) using a solvent system of
0–50 % ethyl acetate in cyclohexane over a period of 20 min.
The title compound 3c was isolated as a colourless solid (21 mg,
74 %), mp 127–1298C. nmax (CHCl3)/cmꢀ1 2986, 1711, 1658,
1617, 1574, 1542, 1502, 1446, 1426, 1375, 1276, 1259, 1153,
1101, 1069, 1021. dH (CDCl3, 400 MHz) 8.53 (1H, s, OH), 7.72
(1H, d, J 2.0, H-4), 7.31 (1H, dd, J 9.0, 2.0, H-6), 7.19 (1H, d,
J 9.0, H-7), 4.48 (2H, q, J 7.2, CH2CH3), 3.88 (3H, s, NMe), 1.46
(3H, t, J 7.2, CH2CH3). dC (CDCl3, 100 MHz) 135.8 (C), 129.0
(C), 127.5 (CH), 124.7 (C), 119.4 (CH), 117.1 (C), 113.4 (C),
111.1 (CH), 77.2 (C), 60.9 (CH2), 31.9 (Me), 14.5 (Me). Found:
MþNaþ 276.0399. C12H1235ClNO3þNaþ requires 276.0403.
Diethyl 2-[N-(4-Methoxycarbonylphenyl)-
N-methylamino]propanedioate (2j)
To methyl 4-(methylamino)benzoate (198 mg, 1.20 mmol) and
diethyl diazopropanedioate (246 mg, 1.32 mmol, 1.1 eq.) in
toluene (2 mL) was added rhodium(II) acetate dimer (2 mol-%).
The reaction vessel was sealed and heated to 1108C for 1.5 h.
The solution was cooled to room temperature and the solvent
was removed under reduced pressure. The residue was purified
over a silica cartridge (20 g) using a solvent system of 0–50 %
ethyl acetate in cyclohexane over a period of 20 min to give the
title compound 2j as a light yellow oil (303 mg, 75 %). nmax
(neat)/cmꢀ1 2984, 1737, 1708, 1604, 1521, 1435, 1367, 1273,
1221, 1186, 1110, 1025. dH (CDCl3, 400 MHz) 7.94 (2H, d,
J 9.0, ArH), 6.77 (2H, d, J 9.0, ArH), 5.19 (1H, s, CH(CO2Et)2),
4.30 (4H, q, J 7.2, CH2CH3), 3.87 (3H, s, NMe), 3.12 (3H, s,
CO2CH3), 1.31 (6H, t, J 7.2, CH2CH3). dC (CDCl3, 100 MHz)
167.0 (C), 167.0 (C), 152.3 (C), 131.3 (CH), 119.6 (C), 111.9
(CH), 65.3 (CH), 62.2 (CH2), 51.7 (Me), 36.0 (Me), 14.1 (Me).
Found: MþHþ 324.1439. C16H21NO6þHþ requires 324.1447.
Ethyl 5-Chloro-3-hydroxy-1-(4-methoxybenzyl)-
1H-indole-2-carboxylate (3d)
Diethyl 2-[N-(4-chlorophenyl)-N-(4-methoxybenzyl)amino]
