Microwave assisted Leimgruber-Batcho reaction for the preparation of indoles, azaindoles and pyrroylquinolines

Article abstract of DOI:10.1039/b313012f

The development of enhanced conditions for Lewis acid catalysed Leimgruber-Batcho indole synthesis using microwave acceleration is described. This approach has permitted the preparation of a variety of heteroaromatic enamine intermediates in good yield and high purities. Subsequent catalytic hydrogenation reactions, under various conditions including the use of a solid-phase encapsulated catalyst, furnish the corresponding indole derivatives in good yields.

Full text of DOI:10.1039/b313012f

View Article Online / Journal Homepage / Table of Contents for this issue
Microwave assisted Leimgruber–Batcho reaction for the
preparation of indoles, azaindoles and pyrroylquinolines
Jason Siu, Ian R. Baxendale and Steven V. Ley*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge,
UK CB2 1EW. E-mail: svl1000@cam.ac.uk; Fax: ϩ44 1223 336442; Tel: ϩ44 1223 336398
Received 17th October 2003, Accepted 19th November 2003
First published as an Advance Article on the web 16th December 2003
The development of enhanced conditions for Lewis acid catalysed Leimgruber–Batcho indole synthesis using
microwave acceleration is described. This approach has permitted the preparation of a variety of heteroaromatic
enamine intermediates in good yield and high purities. Subsequent catalytic hydrogenation reactions, under various
conditions including the use of a solid-phase encapsulated catalyst, furnish the corresponding indole derivatives in
good yields.
the corresponding indole derivative (Scheme 1). Under con-
Introduction
ventional conditions the first condensation reaction usually
requires overnight heating in DMF which often leads to less
than optimal yields due to product instability and solvent
degradation.
Microwave-assisted chemical synthesis is proving to be a power-
ful technique for increasing the throughput of chemical reac-
tions.1,2 Specific approaches such as focused microwave flash
heating, involving elevated temperatures and pressures attained
in sealed reactors, has proven especially useful for achieving
faster reactions and the formation of cleaner products.3,4 We
have applied this form of microwave dielectric heating as the
primary means of accelerating a diverse range of reactions in
order to maximise the quantities of material that can be pro-
gressed through a synthetic sequence. This has been of particu-
larly value in reactions mediated by solid-supported reagents,
examples include a polymer-supported thionating agent,5
a
supported reagent for the conversion of isothiocyanates to
isocyanides6 and in the formation of natural products such as
( )-epibatidine,7 (ϩ)-plicamine8 and (ϩ)-didemniserinolipid
B.9 Due to the power and synthetic expedience of this micro-
wave methodology, we have expanded our investigations to
include other traditional reactions which are known to be
problematic due to the necessity for harsh reaction conditions.
The biological importance of indoles and related motifs in
both natural products10 and many pharmaceutical com-
pounds11 means these systems are of special interest to syn-
thetic chemists. Indeed pyrroloquinolines have recently been
found to be especially useful in a variety of medicinal appli-
cations.12 However, there are few synthetic approaches to these
polycyclic aromatic structures in the literature.13 One powerful
procedure is the Leimgruber–Batcho synthesis of indoles,14
although the reaction suffers from the requirement of pro-
longed reaction times and high reaction temperatures. Here, we
wish to describe the successful modification of this reaction to
the formation of indole, azaindole and pyrroloquinoline deriv-
atives using microwave-assisted organic synthesis to accelerate
compound production.
Scheme 1 The Leimgruber–Batcho synthesis of indoles.
We began our study by examining the direct condensation of
nitrotoluene and DMFDMA (Scheme 1; R = H) as the stand-
ard reaction thus avoiding any possible complications due to
additional electronic or dipolar effects.4c The literature reported
reaction using conventional thermal heating (110 ЊC for 22 h)
yielded the enamine adduct in 97% yield.14b In contrast, using
microwave heating conditions (180 ЊC for only 4.5 h) we
obtained the same product in quantitative conversion and
95% isolated yield following a rapid purification by filtration
through a plug of silica gel. At this stage no further optimis-
ation was carried out on either the reaction conditions (time/
temperature/pressure) or isolation method.
Although the microwave induced reaction demonstrated a
marked improvement in terms of the overall reaction time,
an additional study was conducted to investigate the possible
effects of Lewis acid catalysis on the further enhancement of
the microwave reaction. A variety of transition metal catalysts
were screened as described in Table 1. It was found that both
anhydrous CuI and Yb(OTf )3 were effective catalysts giving the
best overall yields and highest purities within the shortest reac-
tion times. In the subsequent reactions CuI was adopted as the
catalyst of choice due to its higher conversion and lower cost
(Table 1). In order to standardise the reaction conditions, the
volume in the Emrys Liberator microwave tube16 was kept
constant for all the examples. The recorded pressure attained
during the course of the irradiation was within the range of
8–10 bar.
Results and discussion
The Leimgruber–Batcho synthesis is a widely used method for
the preparation of indole containing structures.11b,15 The reac-
tion depends on the acidity of a methyl group positioned
adjacent to an aromatic nitro group (or critically at the α or γ
positions on a pyridine ring). A direct condensation reaction
with dimethylformamide (DMF) or more commonly di-
methylformamide dimethyl acetal (DMFDMA) under acid
catalysis facilitates the introduction of the future indole
α-carbon as the enamine. Subsequent catalytic reduction of the
nitro group leads to spontaneous cyclisation and formation of
It is interesting to note that the addition of a small quantity
of DMF greatly enhanced the reaction rate, possibly due to
better microwave absorption as indicated by a more steeply
rising temperature profile. Decomposition of DMF has also
been noted at such high reaction temperatures in the presence
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 6 0 – 1 6 7
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
160

View Article Online
Table 1 Screening of Lewis acids and additives for Leimgruber–Batcho reaction by 1H NMR
Time (min)
Reaction temp.
Catalysts and additives
Conversion yields
270
180 ЊC
180 ЊC
185 ЊC
180 ЊC
185 ЊC
185 ЊC
180 ЊC
175 ЊC
175 ЊC
170 ЊC
185 ЊC
Without pulsing, no catalyst
No catalyst
CuI (0.02 eq.)
Without pulsing, CuI (0.02 eq.)
DABCO (0.3 eq.)
CuI (0.04 eq.), DMAP (cat.)
Cu(I)OTfؒC6H6 (0.04 eq.), DMAP (cat.)
Yb(OTf )3 (0.05 eq.), DABCO (cat.)
Zn(OTf )2 (0.05 eq.), DABCO (0.04 eq.)
CuI (0.03 eq.), Cs2CO3 (0.04 eq.)
CuBr (0.02 eq.)
100%
100%
98%
99%
93%
85%
86%
88%
90%
90%
93%
30 × 7
20 × 6
165
30 × 7
30 × 2
10 × 4
20 × 3
20 × 3
20 × 10
30 × 6
Table 2 Microwave-assisted Leimgruber–Batcho enamine formation
Yield
(%)
Time
(min)
Yield
(%)
Time
(min)
Entry Substrate
1
Product
Entry Substrate
Product
98%
20 × 6 11
Not
20
isolated
2
92%
20 × 2 12
89%
20
3
4
90%
85%
10
20
13
14
90%
85%
10
10
5
6
82%
83%
20
15
90%
92%
95%
17
20
20 × 9 16
7
8
70%
74%
20
17
20
17
20 × 9 18a
Not
isolated
9
54%
600
(10 h)
19
20
85%
20 × 2
10
Not
20
—
—
isolated
a The homologation of this compound requires the use of DMF diethyl acetal, so as to prevent any transesterification.
of metal catalysts, leading to the formation of carbon mon-
oxide and dimethylamine.17 The generation of these volatile
components is undoubtedly responsible for the rapidly increas-
ing pressure profile during the course of the reactions. As a
consequence the reaction kinetics would be expected to be
enhanced especially for the case of a condensation reaction.
Table 2 lists the enamines formed as intermediates from the
Leimgruber–Batcho reaction. Microwave irradiation of nitro-
toluene with DMFDMA in the presence of anhydrous CuI at
180 ЊC gave the corresponding enamine in 98% yield as a dark
red oil (Table 2; Entry 1). Workup of the reaction involved only
a simple filtration and elution with CH2Cl2 through a bond
elut silica cartridge,18 followed by solvent removal under high
vacuum. As we have previously noted in other chemistries,19 the
application of short bursts of microwave heating can be more
effective than a single prolonged heating profile (Table 1). How-
ever, this effect was in this chemistry less significant than indi-
vidual substrate differences resulting from the substituents on
the aromatic systems. Those bearing an electron-rich methoxy
group where less reactive and required longer reaction times.
