Synthesis of 2-aryl-6-methyl-5-nitroquinoline derivatives as potential prodrug systems for reductive activation

Article abstract of DOI:10.1016/j.tet.2008.01.043

A range of novel 2-aryl-5-nitroquinolines have been synthesised as potential prodrug systems for bioreductive activation. Thus 5-nitroquinoline underwent vicarious nucleophilic substitution at C-6 with bromoform anion to give, after hydrolysis and reduction, the quinoline-6-methanol. Introduction of chlorine at C-2 was followed by palladium-catalysed Suzuki coupling to install the 2-aryl substituent. A fluorescent model 'drug', 7-hydroxy-4-methylcoumarin was coupled to the 6-hydroxymethyl group, and its fragmentation upon reduction of the nitro group was investigated.

Full text of DOI:10.1016/j.tet.2008.01.043

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2816e2823
www.elsevier.com/locate/tet
Synthesis of 2-aryl-6-methyl-5-nitroquinoline derivatives
as potential prodrug systems for reductive activation
Gavin D. Couch a, Philip J. Burke b, Richard J. Knox b, Christopher J. Moody a,
*
a School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
b Morvus Technology Ltd, Porton Down Science Park, Salisbury, Wiltshire SP4 0JQ, UK
Received 1 October 2007; received in revised form 17 December 2007; accepted 10 January 2008
Available online 16 January 2008
Abstract
A range of novel 2-aryl-5-nitroquinolines have been synthesised as potential prodrug systems for bioreductive activation. Thus 5-nitroquino-
line underwent vicarious nucleophilic substitution at C-6 with bromoform anion to give, after hydrolysis and reduction, the quinoline-6-meth-
anol. Introduction of chlorine at C-2 was followed by palladium-catalysed Suzuki coupling to install the 2-aryl substituent. A fluorescent model
‘drug’, 7-hydroxy-4-methylcoumarin was coupled to the 6-hydroxymethyl group, and its fragmentation upon reduction of the nitro group was
investigated.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
In many systems, the activating reaction is hydrolysis of the
prodrug into its active form by enzymes such as carboxypep-
tidases, aminopeptidases, phosphatases, glucuronidases, etc.1
However, a different but complementary strategy uses biore-
duction of aromatic nitro compounds to trigger the formation
of, or release of, a reactive species.2e6 The bioreduction of the
strongly electron-withdrawing nitro group into a hydroxyl-
amino or amino group induces a dramatic change in reactivity
of the aromatic ring that can be used to deliver cytotoxic
species to tumours. Interest in this area stems from early
work on tretazicar [5-(aziridin-1-yl)-2,4-dinitrobenzamide],
formerly designated as CB1954, 1, a compound that shows
true antitumour selectivity. This compound undergoes reduc-
tive activation to the hydroxylamine 2, subsequent acetylation
of which generates a powerful electrophile 3 capable of cross-
linking DNA (Scheme 1).7 However, a more common tactic is
to exploit the ‘electronic switch’ engendered by nitro reduc-
tion to trigger the fragmentation of the prodrug molecule
into the biologically active drug, as illustrated by nitrobenzyl
phosphoramide mustard 4.8 In this case the hydroxylamine
5 formed upon bioreduction initiates cleavage of the benzylic
CeO bond to eliminate the free phosphoramide mustard 7
together with a highly electrophilic quinonemethide derivative
The development of prodrug systems for use in cancer
therapy is of considerable interest to the medicinal chemistry
community since such agents have the potential to improve tu-
mour selectivity of chemotherapeutic agents thereby reducing
unwanted side effects, and hence prodrugs have been devel-
oped that are converted by enzymes into active cytotoxic
agents.1 However, in order for the treatment to be selective,
the enzyme needs to be present in cancer cells at significantly
higher levels than normal cells. Conventional prodrug therapy
relies upon the upregulation of the relevant enzymes in tumours,
i.e., the enzyme is naturally overexpressed in tumour cells, but
not in normal cells. More recent strategies have focused on
targeted drug delivery mechanisms, whereby the activating en-
zyme is specifically delivered into the tumour cells by means of
a tumour specific antibody or gene delivery systemdantibody
directed enzyme prodrug therapy (ADEPT) or gene directed en-
zyme prodrug therapy (GDEPT), respectively.
* Corresponding author.