propanedioate (2f) (8.7 mg, 0.025 mmol) was heated under
vacuum to 2658C for 15 min. The crude product was cooled to
room temperature and purified over silica using a solvent system
of 50 % dichloromethane in light petroleum to give the title
compound 3d as a colourless oil (3.2 mg, 43 %). nmax (CHCl3)/
cmꢀ1 3010, 1745, 1674, 1613, 1514, 1479, 1441, 1370, 1348,
1302, 1250, 1177, 1143, 1111, 1072, 1034, 1014. dH (CDCl3,
400 MHz) 8.65 (1H, s, OH), 7.75 (1H, d, J 2.0, H-4), 7.29 (1H,
dd, J 9.0, 2.0, H-6), 7.21 (1H, d, J 9.0, H-7), 6.93 (2H, d, J 8.8,
ArH), 6.78 (2H, d, J 8.8, ArH), 5.51 (2H, s, NCH2Ar), 4.40 (2H,
q, J 7.2, CH2CH3), 3.76 (3H, s, OMe), 1.34 (3H, t, J 7.2,
CH2CH3). dC (CDCl3, 100 MHz) 158.8 (C), 135.8 (C), 130.1
(C), 127.9 (CH), 127.3 (CH), 125.0 (C), 119.6 (CH), 117.6 (C),
116.5 (C), 114.0 (CH), 111.6 (CH), 109.9 (C), 77.2 (C), 61.0
(CH2), 55.2 (Me), 47.7 (CH2), 14.3 (Me). Found: MþKþ
398.0765. C19H1835ClNO4þKþ requires 398.0561.
Ethyl 7-Bromo-3-hydroxy-1-methyl-
1H-indole-2-carboxylate (3a)
Diethyl 2-[N-(2-bromophenyl)-N-methylamino]propanedioate
(2a) (40 mg, 0.12 mmol) was heated under vacuum to 2658C for
15 min. The crude product was cooled to room temperature and
purified over silica using a solvent system of 20 % ethyl acetate
in light petroleum to give the title compound 3a as a colourless
solid (12 mg, 35 %), mp 118–1208C. nmax (CHCl3)/cmꢀ1 2986,
1713, 1655, 1612, 1571, 1540, 1509, 1446, 1412, 1384, 1351,
1271, 1240, 1170, 1096, 1020. dH (CDCl3, 400 MHz) 8.73 (1H,
s, OH), 7.70 (1H, d, J 7.7, ArH), 7.55 (1H, d, J 7.7, ArH), 6.91
(1H, t, J 7.7, H-5), 4.49 (2H, q, J 7.2, CH2CH3), 4.26 (3H, s,
NMe), 1.47 (3H, t, J 7.2, CH2CH3). dC (CDCl3, 100 MHz) 164.0
(C), 148.5 (C), 134.9 (C), 132.7 (CH), 120.2 (CH), 119.7 (CH),
111.3 (C), 104.5 (C), 77.2 (C), 61.1 (CH2), 34.1 (Me), 14.4 (Me).
Found: MþNaþ 319.9884. C12H1279BrNO3þNaþ requires
319.9898.
Ethyl 3-Hydroxy-5-methoxy-1-methyl-
1H-indole-2-carboxylate (3e)
Diethyl 2-[N-(4-methoxyphenyl)-N-methylamino]propanedioate
(2g) (34 mg, 0.11 mmol) was heated to 2658C under vacuum
for 15 min. The crude product was cooled to room temperature
and purified over a silica cartridge (10 g) using a solvent system
of 0–50 % ethyl acetate in cyclohexane over a period of 20 min
to give the title compound 3e as a colourless solid (15 mg, 55 %),
mp 114–1168C. nmax (CHCl3)/cmꢀ1 1706, 1655, 1627, 1545,
1447, 1429, 1381, 1289, 1272, 1240, 1182, 1133, 1096, 1047,
1022. dH (CDCl3, 400 MHz) 8.58 (1H, s, OH), 7.17 (1H, d, J 9.2,
Ethyl 5-Bromo-3-hydroxy-1-methyl-
1H-indole-2-carboxylate (3b)
Diethyl 2-[N-(4-bromophenyl)-N-methylamino]propanedioate
(2d) (36 mg, 0.11 mmol) was heated to 2658C under vacuum for
15 min. The crude product was cooled to room temperature and
purified over a silica cartridge (10 g) using a solvent system of

1216
M. A. Honey and C. J. Moody
H-7), 7.12 (1H, d, J 2.4, H-4), 7.06 (1H, dd, J 9.2, 2.4, H-6), 4.47
(2H, q, J 7.2, CH2CH3), 3.86 (6H, s, NMeþOMe), 1.46 (3H, t,
J 7.2, CH2CH3). dC (CDCl3, 125 MHz) 153.4 (C), 147.8 (C),
133.5 (C), 119.3 (CH), 115.9 (C), 111.0 (CH), 110.0 (C), 99.4
(CH), 77.2 (C), 60.7 (CH2), 55.7 (Me), 31.8 (Me), 14.5
(Me). Found: MþNaþ 272.0898. C13H15NO4þNaþ requires
272.0899.
[9] Z. Zhang, J. Wang, Tetrahedron 2008, 64, 6577. doi:10.1016/
J.TET.2008.04.074
[10] S. Bachmann, D. Fielenbach, K. A. Jorgensen, Org. Biomol. Chem.
2004, 2, 3044. doi:10.1039/B412053A
[11] B. Liu, S. F. Zhu, W. Zhang, C. Chen, Q. L. Zhou, J. Am. Chem. Soc.