Conversely, aromatic systems with strongly electron withdraw-
ing groups such as a nitrile 5 (Table 2; Entry 3) or a second nitro
unit 26 (Table 2; Entry 14) gave the corresponding enamines in
high yield after only 10 min. Similarly, quinolines and other
pyridyl-related structures which are electron deficient in nature
showed dramatically increased reaction rates when compared to
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 6 0 – 1 6 7
161

View Article Online
Table 3 Reductive cyclisation of enamines to the corresponding indole derivatives (by Pd/C in MeOH)
Yield
(%)
Yield
(%)
Entry
1
Substrate
Product
Entry
7
Substrate
Product
75%
52%a
2
3
4
5
6
65%
60%
67%a
63%
74%a
8
9
90%
75%b
80%b
70%b
63%b, c
10
11
12
a Reduction was done by refluxing Zn/AcOH. b Reduction was done by 10–15 mol% of the Pd/C catalyst in the presence of a small amount of acetic
acid. c An X-ray crystal structure was obtained for compound 51.20
those of the simple phenyl systems (cf. Table 2; Entries 1, 2 and
15–18). All the enamine intermediates were confirmed as the
trans configured geometry as determined by 1H NMR spectro-
scopy. Furthermore, X-ray diffraction studies of single crystals
of 6, 29, 31, 33 (Table 2; Entries 3, 15, 16 and 17), were also
used to confirm the exclusive trans-configuration.20
slow, yielding only 54% of the desired product even after 10 h
of irradiation. Further heating or modification of the heating
parameters failed to improve the yield, resulting in the form-
ation of higher levels of by-products. In contrast to the liter-
ature14a,22a,b we were able to successfully isolate this material for
full characterisation.
Not all the substrates tested proved as susceptible to manipu-
lation, we encountered several difficulties in the preparation of
enamine 35 (Table 2; Entry 18). The reactive α-chloro function-
ality of pyridine 34 was readily substituted by a dimethylamino
unit, which is perceived to arise from the decomposition of the
DMF or the DMF acetal. It was also found necessary to use the
alternative dimethylformamide diethyl acetal (DMFDEA) for
the homologation of this compound in order to prevent addi-
tional transesterification of the pendant methyl ester function-
ality. Finally, enamine 35 was also found to be unstable when
isolation was attempted and it was therefore subjected to the
cyclisation conditions to generate the indole without prior
purification.
A selection of the isolated enamine intermediates were sub-
jected to catalytic hydrogenation using 10% Pd/C in MeOH
(Table 3). Filtration of the catalyst, and removal of the solvent
in vacuo gave the corresponding indoles in good yields. How-
ever, halogen containing enamines (Table 3; Entries 4, 6 and
7) required refluxing Zn/AcOH for reductive cyclisation to
occur.2a,b These methods were also extended to the preparation
of azaindoles and pyrroloquinolines. It was interesting to note
that for entry 17 (Table 2), where a double homologation was
observed on nitropyridine 32, the corresponding enamine
underwent reductive cyclisation with concomitant reduction of
the electron rich double bond at the 5 position of the pyridyl
ring to furnish the corresponding azaindole 50 (Table 3). For
entry 18 (Table 2), the crude enamine was used without purifi-
cation, therefore column chromatography was required after
the reductive cyclisation to obtain the pure product 51 in 60%
yield. For cyclisation to the azaindoles and pyrrolquinolines, a
small amount of acetic acid was added to prevent any catalyst
poisoning by the substrates.
Recently we reported the development of a system for the
reduction of aromatic nitro groups by transfer hydrogenation,
using an encapsulated nanoparticulate Pd catalyst, HCOOH
and Et3N as the reducing agents.24,25 We have successfully trans-
ferred this protocol to the reductive cyclisation of various
enamine derivatives. For example, trans-2-[β-(dimethylamino)-
vinyl]-nitronaphthalene 37 was smoothly converted to the
corresponding 1H-benz[g]indole 47 in 78% yield (Scheme 2).
Hydrogenation of the aromatic nitro group was carried out
with 6 mol% of Pd-EnCat, using 5 eq. of a mixture of HCO-
OH/Et3N. The immobilised catalyst could easily be recycled
without any noticeable loss of catalytic activity. In addition,
this reaction can be accelerated to completion within 2 h by
microwave irradiation at 120 ЊC. The combined use of micro-
wave accelerated enamine formation and the use of a recyclable
Both the 4- and 6-bromonitrotoluenes (Table 2; Entries 10
and 11) reacted rapidly with DMFDMA to give a dark red oil,
however after the usual workup they did not give pure products
1
as indicated by H NMR. Instead the products were accom-
panied by substantial quantities of polyaromatics.21 We initially
envisaged that this was a result of unwanted copper catalysed
polymerisation reactions. Therefore, in an attempt to circum-
vent this problem we substituted the usual copper catalyst for
Yb(OTf )3. This did significantly improve the reaction mixture
composition but did not fully alleviate the problem. Carrying
the unpurified material through to the next stage proved to
be the only viable option and following reductive cyclisation
gave an acceptable yield of the indole product. Interestingly,
the chloro derivatives 22 and 23 (Table 2; Entries 12 and 13)
showed the same rapid reactions but without the propensity for
generating the same complex mixtures.
Entry 9 (Table 2) also deserves a mention. Hydroxynitro-
toluene 17 reacted initially with the DMFDMA to undergo
methylation of the phenol, a reaction that has been reported
previously in the literature.22 Subsequent conversion to the
corresponding enamine 12 (Table 2; Entry 9) was extremely
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 6 0 – 1 6 7
162

View Article Online
catalyst for reductive cyclisation in the Leimgruber–Batcho
reaction provides a clean synthesis of indoles that would find
particular use in an industrial setting.
1505, 1094, 941, 777, 738; m/z (EI) 192.08929 (Mϩ, C10H12N2O2
requires 192.08988); 192.1 (25%) (Mϩ), 119 (45), 68.9 (100).
Methyl trans-2-[ꢀ-(dimethylamino)vinyl]-3-nitrobenzoate (4)14a
Dark red oil, 92% yield, Rf = 0.43 (light petroleum : Et2O =
1 : 1); δH(400 MHz; CDCl3) 7.75 (2H, m, H-4 and H-6), 7.05
(1H, t,J 8 Hz, H-5), 6.35 (1H, d, J 14 Hz, ArCHCHNMe2), 6.72
(1H, d, J 14 Hz, ArCHCHNMe2), 3.80 (3H, s, OMe), 2.80 (6H,
s, NMe ); δ (100 MHz; CDCl ) 168.9 (C᎐O), 149.1 (C-3), 145.8
᎐
2
C
3
Scheme 2 Reductive cyclisation using Pd-EnCat.
(ArCHCHNMe2), 134.0 (C-2), 132.9 (C-6), 131.3 (C-1), 126.54
(C-4), 122.7 (C-5), 88.8 (ArCHCHNMe2), 52.2 (OMe), 40.4
(NMe2); νmax(neat)/cmϪ1 2948, 1719, 1626, 1592, 1520, 1433,
1374, 1256, 1191, 1116, 1092, 954, 767, 739, 704; m/z (EI)
250.09679 (Mϩ, C12H14N2O4 requires 250.09564); 250.1 (25%),
(Mϩ), 181 (100%).
Conclusion
An efficient synthesis of indoles, azaindoles and pyrrolo-
quinolines using a Leimgruber–Batcho process where the reac-
tion is conducted by focused microwave heating is reported.