E-mail address: c.j.moody@nottingham.ac.uk (C.J. Moody).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.043

G.D. Couch et al. / Tetrahedron 64 (2008) 2816e2823
2817
NO2
NO2
NO2
CONH2
CONH2
CONH2
acetyl-CoA
bioreduction
DNA
cross-links
AcOHN
O2N
HOHN
N
N
N
3
2
1
: Nuc
+
N(CH2CH2Cl)2
N(CH2CH2Cl)2
HON
P
P
bioreduction
6
O
O
O
O
NH2
NH2
..
O
P
NH2
O2N
HOHN
Nuc :
5
O-
4
(ClCH2CH2)2N
7
Scheme 1. Bioreductive activation of nitroarenes triggers formation of electrophilic species capable of alkylating DNA. Only bioreduction to the hydroxylamine is
showndreduction to the aniline would result in a similar fragmentation.
6; both 6 and 7 can act as electrophiles towards DNA
(Scheme 1).
the substrates for NQO1, and therefore represent a new family
of potential bioreductively activated prodrug systems. The pro-
posed fragmentation of such nitroquinolines 9 upon reductive
activation is also shown in Scheme 2.
In conventional prodrug strategies, the aerobic bioreduction
of nitroarenes can only be carried out by two endogenous en-
zymes (although other enzymes can reduce them under hypoxic
conditions). These are the related flavoenzymes NAD(P)H qui-
none oxidoreductase 1 (NQO1), also known as DT-diaphorase
or QR1 (EC 1.6.99.2), and NAD(P)H quinone oxidoreductase
2 (NQO2), now known as NRH quinone oxidoreductase 2 or
QR2. However, an alternative bioreductive prodrug approach
utilises an exogenous nitroreductase enzyme (NTR), isolated
from Escherichia coli, that appears to be a much better nitrore-
ductase than NQO1dtretazicar is reduced about 90-fold more
rapidly by NTR than by NQO1dand a targeted drug delivery
mechanism based on ADEPT or GDEPT.6 As a result of these
efforts, there are now a number of strategies based on the
bioreduction of nitroarenes, including prodrugs based on
4-nitrobenzyl derivatives,8,9 4-nitrobenzyl carbamates,10e13
2-nitrophenyl acetates14 and heteroaromatic nitro compounds
(imidazoles, furans and thiophenes).15e21 In view of this inter-
est, we now report a new series of heteroaromatic nitro com-
pounds, based on 5-nitroquinoline, as potential prodrug
systems for bioreductive activation.
The starting point was the high yielding vicarious nucleo-
philic substitution reaction of commercially available 5-nitro-
quinoline with the anion derived from bromoform.24,25 The
resulting 6-dibromomethylquinoline 10 was readily converted
into the quinoline-6-aldehyde 11 by treatment with aqueous
ethanolic silver nitrate.24 Reduction (96%) and acetylation
(93%) then gave quinoline 13 ready for introduction of the
2-substituent. This was achieved by treatment of the corre-
sponding N-oxide 14 with sulfuryl chloride (67%); final
hydrolysis gave 2-chloro-5-nitroquinoline-6-methanol 16
(Scheme 3). A range of aryl substituents were introduced
into the 2-position of the 2-chloroquinoline 16 in good yield
by Suzuki coupling with commercially available boronic acids
in the presence of Pd(dppf)Cl2 catalyst to give the correspond-
ing 2-aryl derivatives 17 (Scheme 3). In order to monitor the
proposed bioreductive activation and subsequent fragmenta-
tion of nitroquinoline-based prodrug systems, we elected to
incorporate a fluorescent model ‘drug’ moiety, namely 7-
hydroxy-4-methylcoumarin. A similar approach has been
used with 7-aminocoumarin derivatives using 4-nitrobenzyl
carbamates.26 Although the Mitsunobu coupling between the
7-hydroxycoumarin and the quinoline-6-methanol 17a was
unsuccessful, after some experimentation, it was found that
conversion of 17a into the corresponding bromide by treat-
ment with phosphorus tribromide followed by reaction with
7-hydroxy-4-methylcoumarin in the presence of caesium car-
bonate as base gave the desired quinoline 18a (Scheme 3).
2. Results and discussion
Our choice of nitroquinolines was influenced by our earlier
work on quinolinequinones 8 (Scheme 2).22,23 These simple qui-
nones are excellent substrates for recombinant human NQO1
(hNQO1), and hence we speculated that other 2-arylquinoline
derivatives such as 2-aryl-5-nitroquinolines 9 might also be
O
+
:NHOH
D
NO2
MeO
D
NOH
bioreduction
N
Ar
N
Ar
O
N
R
N
R
8
9
cytotoxic
DH
Scheme 2. Structure of quinolinequinone substrates 8 for hNQO1, and proposed reductive fragmentation of 5-nitroquinolines 9 showing release of the drug D and
formation of a cytotoxic species.