2007, 129, 5834. doi:10.1021/JA0711765
[12] E. C. Lee, G. C. Fu, J. Am. Chem. Soc. 2007, 129, 12066. doi:10.1021/
JA074483J
[13] C. J. Moody, Angew. Chem. Int. Ed. 2007, 46, 9148. doi:10.1002/
ANIE.200703016
2-Ethyl 5-Methyl 3-hydroxy-1-methyl-
1H-indole-2,5-dicarboxylate (3f)
[14] E. Aller, R. T. Buck, M. J. Drysdale, L. Ferris, D. Haigh, C. J. Moody,
N. D. Pearson, J. B. Sanghera, J. Chem. Soc., Perkin Trans. 1 1996,
2879. doi:10.1039/P19960002879
Diethyl
2-[N-(4-methoxycarbonylphenyl)-N-methylamino]
propanedioate (2j) (34 mg, 0.11 mmol) was heated to 2658C
under vacuum for 15 min. The crude product was cooled to
room temperature and purified over a silica cartridge (10 g)
using a solvent system of 0–50 % ethyl acetate in cyclohexane
over a period of 20 min. The title compound 3f was isolated
as a colourless solid (18 mg, 62 %), mp 122–1248C. nmax
(CHCl3)/cmꢀ1 3323, 2990, 2953, 1705, 1657, 1615, 1573, 1553,
1481, 1437, 1382, 1346, 1302, 1270, 1240, 1191, 1146, 1110,
1090, 1039, 1019. dH (CDCl3, 400 MHz) 8.69 (1H, s, OH), 8.55
(1H, d, J 1.8, H-4), 8.05 (1H, dd, J 9.0, 1.8, H-6), 7.27 (1H, d, J
9.0, H-7), 4.49 (2H, q, J 7.0, CH2CH3), 3.94 (3H, s, Me), 3.92
(3H, s, Me), 1.47 (3H, t, J 7.0, CH2CH3). dC (CDCl3, 100 MHz)
167.4 (C), 139.1 (C), 127.8 (CH), 123.8 (CH), 121.2 (C), 116.2
(C), 110.5 (C), 109.5 (CH), 77.2 (C), 71.9 (C), 61.0 (CH2),
51.9 (Me), 32.0 (Me), 14.5 (Me). Found: MþNaþ 300.0841.
C14H1535ClNO5þNaþ requires 300.0848.
[15] L. Ferris, D. Haigh, C. J. Moody, J. Chem. Soc., Perkin Trans. 1 1996,
2885. doi:10.1039/P19960002885
[16] K. Yamazaki, Y. Kondo, Chem. Commun. 2002, 210. doi:10.1039/
B109987F
[17] M. M. Yang, X. Wang, P. Livant, J. Org. Chem. 2001, 66, 6729.
doi:10.1021/JO010583A
[18] Z. Zhu, J. H. Espenson, J. Am. Chem. Soc. 1996, 118, 9901.
doi:10.1021/JA954039T
[19] E. Galardon, P. LeMaux, G. Simonneaux, J. Chem. Soc., Perkin Trans.
1 1997, 2455. doi:10.1039/A704687A
[20] C. J. Moody, E. Swann, Synlett 1998, 135. doi:10.1055/S-1998-1610
[21] K. E. Bashford, A. L. Cooper, P. D. Kane, C. J. Moody, S. Muthusamy,
E. Swann, J. Chem. Soc., Perkin Trans. 1 2002, 1672. doi:10.1039/
B202666J
[22] M. A. Honey, A. J. Blake, I. B. Campbell, B. D. Judkins, C. J. Moody,
Tetrahedron 2009, 65, 8995. doi:10.1016/J.TET.2009.07.077
[23] For related work, see: R. H. Prager, C. M. Williams, Aust. J. Chem.
1996, 49, 1315. doi:10.1071/CH9961315
[24] C. J. Moody, M. C. Bagley, J. Chem. Soc., Perkin Trans. 1 1998, 601.
doi:10.1039/A704094F
Supplementary Material
Copies of NMR spectra are available on the Journal’s website.
[25] M. C. Bagley, K. E. Bashford, C. L. Hesketh, C. J. Moody, J. Am.
Chem. Soc. 2000, 122, 3301. doi:10.1021/JA994247B
[26] R. T. Buck, P. A. Clarke, D. M. Coe, M. J. Drysdale, L. Ferris,
D. Haigh, C. J. Moody, N. D. Pearson, E. Swann, Chem. Eur. J.
2000, 6, 2160. doi:10.1002/1521-3765(20000616)6:12,2160::AID-
CHEM2160.3.0.CO;2-Y
Acknowledgements
The authors thank the EPSRC and GlaxoSmithKline for support under the
Array Chemistry Program.
[27] J. R. Davies, P. D. Kane, C. J. Moody, A. M. Z. Slawin, J. Org. Chem.
2005, 70, 5840. doi:10.1021/JO050303H
[28] R. A. Hughes, S. P. Thompson, L. Alcaraz, C. J. Moody, J. Am. Chem.
Soc. 2005, 127, 15644. doi:10.1021/JA0547937
[29] J. Linder, A. J. Blake, C. J. Moody, Org. Biomol. Chem. 2008, 6, 3908.
doi:10.1039/B810855B
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