The presence of Lewis acids greatly reduce the reaction times
and give much better quality of products when compared with
conventional heating methods.
trans-4-[ꢀ-(Dimethylamino)vinyl]-3-nitrobenzonitrile (6)27
Deep red crystals, 90% yield, Rf = 0.27 (light petroleum :
CH2Cl2 = 1 : 1); mp 134 ЊC (lit. mp 134–137.5 ЊC);27 (Found: C,
60.06; H, 5.42; N, 17.41 C13H13N3O2 requires C, 60.21; H, 5.32;
N, 17.54%); δH(400 MHz; CDCl3) 8.11 (1H, s, H-2), 7.47 (1H, d,
J 8 Hz, H-6), 7.41 (1H, d, J 8 Hz, H-5), 7.20 (1H, d, J 14 Hz,
ArCHCHNMe2), 5.92 (1H, d, J 14 Hz, ArCHCHNMe2), 3.05
(6H, s, NMe2); δC(100 MHz; CDCl3) 147.7 (ArCHCHNMe2),
Experimental
General
Melting points were determined on a Reichert hot stage appar-
1
atus and are reported uncorrected. H and 13C NMR spectra
143.3 (C-3), 140.4 (C-4), 134.0 (C-5), 130.3 (C-2), 123.9 (C-6),
were recorded either on a Brüker DRX-600 or on a DPX-400
instrument with CHCl3 (δ = 7.26) and CDCl3 (δ = 77.0) as
internal reference signals. Signals were assigned by means of
DEPT and 2D spectra (COSY, HMQC, HMBC). IR spectra
were recorded on a Perkin-Elmer ‘Spectrum-One’ spectrometer
equipped with an Attenuated Total Reflectance (ATR) sam-
pling accessory. Mass spectra were recorded on a Kratos – TOF
spectrometer or a Bruker BIOAPEX 4.7 FTICR spectrometer
using electrospray (ESI) or electron impact (EI) techniques (the
matrix was m-nitrobenzyl alcohol (NOBA)) at the Department
of Chemistry, University of Cambridge: relative abundances
and assignments are given in parentheses. LC-MS was per-
formed on a Hewlett Packard HPLC 1100 chromatograph
(Mercury hexylphenyl column) attached to a HP LC/MSD plat-
form LC APCI mass spectrometer. Reactions were monitored
using TLC on precoated glass-backed plates (Merck Kieselgel
60 F254) and visualised by UV. Microanalyses were deter-
mined in the microanalytcal laboratories at the Department of
Chemistry, University of Cambridge.
᎐
118.1 (C᎐N), 103.6 (C-1), 90.0 (ArCHCHNMe ), 40.1 (NMe );
᎐
2
2
νmax(neat)/cmϪ1 2910, 2214, 1590, 1535, 1434, 1396, 1337,
1260, 1221, 1180, 1102, 1067, 919, 834; m/z (ϩESI) 240.0749
(M ϩ Na, C11H11N3O2Na requires 240.0749); 241.2 (100%)
(M ϩ Na), 224.1 (40%), 200.1 (62%).
3-Fluoro-trans-2-[ꢀ-(dimethylamino)vinyl]-nitrobenzene (8)28
Dark red oil, 85% yield, Rf = 0.54 (light petroleum : CH2Cl2 =
1 : 1); δH(400 MHz; CDCl3) 7.52 (1H, d, J 8 Hz, H-6), 7.26 (1H,
d, J 14 Hz, ArCHCHNMe2), 7.12 (1H, m, H-4), 6.85 (1H, m,
H-5), 5.38 (1H, d, J 14 Hz, ArCHCHNMe2), 2.80 (6H, s,
NMe2); δC(100 MHz; CDCl3) 158.2 (JC–F 185 Hz, C-3), 147.6
(JC–F 19 Hz, ArCHCHNMe2), 147.1 (JC–F 8 Hz, C-1), 124.2
(JC–F 16 Hz, C-2), 121.0 (JC–F8 Hz, C-5), 120.8 (JC–F 3.3 Hz, C-6),
118.8 (JC–F 25 Hz, C-4), 84.2 (ArCHCHNMe2), 40.4 (NMe2);
νmax(neat)/cmϪ1 2906, 2808, 1620, 1570, 1515, 1474, 1380, 1334,
1270, 1211, 1182, 1093, 937, 871, 821 and 799; m/z (EI) 210.07958
(Mϩ, C10H11N2O2F requires 210.08046), 210.1 (20%) (Mϩ), 169
(35%); 131 (56%), 86 (65%).
General procedure for the synthesis of enamine derivatives
5-Fluoro-trans-2-[ꢀ-(dimethylamino)vinyl]-nitrobenzene (10)29
A solution of the 2-nitrotoluene derivative (3.65 mmol) and
copper() iodide (2 mol%) in a mixture of DMFDMA (5 mL;
37.6 mmol) and DMF (0.1 mL) was heated at 180 ЊC in a sealed
vial under microwave irradiation (20 min × 7);16 an internal
pressure of 8–10 bar was observed during the heating sequence.
The crude reaction mixture was directly filtered through a pre-
packed silica bond elut cartridge18 (22 mm in diameter, 2 g
silica), and eluted with either CH2Cl2 (10 mL × 3) or EtOAc
(10 mL × 3) for the more polar systems. The combined filtrates
were concentrated under reduced pressure to yield the corre-
sponding enamine products without the need for further
purification.
Dark red oil, 82% yield, Rf = 0.38 (light petroleum : Et2O =
3 : 2); δH(400 MHz; CDCl3) 7.58 (1H, dd, J 2.7 Hz, 8 Hz, H-3),
7.95 (1H, dd, J6 Hz, 9 Hz, H-6), 7.08 (1H, m, H-4), 6.75 (1H, d,
J 14 Hz, ArCHCHNMe2), 5.83 (1H, d, J 14 Hz, ArCHCH-
NMe2), 2.94 (6H, s, NMe2); δC(100 MHz; CDCl3) 156.6 (JC–F
245 Hz, C-5), 144.6 (ArCHCHNMe), 132.5 (JC–F 3 Hz, C-2),
126.1 (JC–F7 Hz, C-3), 120.5 (JC–F 23 Hz, C-6), 111.8 (JC–F 23
Hz, C-4), 90.9 (ArCHCHNMe), 40.7 (NMe2); νmax(neat)/cmϪ1
2906, 1620, 1515, 1380, 1270, 1211, 1093, 937, 799; m/z (EI)
210.07947 (Mϩ, C10H11N2O2F requires 210.08046), 210.1 (20%)
(Mϩ), 169 (40%); 131 (50%), 86 (40%).
trans-2-[ꢀ-(Dimethylamino)vinyl]-nitrobenzene (2)26
3-Methoxy-trans-2-[ꢀ-(dimethylamino)vinyl]-nitrobenzene
(12)14a
Dark red oil, 98% yield, Rf = 0.56 (light petroleum : Et2O =
1 : 1); δH(400 MHz; CDCl3) 7.81 (1H, d, J 8 Hz, H-6), 7.42 (1H,
d, J 9 Hz, H-3), 7.30 (1H, t, J 8 Hz, H-4), 6.95 (1H, t, J 8 Hz,
H-5), 6.87 (1H, d, J 14 Hz, ArCHCHNMe2), 5.83 (1H, d, J 14
Hz, ArCHCHNMe2), 2.94 (6H, s, NMe2); δC(100 MHz; CDCl3)
145.22 (C-1), 144.57 (ArCHCHNMe2), 135.74 (C-2), 132.39
(C-4), 125.34 (C-6), 124.39 (C-3), 122.44 (C-5), 91.30 (ArCH-
CHNMe2), 40.67 (NMe2); νmax(neat)/cmϪ1 3400, 1620, 1594,
Dark red oil, 83% yield; Rf = 0.52 (light petroleum : Et2O =
1 : 1); δH(400 MHz; CDCl3) 7.40 (1H, d, J 14 Hz, ArCHCH-
NMe2), 7.22 (1H, m, H-5), 6.93 (2H, m, H-4, H-6), 5.30 (1H, d,
J 14 Hz, ArCHCHNMe2), 3.80 (3H, s, OMe), 2.80 (6H, s,
NMe2); δC(100 MHz; CDCl3) 156.9 (C-3), 148.6 (C-1), 147.2
(ArCHCHNMe2), 124.0 (C-2), 122.4 (C-5), 117.1 (C-6), 113.6
(C-4), 86.6 (ArCHCHNMe2), 56.4 (OMe), 40.8 (NMe2);
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 6 0 – 1 6 7
163

View Article Online
νmax(neat)/cmϪ1 2938, 1620, 1586, 1516, 1463, 1365, 1274, 1260,
1227, 1087, 1050, 949, 916, 764, 749; m/z (ϩESI) 245.0902 (M
ϩ Na, C11H14N2O3Na requires 245.0902).
trans-6-[ꢀ-(Dimethylamino)vinyl]-5-nitroquinoline (29)
Brilliant red crystals, 90% yield, Rf = 0.37 (light petroleum :
Et2O = 9 : 1); mp 175 ЊC; (Found: C, 63.83; H, 5.41; N, 17.06
C13H13N3O2 requires C, 64.19; H, 5.39; N, 17.27%); δH(600
MHz; CDCl3) 8.71 (1H, d, J 9 Hz, H-2), 7.92 (2H, d, J 9 Hz,
H-4, H-8), 7.71 (1H, d, J 9 Hz, H-7), 7.37 (1H, m, H-3), 7.06
(1H, d, J 14 Hz, ArCHCHNMe2), 5.20 (1H, d, J 14 Hz, ArCH-
CHNMe2), 2.70 (6H, s, NMe2); δC(150 MHz; CDCl3) 148.3
(C-2), 145.2 (ArCHCHNMe2), 144.6 (C-8Ј), 140.1 (C-6), 131.6
(C-8), 131.47 (C-5), 128.8 (C-4), 124.7 (C-7), 122.9 (C-3), 121.7
(C-4Ј), 88.3 (ArCHCHNMe2), 40.5 (NMe2); νmax(neat)/cmϪ1
2895, 1632, 1614, 1512, 1432, 1360, 1206, 1164, 1137, 1103, 926,
873, 818, 797, 778, 728; m/z (EI) 243.10033 (Mϩ, C13H13N3O2
requires 243.10078); 243.1 (25%) (Mϩ), 131.0 (70%), 119.0
(50%).