2818
G.D. Couch et al. / Tetrahedron 64 (2008) 2816e2823
The thiophene derivative 18b was similarly prepared, although
in poor yield.
separated by chromatography to give the fluorescent 7-
hydroxy-4-methylcoumarin (95%) and 5-amino-6-methyl-2-
phenylquinoline 20 (95%) (Scheme 4) and identified by
comparison with authentic sample obtained by independent
synthesis as described in Section 3.4. It therefore appears
that 5-nitroquinoline derivatives do undergo fragmentation
upon reduction resulting in release of a phenolic leaving group
from the 6-methyl position. Detailed biological evaluation of
such systems is awaited.
NO2
NO2
t
BuOK, CHBr3
Br2HC
THF, DMF
(85%)
N
N
10
aq AgNO3
EtOH
(86%)
3. Experimental section
NO2
NO2
OHC
NaBH4, MeOH
(96%)
HO
3.1. General procedures
N
N
11
12
Commercially available reagents and solvents were used
throughout without further purification, except tetrahydrofu-
ran, dichloromethane and diethyl ether, which were freshly
distilled. Light petroleum refers to the fraction with bp 40e
60 ꢀC and ether refers to diethyl ether. All reactions were
carried out under a nitrogen atmosphere. Thin layer chroma-
tography was carried out on Merck Kieselgel 60GF254 alumin-
ium foil backed plates. The plates were visualised under UV
light or by potassium permanganate stain. Flash chromatogra-
phy was carried out using Merck Kieselgel 60H silica or
Matrix silica 60, with the eluent specified. IR spectra were re-
corded using a Nicolet Magna FT-550 spectrometer. Spectra
were recorded as films between NaCl plates or as KBr disks.
1H and 13C NMR spectra were recorded using Bruker
AC300, AC400, AV400 and DRX500 machines (1H frequen-
cies 300, 400 and 500 MHz, 13C frequencies 75, 100 and
125 MHz, respectively); chemical shifts are quoted in parts
per million and coupling constants, J, are quoted in hertz. In
the 13C spectra, signals corresponding to CH, CH2 or Me
groups, as assigned from DEPT, are noted; all others are C.
High and low resolution mass spectra were carried out on a
Micromass GCT TOF high resolution mass spectrometer.
Ac2O, py
(95%)
NO2
NO2
AcO
aq H2O2, AcOH
AcO
+
(79%)
N
N
O-
13
14
SO2Cl2
(67%)
NO2
NO2
K2CO3,
aq MeOH
AcO
HO
(80%)
N
Cl
N
Cl
15
16
ArB(OH)2
Pd(dppf)Cl2
aq Na2CO3
DME
NO2
HO
N
Ar
3.1.1. General procedure A: Suzuki biaryl cross-coupling
reactions
17a Ar = Ph (80%)
1. PBr3, CHCl3
17b Ar = 2-naphthyl (65%)
17c Ar = 1-naphthyl (76%)
17d Ar = 2-thienyl (~76%))
17e Ar = 2-furyl (62%)
2. 4-Me-7-OH-coumarin
Cs2CO3, acetone
A solution of 2-chloro-5-nitroquinoline-6-methanol 16
(0.500 g, 2.1 mmol) and arylboronic acid (2.5 mmol) in 1,2-
dimethoxyethane (45 mL) was degassed under reduced pressure
and flushed with nitrogen. Pd(dppf)Cl2 (0.077 g, 0.1 mmol) was
added and the system was degassed again. Finally sodium car-
bonate (0.890 g, 8.4 mmol) dissolved in water (5 mL) was
added and the mixture was heated under reflux for 1e3 h. After
cooling, 1,2-dimethoxyethane was removed in vacuo, dichloro-
methane (50 mL) was added and the organic layer washed with
water (3ꢁ30 mL). The organic phase was dried (MgSO4), fil-
tered and the filtrate concentrated in vacuo, and the crude prod-
uct purified by column chromatography.
Me
O
NO2
O
O
N
Ar
18a Ar = Ph (62%)
18b Ar = 2-thienyl (18% from 16)
Scheme 3.