4-Methoxy-trans-2-[ꢀ-(dimethylamino)vinyl]-nitrobenzene (14)30
Dark red oil, 70% yield, Rf = 0.48 (light petroleum : EtOAc =
9 : 1); δH(400 MHz; CDCl3) 7.91 (1H, J 9 Hz, H-6), 6.93 (1H, d,
J 14 Hz, ArCHCHNMe2), 6.79 (1H, d, J2 Hz, H-3), 6.47 (1H,
dd, J 9 Hz, 2 Hz, H-5), 6.03 (1H, d, J 14 Hz, ArCHCHNMe2),
3.83 (3H, s, OMe), 2.89 (6H, s, NMe2); δC(100 MHz; CDCl3)
162.7 (C-4), 145.0 (ArCHCHNMe2), 139.0 (C-2), 138.5 (C-1),
128.3 (C-6), 109.2 (C-5), 107.5 (C-3), 92.3 (ArCHCHNMe2),
55.6 (OMe), 40.7 (NMe2); νmax(neat)/cmϪ1 2903, 1593, 1492,
1235, 1095, 838, 786, 732; m/z (ϩESI) 245.0902 (M ϩ Na,
C11H14N2O3Na requires 245.0902); 246 (100%), 234.1 (60%),
205.1 (88%).
trans-7-[ꢀ-(Dimethylamino)vinyl]-8-nitroquinoline (31)33
5-Methoxy-trans-2-[ꢀ-(dimethylamino)vinyl]-nitrobenzene (16)
Lustrous red crystals, 92% yield, Rf = 0.46 (light petroleum :
Et2O = 9 : 1); mp 180 ЊC (lit. mp 181–183 ЊC);33 (Found: C,
63.91; H, 5.45; N, 17.13 C13H13N3O2 requires C, 64.19; H,
5.39; N, 17.27%); δH(400 MHz; CDCl3) 8.77 (1H, d, J 8 Hz,
H-2), 7.95 (1H, d, J 8 Hz, H-4), 7.49 (2H, m, H-5, H-6), 7.24
(1H, m, H-3); 7.03 (1H, d, J14 Hz, ArCHCHNMe2), 4.99
(1H, d, J 14 Hz, ArCHCHNMe2), 2.87 (6H, s, NMe2); δC(100
MHz; CDCl3) 151.6 (C-2), 144.9 (ArCHCHNMe2), 142.4
(C-7), 141.1 (C-8Ј), 135.3 (C-4), 132.6 (C-8), 128.5 (C-5), 124.5
(C-4Ј), 121.9 (C-6), 120.0 (C-3), 88.1 (ArCHCHNMe2), 40.6
(NMe2); νmax(neat)/cmϪ12912, 1633, 1607, 1516, 1366, 1306,
1269, 1200, 1105, 870, 824, 760; m/z (EI) 243.10059 (Mϩ,
C13H13N3O2 requires 243.10078), 243.1 (40%) (Mϩ), 226.1
(25%), 142.1 (25%).
Dark red oil, 74% yield, Rf = 0.44 (light petroleum : CH2Cl2 =
1 : 1); δH(400 MHz; CDCl3) 7.39 (1H, d, J 3 Hz, H-6), 7.35 (1H,
d, J 9 Hz, H-3), 6.98 (1H, dd, J 8 Hz, 2 Hz, H-4), 6.77 (1H, d,
J 14 Hz, ArCHCHNMe2), 5.84 (1H, d, J 14 Hz, ArCHCH-
NMe2), 3.80 (3H, s, OMe), 2.95 (6H, s, NMe2); δC(100 MHz;
CDCl3) 155.3 (C-5), 148.7 (C-1), 143.6 (ArCHCHNMe2), 126.1
(C-3), 123.7 (C-2), 121.4 (C-4), 108.2 (C-6), 91.8 (ArCHCH-
NMe2), 56.0 (OMe), 40.7 (NMe2); νmax(neat)/cmϪ1 2933, 1622,
1513, 1367, 1286, 1091, 1034, 794; m/z (ϩESI) 223.1082 (M ϩ
H, C11H15N2O3 requires 223.1083); 223.10 (30%) (M ϩ H),
205.09 (45%), 193.14 (100%).
3-Chloro-trans-2-[ꢀ-(dimethylamino)vinyl]-nitrobenzene (23)31
Dark red oil, 89% yield, Rf = 0.44 (light petroleum : CH2Cl2 =
1 : 1); δH(400 MHz; CDCl3) 7.45 (1H, d, J 8 Hz, H-6), 7.41 (1H,
d, J 8 Hz, H-4), 6.96 (1H, t, J 8 Hz, H-5), 6.68 (1H, d, J 14 Hz,
ArCHCHNMe2), 5.08 (1H, d, J 14 Hz, ArCHCHNMe2), 2.84
(6H, s, NMe2); δC(100 MHz; CDCl3) 148.1 (C-1), 145.8
(ArCHCHNMe2), 133.1 (C-3), 132.7 (C-6), 131.9 (C-2), 123.2
(C-5), 122.3 (C-4), 86.8 (ArCHCHNMe2), 40.3 (NMe2);
νmax(neat)/cmϪ1 2894, 1629, 1520, 1373, 1263, 1098, 772, 751,
723; m/z (ϩESI) 227.05980 (M ϩ H, C10H12N2O2Cl requires
227.05873), 227.1 (82%) (M ϩ H), 250.1 (20%).
2,6-Bis-trans-[ꢀ-(dimethylamino)vinyl]-3-nitropyridine (33)
Deep red crystals, 95% yield, Rf = 0.4 (100% ether); mp 131 ЊC;
(Found: C, 59.26, H, 6.70, N, 21.32 C13H18N4O2 requires C,
59.53, H, 6.92, N, 21.36%); δH(400 MHz; CDCl3) 7.96 (1H, d,
J 14 Hz, H-4), 7.94 (1H, d, J 9 Hz, C-2-CHCHNMe2), 7.52
(1H, d, J 14 Hz, C-6-CHCHNMe2), 6.36 (1H, d, J 14 Hz, C-2-
CHCHNMe2), 6.32 (1H, d, J 9 Hz, H-5), 5.04 (1H, d, J 14 Hz,
C-6-CHCHNMe2), 2.94 (6H, s, NMe2), 2.89 (6H, s, NMe2);
δC(100 MHz; CDCl3) 162.4 (NMe2), 161.5 (C-6), 153.7 (C-2),
150.0 (C-2-CHCHNMe2), 147.4 (C-6-CHCHNMe2), 134.0
(C-4), 133.2 (C-3), 112.4 (C-5), 96.0 (C-6-CHCHNMe2), 93.0
(C-2-CHCHNMe2), 40.9 (NMe2), 36.4 (NMe2), 31.3 (NMe2);
νmax(neat)/cmϪ1 2877, 1613, 1533, 1357, 1253, 1225, 1093, 1069,
825, 793; m/z (EI) 262.1440 (Mϩ, C13H18N4O2 requires
262.1430), 262.1 (13%) (Mϩ), 181.0 (30%), 131.0 (40%).
5-Chloro-trans-2-[ꢀ-(dimethylamino)vinyl]-nitrobenzene (25)32
Dark red oil, 90% yield, Rf = 0.33 (light petroleum : Et2O =
1 : 1); δH(400 MHz; CDCl3) 7.82 (1H, s, H-6), 7.35 (1H, m,
H-3), 7.24 (1H, m, H-4), 6.91 (1H, d, J 14 Hz, ArCHCHNMe2),
5.79 (1H, d, J 14 Hz, ArCHCHNMe2), 2.90 (6H, s, NMe2);
δC(100 MHz; CDCl3) 145.2 (ArCHCHNMe2), 144.6 (C-2),
134.7 (C-4), 132.6 (C-6), 127.0 (C-1), 125.4 (C-5), 125.1 (C-3),
90.3 (ArCHCHNMe2), 40.7 (NMe2); νmax(neat)/cmϪ1 2927,
1618, 1597, 1384, 1354, 1256, 1218, 1097, 1030, 893, 879, 821,
760, 737; m/z (EI) 226.05163 (Mϩ, C10H11N2O2Cl requires
226.05091); 226.1 (25%) (Mϩ), 205.1 (20%), 119.0 (45%).
trans-2-[ꢀ-(Dimethylamino)vinyl]-nitronaphthalene (37)33
Dark red crystals, 85% yield, Rf = 0.48 (CH2Cl2 : Et2O = 1 : 1);
mp 101 ЊC (lit. mp 98–110 ЊC);33 (Found: C, 69.52, H, 5.97, N,
11.58 C14H14N2O2 requires C, 69.41, H, 5.82, N, 11.56%);
δH(600 MHz; CDCl3) 7.70 (1H, d, J 8 Hz, ArH), 7.66 (1H, d, J 8
Hz, ArH), 7.58 (1H, d, J 8 Hz, ArH), 7.48 (2H, m, ArH), 7.32
(1H, m, ArH), 6.97 (1H, d, J 14 Hz, ArCHCHNMe2), 5.11 (1H,
d, J 14 Hz, ArCHCHNMe2), 2.86 (6H, s, NMe2), δC(150 MHz;
CDCl3) 144.4, 142.3, 130.0, 128.3, 127.8, 125.8, 124.8, 121.3,
120.4, 88.7, 40.5; νmax(neat)/cmϪ1 2933, 1634, 1614, 1514, 1377,
1265, 1030, 814, 734, 637; m/z (ϩESI) 265.0953 (M ϩ Na,
C14H14N2O2Na requires 265.0953).
3-Nitro-trans-2-[ꢀ-(dimethylamino)vinyl]-nitrobenzene (27)22a
Deep red crystals, 85% yield, Rf = 0.72 (light petroleum : Et2O =
7 : 3); mp 94 ЊC (lit. mp 90–93 ЊC);22a (Found: C, 50.45, H, 4.94,
N, 17.47 C10H11N3O4 requires C, 50.63, H, 4.67, N, 17.71%);
δH(400 MHz; CDCl3) 8.10 (2H, d, J 8 Hz, H-4, H-6), 7.10
(1H, t, J 8 Hz, H-5), 6.45 (1H, d, J 14 Hz, ArCHCHNMe2),
5.45 (1H, d, J 14 Hz, ArCHCHNMe2), 2.85 (6H, s, NMe2);
δC(100 MHz; CDCl3) 149.1 (C-1, C-3), 146.5 (ArCHCHNMe2),
129.1 (C-2), 127.2 (C-4, C-6), 122.4 (C-5), 83.5 (ArCHCH-
NMe2), 40.5 (NMe2); νmax(neat)/cmϪ1 2899, 1625, 1594, 1519,
1442, 1417, 1382, 1346, 1280, 1217, 1100, 958, 920, 879, 847,
771, 734, 707; m/z (EI) 237.07489 (Mϩ, C10H11N3O4 requires
237.07496).
General procedure for the catalytic hydrogenation of nitro-
enamines to the corresponding indole derivatives
To a stirred suspension of Pd/C (10 wt%) (0.14 g, 0.13 mmol) in
MeOH (40 mL) was added a solution of trans-2-[β-(di-
methylamino)vinyl]-2-nitrobenzene (0.25 g, 1.30 mmol) in
CH2Cl2 (5 mL). For compounds 29, 31, 33 and 35, acetic acid
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 6 0 – 1 6 7
164

View Article Online
(2.5 mL) was added to prevent catalyst poisoning. The solution
was then saturated with H2 gas and stirred overnight under H2
at room temperature. The reaction mixture was then purged
with Ar and the Pd/C was filtered through a short pad of
celite before washing with EtOAc (15 mL). The filtrate was
concentrated (1 mL) and purified by passing through a
bond elut silica cartridge18 followed by elution with EtOAc
(2 × 30 mL). The combined filtrates were then concentrated and
recrystallised.
H-6), 7.09 (1H, m, H-7), 6.94 (1H, d, J 8 Hz, H-2), 6.72 (1H, bd,
H-5), 6.38 (1H, d, J 8 Hz, H-3), 4.00 (3H, s, OMe); δC(100 MHz;
CDCl3) 153.4 (C-4), 137.3 (C-7Ј), 122.8 (C-6, C-7), 118.6 (C-3Ј),
104.6 (C-2), 99.8 (C-3, C-5), 55.4 (OMe); νmax(neat)/ cmϪ1 3381,
1615, 1586, 1507, 1497, 1350, 1281, 1242, 1078, 1054, 961, 744,
726; m/z (EI) 147.06774 (Mϩ, C9H9NO requires 147.17390),
147.1 (100%) (Mϩ), 132.0 (100%), 116.0 (20%), 104.1 (80%),
83.0 (30%).
4-Chloroindole (45)38
Indole (40)34
Light pink oil, 74% yield, Rf = 0.38 (light petroleum : CH2Cl2 =
4 : 1); (Found: C, 63.59, H, 4.15, N, 9.16 C8H6NCl requires C,
63.38, H, 3.99, N, 9.24%); δH(600 MHz; CDCl3) 8.13 (1H, bs,
NH ), 7.29 (1H, t, J 7 Hz, H-7), 7.24 (1H, t, J 3 Hz, H-2), 7.13
(2H, m, H-6, H-5), 6.67 (1H, t, J 3 Hz, H-3); δC(150 MHz;
CDCl3) 136.5 (C-7Ј), 126.8 (C-3Ј), 126.1 (C-4), 124.7 (C-2),
122.6 (C-5), 119.6 (C-6), 109.6 (C-7), 101.4 (C-3); νmax(neat)/
cmϪ1 3421, 1571, 1485, 1432, 1338, 1182, 928, 745; m/z (EI)
151.01852 (Mϩ, C8H6NCl requires 151.01888), 153 (55%), 151.1
(50%) (Mϩ), 116.1 (30%), 89.1 (42%).
Colourless prisms, 75% yield, Rf = 0.61 (light petroleum :
CH2Cl2 = 1 : 1); mp 53 ЊC (lit. mp 52–54 ЊC);34 (Found: C, 82.30,
H, 6.24, N, 12.02 C8H7N requires C, 82.02, H, 6.02, N, 11.96%);
δH(400 MHz; CDCl3) 8.02 (1H, bs, NH ), 7.80 (1H, d, J 7 Hz,
H-4), 7.40 (1H, d, J 7 Hz, H-7), 7.35 (1H, t, J 7 Hz, H-6), 7.28
(1H, t, J 7 Hz, H-5), 7.17 (1H, bd, H-2), 6.68 (1H, bd, H-3);
δC(100 MHz; CDCl3) 135.9 (C-7Ј), 128.0 (C-3Ј), 124.4 (C-2),
122.1 (C-5), 120.8 (C-4), 119.9 (C-6), 111.3 (C-7), 102.5 (C-3);
νmax(neat)/cmϪ1 3405, 1454, 1413, 1334, 1245, 1091, 907, 740,
723; m/z (EI) 117.05736 (Mϩ, C8H7N requires 117.05785), 130.1
(10%), 117.1 (52%) (Mϩ), 90.0 (80%), 63 (100%).
6-Bromoindole (46)23b–d
Off-white solid, 52% yield, mp 94 ЊC (lit. mp 95–96 ЊC);23b
δH(600 MHz; CDCl3) 8.15 (1H, bs, NH ), 7.55 (1H, d, J 2 Hz,
H-7), 7.53 (1H, d, J 9 Hz, H-4), 7.24 (1H, dd, J 2 Hz, 9 Hz,
H-5), 7.19 (1H, t, J 3 Hz, H-2), 6.61 (1H, m, H-3); H NMR
data was in agreement to the literature assignments.