With the novel nitroquinolines available and a model drug
molecule incorporated, it only remained to establish whether
the desired fragmentation (Scheme 2) did indeed occur upon
reduction of the nitro group. Thus, the nitroquinoline-couma-
rin conjugate 18a was reduced chemically using zinc in acetic
acid; following the reaction, which likely results in complete
reduction of the nitro group to the aniline, the products were
3.1.2. General procedure B: bromination reactions
To a solution of 2-aryl-5-nitroquinoline-6-methanol 17
(1.2 mmol) in tetrahydrofuran (7 mL) and chloroform (2 mL)
was added phosphorus tribromide (0.12 mL, 1.2 mmol) at
0 ꢀC. The reaction mixture was then heated to 50 ꢀC and left

G.D. Couch et al. / Tetrahedron 64 (2008) 2816e2823
2819
Me
O
Me
NH2
O
O
NO2
Zn, AcOH
THF, heat
H3C
+
O
O
OH
N
Ph
18a
N
Ph
20
Scheme 4.
to stir overnight. After cooling, the solvents were removed in
vacuo and the residue was partitioned between saturated so-
dium hydrogen carbonate solution (10 mL) and ethyl acetate
(10 mL). The aqueous phase was further extracted with ethyl
acetate (2ꢁ10 mL). The organic phases were combined, dried
(MgSO4), filtered and the filtrate concentrated in vacuo. The
crude product was then purified by column chromatography.
of silver nitrate (4.1 g, 24.1 mmol) in hot (60 ꢀC) distilled wa-
ter (25 mL), and the reaction mixture was heated under reflux
for 2 h. After cooling, concentrated hydrochloric acid was
added (25 mL) and solvent was removed in vacuo. The residue
was treated with saturated sodium hydrogen carbonate solu-
tion, extracted with dichloromethane (3ꢁ250 mL) and the
organic phases were washed with water (150 mL). The com-
bined organic phases were dried (MgSO4) and concentrated
in vacuo to give the title compound as a brown solid (2.0 g,
86%), mp 159e160 ꢀC (from light petroleum/ethyl acetate)
(lit.24 mp 156e158 ꢀC). nmax (KBr)/cmꢂ1 1699 (C]O),
1612, 1529 (NO2), 1344 (NO2); dH (300 MHz; CDCl3) 7.62
(1H, dd, J 8.7, 4.1, H-3), 8.17 (1H, d, J 8.9, ArH), 8.26 (1H,
d, J 8.9, ArH), 8.35 (1H, d, J 8.7, H-4), 9.08 (1H, d, J 4.1,
H-2), 10.15 (1H, s, CHO); m/z (EI) 202 (Mþ, 10%), 155
(60), 144 (96), 115 (57), 102 (78), 101 (94), 99 (49), 90
(42), 89 (97), 52 (40), 51 (81).
3.1.3. General procedure C: alkylation reactions
A
solution of 7-hydroxy-4-methylcoumarin (0.070 g,
0.4 mmol) in acetone (4 mL) was treated with caesium carbon-
ate (0.240 g, 0.7 mmol) and stirred at room temperature for
15 min. The solution was then cooled to 0 ꢀC and the 6-bromo-
methylquinoline (0.4 mmol) dissolved in acetone (4 mL) was
added dropwise. The reaction mixture was allowed to reach
room temperature and stirred for 1 h. The acetone was then re-
moved in vacuo, the residue partitioned between water (25 mL)
and dichloromethane (10 mL) and the layers were separated.
The organic phase was dried (MgSO4), filtered and the filtrate
concentrated in vacuo to give the crude product. Purification
was specific to each compound.