Methyl indole-4-carboxylate (41)35
Off white solid, 65% yield, Rf = 0.62 (light petroleum : EtOAc =
1 : 1); mp 64 ЊC (lit. mp 63–65 ЊC);35 (Found: C, 68.64, H, 5.31,
N, 7.82 C10H9NO2 requires C, 68.56, H, 5.18, N, 8.00%); δH(400
MHz; CDCl3) 9.16 (1H, bs, NH ), 7.92 (1H, d, J 7 Hz, H-5),
7.55 (1H, d, J 7 Hz, H-7), 7.29 (1H, m, H-6), 7.20 (1H, bd, H-2),
7.18 (1H, bd, H-3), 3.98 (3H, s, OMe); δC(100 MHz; CDCl3)
1
1H-Benz[g]indole (47)39
Off-white solid; 90% yield, Rf = 0.41 (light petroleum : EtOAc =
4 : 1); mp 178 ЊC (lit. mp 179 ЊC);39 (Found: C, 86.04, H, 5.52,
N, 8.42 C12H9N requires C, 86.20, H, 5.43, N, 8.38%); δH(400
MHz; CDCl3) 8.79 (1H, bs, NH ), 7.93 (2H, d, ArH), 7.75 (1H,
d, ArH), 7.44 (3H, d, ArH), 7.24 (1H, m, ArH), 6.73 (1H, m,
ArH); δC(100 MHz; CDCl3) 130.5, 128.9 (CH), 125.5 (CH),
123.9 (CH), 122.3 (CH), 120.8 (CH), 120.7 (CH), 119.3 (CH),
104.3 (CH); νmax(neat)/cmϪ1 3412, 1494, 1379, 1110, 1078, 809,
719, 687; m/z (EI) 167.07290 (Mϩ, C12H9N requires 167.07350),
167.1 (50%) (Mϩ).
168.5 (C᎐O), 136.8 (C-7Ј), 127.4 (C-3Ј), 126.7 (C-6), 123.3
᎐
(C-5), 121.3 (C-4), 120.9 (C-2), 116.3 (C-7), 103.4 (C-3), 51.8
(OMe); νmax(neat)/cmϪ13346, 1697, 1273, 1192, 1142, 909, 898,
753, 731; m/z (EI) 175.06353 (Mϩ, C10H9NO2 requires
175.06333), 175.1 (70%) (Mϩ), 144.0 (92%), 116.1 (70%), 68.9
(70%).
4-Fluoroindole (42)36
Colourless crystals, 60% yield, Rf = 0.74 (light petroleum :
CH2Cl2 = 1 : 1); mp 26 ЊC (lit. mp 25–28 ЊC);36 (Found: C, 70.98,
H, 4.67, N, 10.21 C8H6NF requires C, 71.10, H, 4.48, N,
10.36%); δH(400 MHz; CDCl3) 8.26 (1H, bs, NH ), 7.21–7.13
(3H, m, H-2, H-6, H-7), 6.81 (1H, m, H-5), 6.67 (1H, bd, H-3);
1H-Pyrrole[2,3-f ]quinoline (48)40
Light tan solid, 80% yield, Rf = 0.7 (EtOAc : MeOH = 4 :1); mp
224 ЊC (lit. mp 222–224 ЊC);40 (Found: C, 78.03, H, 7.79, N,
16.39 C11H8N2 requires C, 77.96, H, 8.05, N, 16.66%); δH(600
MHz; CD3OD) 12.55 (1H, bs, NH ), 9.90 (1H, d, J 7 Hz, H-7),
8.97 (1H, d, J 7 Hz, H-9), 8.32 (1H, d, J 7 Hz, H-4), 8.03 (1H,
m, H-8), 7.73 (1H, m, H-5), 7.69 (1H, bd, H-2), 6.78 (1H, bd,
H-3); δC(100 MHz; CD3OD) 139.7 (C-7), 139.9 (C-9), 136.0
(C-5Ј), 131.2 (C-4), 127.5 (C-2), 123.3 (C-3Ј), 121.9 (C-9Љ),
120.2 (C-8), 118.3 (C-9Ј), 110.2 (C-5), 99.8 (C-3); νmax(neat)/
cmϪ1 2658, 1587, 1345, 1267, 877, 812, 736, 720, 678; m/z (EI)
168.06849 (Mϩ, C11H8N2 requires 168.06875) 168.1 (100%)
(Mϩ), 140.1 (30%), 100.0 (32%).
δC(100 MHz; CDCl3) 155.3 (J
246 Hz, C-4), 138.5 (JC–F 11
C–F
Hz, C-7Ј), 124.1 (C-2), 122.5 (J C–F 11 Hz, C-6), 117.0 (J C–F 21
Hz, C-3Ј), 107.1 (C-7), 104.4 (J
21 Hz, C-5), 98.7 (C-3);
C–F
νmax(neat)/cmϪ1 3421, 1579, 1501, 1353, 1225, 1078, 1012, 738,
670; m/z (EI) 135.04913 (Mϩ C8H6NF requires 135.04843), 135
(70%) (Mϩ), 119 (45%), 68.9 (100%).
4-Bromoindole (43)23a
Colourless oil, 67% yield, Rf = 0.55 (light petroleum : CH2Cl2 =
3 : 2); (Found: C, 49.29, H, 3.21, N, 7.18 C8H6NBr requires C,
49.01, H, 3.08, N, 7.14%); δH(600 MHz; CDCl3) 8.26 (1H, bs,
NH ), 7.33 (1H, d, J 8 Hz, H-7), 7.30 (1H, d, J 8 Hz, H-5), 7.24
(1H, t, J 3 Hz, H-2), 7.06 (1H, t, J 8 Hz, H-6), 6.63 (1H, t, J 3
Hz, H-3); δC(150 MHz; CDCl3) 136.0 (C-7Ј), 128.7 (C-3Ј), 124.7
(C-2), 122.9 (C-6), 122.8 (C-5), 114.8 (C-4), 110.2 (C-7), 103.1
(C-3); νmax(neat)/cmϪ1 3419, 1564, 1428, 1332, 1177, 889, 743;
m/z (EI) 194.96849 (Mϩ, C8H6NBr requires 194.96836), 197
(92%), 195 (93%) (Mϩ).
1H-Pyrrole[3,2-h]quinoline (49)12a
Pale green solid, 75% yield, Rf = 0.58 (light petroleum : EtOAc =
1 : 9); mp 100 ЊC (lit. mp 99–101 ЊC);12a (Found: C, 78.09, H,
7.94, N, 16.45 C11H8N2 requires C, 77.96, H, 8.05, N, 16.66%);
δH(400 MHz; CDCl3) 13.03 (1H, bs, NH ), 8.77 (1H, d, J 7 Hz,
H-8), 8.74 (1H, bd, H-6), 8.04 (1H, d, J 8 Hz, H-2), 7.70 (2H, s,
H-4, H-5), 7.61 (1H, d, J 8 Hz, H-7), 6.83 (1H, bd, H-3); δC(100
MHz; CDCl3) 145.0 (C-8), 138.2 (C-6), 131.8 (C-9Ј), 129.6
(C-2), 129.5 (C-3Ј), 126.5 (C-5Ј), 125.9 (C-5), 123.0 (C-9Љ),
118.8 (C-4), 117.6 (C-7), 105.1 (C-3); νmax(neat)/cmϪ1 3047,
2336, 1534, 1392, 1375, 1213, 794, 742, 710, 676; m/z (EI)
168.06813 (Mϩ, C11H8N2 requires 168.06875), 168.1 (60%)
(Mϩ), 155.0 (40%), 91 (100%).
4-Methoxyindole (44)37
Off-white crystals, 63% yield, Rf = 0.41 (light petroleum :
CH2Cl2 = 1 : 1); mp 68 ЊC (lit. mp 68–69 ЊC);37 (Found: C, 73.43;
H, 6.16; N, 9.51. C9H9NO requires C, 73.45; H, 6.16; N, 9.51%);
δH(600 MHz; CDCl3) 8.13 (1H, bs, NH ), 7.15 (1H, t, J 8 Hz,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 6 0 – 1 6 7
165

View Article Online
5-(N,N-dimethylaminoethyl)-4-azaindole (50)
Acknowledgements
Pale yellow solid, 70% yield, Rf = 0.4 (EtOAc : MeOH = 9 : 1);
mp 174–175 ЊC; (Found: C, 70.04, H, 8.10, N, 22.27 C11H15N3
requires C, 69.81, H, 7.99, N, 22.20%); δH(400 MHz; CD3OD)
8.20 (1H, d, J 9 Hz, H-7), 7.96 (1H, bd, H-2), 7.53 (1H, d, J 9
Hz, H-6), 6.90 (1H, bd, H-3), 3.94 (2H, m, ArCH2CH2NMe2),
3.64 (2H, m, ArCH2CH2NMe2), 3.08 (6H, s, NMe2); δC(100
MHz; CD3OD) 148.6 (C-5), 145.2 (C-3Ј), 129.9 (C-2), 128.2
(C-7Ј), 120.7 (C-7), 116.3 (C-6), 101.2 (C-3), 57.8 (ArCH2-
CH2NMe2), 43.0 (NMe2), 34.7 (NMe2), 30.9 (ArCH2CH2-
NMe2); νmax(neat)/cmϪ1 3363, 2964, 2760, 1613, 1570, 1467,
1409, 1022, 890, 791, 744; m/z (EI) 189.12675 (Mϩ, C11H15N3
requires 189.12660) 189.1 (21%) (Mϩ), 145.1 (20%), 118.1
(18%).
We gratefully acknowledge the financial support from the
Croucher Foundation Research Fellowship (to J.S.), Pfizer
Global Research and Development for a Postdoctoral Fellow-
ship (to J.S.), the B. P. Endowment (to S.V.L.) and Novartis
Research Fellowship (to S.V.L.) for funding. We wish to thank
J.E. Davis for determining crystal structures and C. Mitchell for
helpful discussions.
References
1 R. Gadye, F. Smith, K. Westaway, H. Ali and L. Baldisera,
Tetrahedron Lett., 1986, 27, 279.
2 R. J. Giguere, T. L. Bray, S. M. Ducan and G. Majetich, Tetrahedron
Lett., 1986, 27, 4945.
Ethyl 5-(N,N-dimethylamino)-6-cyano-4-azaindole-7-
carboxylate (51)
3 (a) S. Caddick, Tetrahedron, 1995, 51, 10403; (b) C. R. Strauss and
R. W. Trainer, Aust. J. Chem., 1995, 48, 1665; (c) S. A. Galema,
Chem. Soc. Rev., 1997, 26, 233; (d ) B. C. Ranu, S. K. Guchhait,
K. Gosh and A. Patre, Green Chem., 2000, 2, 5.
4 (a) A. Loupy and L. Perreux, Tetrahedron, 2001, 57, 9199;
(b) R. Lindström, J. Tierney, B. Wathey and J. Westman,
Tetrahedron, 2001, 57, 9225; (c) In Microwave in Organic Synthesis,
ed. A. Loupy, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim,
2002; (d ) H. E. Blackwell, Org. Biomol. Chem., 2003, 1, 1251.
5 S. V. Ley, A. G. Leach and R. I. Storer, J. Chem. Soc., Perkin Trans.
1, 2001, 358.
Yellow solid, 63% yield, Rf = 0.33 (light petroleum : EtOAc =
7 : 3); mp 150 ЊC; (Found: C, 61.19, H, 6.54, N, 20.12 C13-
H14N4O4 requires C, 61.30, H, 6.61, N, 20.42%); δH(400 MHz;
CDCl3) 9.60 (1H, bs, NH ), 7.61 (1H, m, H-3), 6.60 (1H, m, H-
2), 4.54 (2H, q, J 7 Hz, CH2CH3), 3.14 (6H, s, NMe2), 1.53 (3H,
t, J 7 Hz, CH CH ); δ (100 MHz; CDCl ) 164.5 (C᎐O), 161.4
᎐
2
3
C
3
᎐
(C-5), 149.0 (C-3Ј), 133.5 (C-3), 123.0 (C-7Ј), 117.5 (C᎐N),
᎐
115.4 (C-6), 103.1 (C-2), 90.2 (C-7), 62.8 (CH2CH3), 42.7
(NMe2), 14.0 (CH2CH3); νmax(neat)/cmϪ1 3313, 2935, 1725,
1605, 1412, 1382, 1269, 1114, 1024, 876, 789; m/z (ϩESI)
281.1012 (Mϩ, C13H14N4O4 requires 281.1014) 206.1 (40%),
231.1 (30%), 259.1 (28%).
6 S. V. Ley and S. J. Taylor, Bioorg. Med. Chem. Lett., 2002, 12, 1813.
7 J. Habermann, S. V. Ley and J. S. Scott, J. Chem. Soc., Perkin Trans.
1, 2001, 1253.
8 (a) I. R. Baxendale, S. V. Ley and C. Piutti, Angew. Chem., Int. Ed.,
2002, 41, 2194; (b) I. R. Baxendale, S. V. Ley, M. Nesi and C. Piutti,
Tetrahedron, 2002, 58, 6285.
9 H. Kiyota, D. J. Dixon, C. K. Luscombe, S. Hettstedt and S. V. Ley,
Org. Lett., 2002, 4, 3223.
Transfer hydrogenation of enamines to the corresponding indoles
10 (a) J. E. Saxton, Nat. Prod. Rep., 1997, 559; (b) M. Somei and
F. Yamada, Nat. Prod. Rep., 2003, 20, 216; (c) U. Pindur and
T. Lemster, Curr. Med. Chem., 2001, 8, 1681; (d ) U. Pindur and
A. Aygun, Curr. Med. Chem., 2003, 10, 1113; (e) J. W. Blunt,
B. R. Copp, M. H. G. Munno, P. T. Northcote and M. R. Prinsep,
Nat. Prod. Rep., 2003, 20, 1; ( f ) T. J. Mabry, J. Nat. Prod., 2001,
64, 1594; (g) J. W. Fahey, A. T. Zalcmann and P. Talalay,
Phytochemistry, 2002, 59, 237; (h) V. M. Dembitsky, Russ. J. Bioorg.
Chem., 2002, 28, 170.
11 (a) For a general overview of the area see: R. J. Sundberg, in Indoles,
ed. A.R. Katritzky, O. Meth-Cohn and C.W. Rees, Academic Press,
London, 1996; (b) G. W. Gribble, J. Chem. Soc., Perkin Trans. 1,
2000, 1045; (c) T. L. Gilchrist, J. Chem. Soc., Perkin Trans. 1, 2001,
2491; (d ) P. G. Baraldi, R. Romagnoli, N. Bianchi and R. Gambari,
Bioorg. Med. Chem., 2003, 11, 2381; (e) P. Barraja, P. Diana,
A. Lauria, A. Montalbano, A. M. Almerico, G. Dattolo and
G. Cirrincione, Anticancer Res., 2002, 22, 837; ( f ) H. Yu,
T. Prisinzano, C. M. Dersch, J. Marcus, R. B. Rothman, A. E.
Jacobson and K. C. Rice, Bioorg. Med. Chem. Lett., 2002, 12, 165;
(g) I. Moubax, N. Bontemps-Subielos, B. Banaigs, G. Combaut,
P. Huitorel, J. P. Girard and D. Pesands, Environ. Toxicol. Chem.,
2001, 20, 589; (h) T. M. Kamenecka and S. J. Danishefsky, Chem.
Eur. J., 2001, 7, 41; (i) D. O. Arnaiz, Z. S. Zhao, A. Liang, L. Trinh,
M. Whitlow, S. K. Koovakkat and K. J. Shaw, Bioorg. Med. Chem.
Lett., 2000, 10, 957; (j) H. Seto, S. Fujioka, H. Koshino, T. Suengo,
S. Yoshida, T. Watanabe and S. Takatsuto, Phytochemistry, 1999, 52,
815; (k) S. M. Bromidge, S. Dabbs, D. T. Davies, D. M. Duckworth,
I. T. Forbes, P. Ham, G. E. Jones, F. D. King, D. V. Saunders,
S. Starr, K. M. Thewlis, P. A. Wyman, F. E. Blaney, C. B. Naylor,
F. Bailey, T. P. Balckburn, V. Holland, G. A. Kennett, G. J. Riley and
M. D. Wood, J. Med. Chem., 1998, 41, 1598.
using Pd-EnCat/HCOOH/Et3N25b
trans-2-[β-(Dimethylamino)vinyl]-nitronaphthalene 37 (70 mg,
0.29 mmol., 1 eq.) was dissolved in anhydrous EtOAc (5 mL).
To the solution was added, catalyst Pd-EnCat (loading
0.4 mmol gϪ1) (43.58 mg, 0.017 mmol., 6 mol%) followed by
Et3N (0.203 mL, 147 mg, 1.45 mmol., 5 eq.) and HCOOH
(0.06 mL, 67 mg, 1.45 mmol., 5 eq.). The mixture was stirred at
room temperature for 24 h. The reaction was monitored by
TLC and LCMS. Pd-EnCat catalyst was removed by fil-
tration, and the filtrate was washed with saturated NH4Cl solu-
tion (3 × 10 mL). The organic solution was dried over Na2SO4,
before concentrating under reduced pressure. Filtration of the
crude material through a bond elut silica cartridge and re-
crystallisation from CH2Cl2/light petroleum (1 : 3) gave the
corresponding indole, 1H-benz[g]indole 47, (48.5 mg, 78%) as
an off-white solid. 1H NMR was in agreement with the
previously prepared sample.
Microwave-assisted transfer hydrogenation of enamines to the
corresponding indoles using Pd-EnCat/HCOOH/Et3N
To
a
solution of trans-2-[β-(dimethylamino)vinyl]-nitro-
naphthalene37 (40 mg, 0.165 mmol., 1 eq.) dissolved in
anhydrous EtOAc (3 mL) was added Pd-EnCat catalyst
(0.4 mmol gϪ1) (41.2 mg, 0.017 mmol., 10 mol%) followed
by Et3N (0.115 mL, 83 mg, 0.82 mmol., 5 eq.) and HCOOH
(0.311 mL, 38 mg, 0.82 mmol., 5 eq.). The mixture was
heated in the Emrys Liberator for 2 h at 120 ЊC.16 Pd-EnCat
catalyst was removed by filtration, and the filtrate was
washed with saturated NH4Cl solution (3 × 10 mL). The
organic solution was dried over Na2SO4 before concentrating
under reduced pressure. Filtration of the crude material
through a bond elut silica cartridge and recrystallisation
from CH2Cl2/light petroleum (1 : 3) gave the corresponding
indole, 1H-benz[g]indole 47, (18 mg, 68%) as an off-white solid.
1H NMR was in agreement with the previously prepared
sample.
12 (a) M. Vlachou, A. Tsotinis, L. R. Kelland and D. E. Thurston,
Heterocycles, 2002, 57, 129; (b) M. Vlachou, A. Tsotinis, L. R.
Kelland and D. E. Thurston, Eur. J. Pharm. Sci., 2002, 17, 139;
(c) H. R. Peng, D. I. Kim, J. N. Sarkaria, Y. S. Cho, R. T. Abraham
and L. H. Zalkow, Bioorg. Med. Chem., 2002, 10, 167; (d ) M. E. Suh,
M. J. Kang and S. Y. Park, Bioorg. Med. Chem., 2001, 9, 2987;
(e) M. G. Ferlin, G. Chiarelotto, F. Antonucci, L. Caparrotta and
G. Froldi, Eur. J. Med. Chem., 2002, 37, 427; ( f ) M. F. Brana,
M. Cacho, A. Gradillas, B. de Pascual-Teresa and A. Ramos,
Curr. Pharm. Design, 2001, 7, 1745.
13 (a) M. G. Ferlin, B. Gatto, G. Chiarelotto and M. Palumbo,
Bioorg. Med. Chem., 2000, 8, 1415; (b) M. G. Ferlin, B. Gatto,
G. Chiarelotto and M. Palumbo, Bioorg. Med. Chem., 2001, 9, 1843.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 6 0 – 1 6 7
166

View Article Online
14 (a) D. B. Repke and R. D. Clark, Heterocycles, 1984, 22, 195;
(b) A. D. Batcho and W. Leimgruber, Org. Synth., 1985, 63, 214;
(c) A. D. Batcho and W. Leimgruber, US Patent, 1973, 3 732 245;
(d ) A. D. Batcho and W. Leimgruber, US Patent, 1976, 3 976 639;
(e) A. D. Batcho and W. Leimgruber, Third International Congress
of Heterocyclic Chemistry, Japan, 1971, Aug. 23–27.
15 (a) C. I. Clark, J. M. White, D. P. Kelly, R. F. Martin and
P. Lobachevsky, Aust. J. Chem., 1998, 51, 243; (b) J. W. Coe, M. G.
Vetelino and M. J. Bradlee, Tetrahedron Lett., 1996, 37, 6045;
(c) E. C. Taylor, W. B. Young and C. C. Ward, Tetrahedron Lett.,
1993, 34, 4595; (d ) S. Grivas, Curr. Org. Chem., 2000, 4, 707.
16 A fully automated coherent Emrys Liberator microwave system
was used. This was purchased from Personal Chemistry: Hamnes-
planaden 5, 75319 Uppsala, Sweden; www.personalchemistry.com.
17 (a) Y. Wan, M. Alterman, M. Larhed and A. Hallberg, J. Org.
Chem., 2002, 67, 6232; (b) A. Rusina and A. A. Vlcek, Nature, 1965,
206, 295; (c) P. Serp, M. Hernandez, B. Richard and P. Kalck, Eur. J.
Inorg. Chem., 2001, 2327.
S. Miao, Tetrahedron, 1992, 48, 2919; (d ) P. J. Harrington and L. S.
Hegedus, J. Org. Chem., 1984, 15, 2657.
24 (a) C. Ramarao, S. V. Ley, S. C. Smith, I. M. Shirley and
N. DeAlmeida, Chem. Commun., 2002, 1132; (b) S. V. Ley,
C. Ramarao, R. S. Gordon, A. B. Holmes, A. J. Morrison, I. F.
McConvey, I. M. Shirley, S. C. Smith and M. D. Smith, Chem.
Commun., 2002, 1134.
25 (a) N. Bremeyer, S. V. Ley, C. Ramarao, I. M. Shirley and S. C.
Smith, Synlett, 2002, 1843; (b) J. Q. Yu, H. C. Wu, C. Ramarao, J. B.
Spencer and S. V. Ley, Chem. Commun., 2003, 678.
26 A. A. A. Robertson and N. P. Botting, Tetrahedron, 1999, 55, 13269.
27 Hoffman-La Roche, US Patent, 1976, 3976639.
28 U. Laban, D. Kurrash-Orbaugh, D. Marona-Lewicka and D. E.
Nicholas, Bioorg. Med. Chem. Lett., 2001, 11, 793.
29 (a) R. D. Clark and D. B. Repke, J. Heterocycl. Chem., 1985, 22, 121;
(b) D. J. Madge, R. Hazelwood, R. Iger, H. T. Jones and M. Salters,
Bioorg. Med. Chem. Lett., 1996, 6, 857.
30 G. W. Gribble, M. G. Saulnier, J. A. Obaza-Nutaitis and D. M.
Ketcha, J. Org. Chem., 1992, 57, 5891.
31 M. Katayama, Biosci. Biotechnol., Biochem., 2000, 808.
32 H. Biere, E. Schroeder, H. Ahrens, J.-F. Kapp and I. Boettcher,
Eur. J. Med. Chem., 1982, 17, 27.
33 E. C. Riesgo, X. Jin and R. P. Thummel, J. Org. Chem., 1996, 61,
3017.
34 Aldrich Chemical Catalogue 2003-2004, Catalogue No.: I-340-8;
CAS No.: 120-72-9.
18 The Bond Elut cartridges were purchased from Varian Ltd: 28,
Manor Road, Walton-on-Thames, Surrey, UK KT12 2QF [fax:
ϩ44(0)-1932-228769, www.varianinc.com].
19 T. Durand-Reville, L. B. Gobbi, B. L. Gray, S. V. Ley and J. S. Scott,
Org. Lett., 2002, 4, 3847.
20 CCDC reference numbers 217042 (compound 6), 218709
(compound 29), 217043 (compound 31), 217044 (compound 33),
220449 (compound 51). See http://www.rsc.org/suppdata/ob/b3/
b313012f/ for crystallographic data in.cif or other electronic format.
21 Similar problems were encountered when 2-nitro-m-xylene was
irradiated using the same reaction conditions (180 ЊC for 2 h), it was
found that substantial quantities of starting material still remained
accompanied by the formation of polymeric structures as indicated
by 1H NMR and MS.
35 M. P. Collins, G. B. Drew, J. Mann and H. Finch, J. Chem. Soc.,
Perkin Trans. 1, 1992, 23, 3211.
36 K. Masami, A. K. Sinhabahu and R. T. Borchardt, J. Heterocycl.
Chem., 1987, 24, 1499.
37 D. B. Repko and M. J. Ferguson, J. Heterocycl. Chem., 1982, 19,
845.
22 (a) L. I. Kruse, Heterocycles, 1981, 16, 1981; (b) H. Vorbrüggen,
38 M. Kawase, T. Kitamura and Y. Kikugawa, J. Org. Chem., 1989, 54,
Angew. Chem., Int. Ed., 1963, 2, 211.
3394.
23 (a) M. P. Moyer, J. F. Shiurba and H. Rapoport, J. Org. Chem., 1986,
5, 5106; (b) Y. Konda-Yamada, C. Okada, K. Yoshida, Y. Umeda,
S. Arima, M. Sato, T. Kai, H. Takayanagi and Y. Harigaya,
Tetrahedron, 2002, 58, 7851; (c) W. A. Ayer, P. A. Craw, Y.-T. Ma and
39 R. S. Hosmane, S. P. Hiremath and S. W. Schneller, J. Chem. Soc.,
Perkin Trans 1, 1973, 2450.
40 G. Bartoli, G. Palmieri, M. Bosco and R. Dalpozzo, Tetrahedron
Lett., 1989, 30, 2129.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 6 0 – 1 6 7
167