3.2.3. 5-Nitroquinoline-6-methanol 12
To a solution of 5-nitroquinoline-6-carbaldehyde 11 (1.7 g,
8.2 mmol) in wet methanol (200 mL) was added sodium boro-
hydride (0.5 g, 13 mmol) portionwise. The reaction was stirred
at room temperature for 1 h. The reaction mixture was
quenched with hydrochloric acid (2 M) until pH 7 was
achieved and the solvent removed in vacuo. The residue was
partitioned between ethyl acetate (100 mL) and water
(50 mL), the layers were separated, the organic layer was dried
(MgSO4) and concentrated in vacuo to give the title compound
as a yellow solid (1.6 g, 96%), Rf 0.13 (light petroleum/ethyl
acetate 1:1); mp 105e107 ꢀC (from ethanol). (Found: C,
58.53; H, 3.70; N, 13.72. C10H8N2O3 requires C, 58.82; H,
3.95; N, 13.72%.) (Found: MHþ, 205.0621. C10H8N2O3þH
requires 205.0613.) nmax (KBr)/cmꢂ1 3176 (OH), 1594, 1516
(NO2), 1354 (NO2); dH (300 MHz; CDCl3) 2.97 (1H, br s,
OH), 4.86 (2H, s, CH2), 7.50 (1H, dd, J 8.6, 4.1, H-3), 7.89
(1H, d, J 8.8, ArH), 8.15 (1H, d, J 8.6, H-4), 8.21 (1H, d, J
8.8, ArH), 8.91 (1H, d, J 4.1, H-2); dC (75 MHz; CDCl3)
61.5 (CH2), 120.6 (C), 123.9 (CH), 129.4 (CH), 131.3 (CH),
133.2 (C), 133.6 (CH), 145.6 (C), 147.4 (C), 151.9 (CH);
m/z (CI) 205 (MHþ, 49%), 203 (21), 201 (32), 188 (60), 173
(32), 158 (15), 157 (10), 130 (12), 129 (10).
3.2. Nitroquinolines
3.2.1. 6-(Dibromomethyl)-5-nitroquinoline 10
To a well-stirred solution of potassium tert-butoxide (13.2 g,
117 mmol), in a mixture of dry THF (12 mL) and dry DMF
(9 mL) cooled to around ꢂ73 ꢀC, a solution of 5-nitroquinoline
(4.8 g, 27 mmol) and bromoform (7.6 g, 30 mmol) in dry DMF
(14 mL) was added dropwise, being careful that the tempera-
ture did not exceed ꢂ68 ꢀC. The mixture was allowed to stir
for 1 min and then acidified with acetic acid (15 mL). After al-
lowing the mixture to return to room temperature it was poured
into water (900 mL) and the aqueous solution was extracted
with dichloromethane (3ꢁ250 mL). The combined organic ex-
tracts were washed with water (3ꢁ350 mL), dried (MgSO4) and
concentrated in vacuo. The crude product was purified by col-
umn chromatography eluting with light petroleum/ethyl acetate
(1:1) to give the title compound as a yellow solid (7.9 g, 85%),
mp 106e108 ꢀC (from ethanol) (lit.24 mp 108e109 ꢀC). nmax
(KBr)/cmꢂ1 1593, 1524 (NO2), 1346 (NO2); dH (300 MHz;
DMSO-d6) 7.52 (1H, s, CHBr2), 7.80 (1H, dd, J 8.7, 4.2, H-
3), 8.23 (1H, d, J 8.7, H-4), 8.34 (1H, d, J 9.1, ArH), 8.42
(1H, d, J 9.1, ArH), 9.11 (1H, d, J 4.2, H-2).
3.2.4. 6-Acetoxymethyl-5-nitroquinoline 13
Acetic anhydride (12 mL) and pyridine (24 mL) were
added to 5-nitroquinoline-6-methanol 12 (1.6 g, 7.8 mmol) in
acetonitrile (40 mL). The reaction mixture was stirred at
room temperature for 1 h and quenched with saturated sodium
hydrogen carbonate solution (150 mL). The aqueous layer was
3.2.2. 5-Nitroquinoline-6-carbaldehyde 11
To a solution of 6-(dibromomethyl)-5-nitroquinoline 10
(4.0 g, 11.6 mmol) in ethanol (200 mL) was added a solution

2820
G.D. Couch et al. / Tetrahedron 64 (2008) 2816e2823
extracted with dichloromethane (3ꢁ50 mL). The combined or-
ganic phases were washed with copper sulfate solution (10%;
3ꢁ60 mL) and saturated aqueous brine solution (20 mL), dried
(MgSO4) and concentrated in vacuo to give the title compound
as an orange solid (1.8 g, 95%), Rf 0.24 (light petroleum/ethyl
acetate 1:1); mp 64e65 ꢀC (from light petroleum/ethyl ace-
tate). (Found: C, 58.45; H, 4.06; N, 11.36. C12H10N2O4
requires C, 58.54; H, 4.09; N, 11.38%.) (Found: MHþ,
247.0721. C12H10N2O4þH requires 247.0719.) nmax (KBr)/
cmꢂ1 2956, 1737 (C]O), 1625, 1595, 1523 (NO2), 1349
(NO2); dH (300 MHz; DMSO-d6) 2.08 (3H, s, Me), 5.35
(2H, s, CH2), 7.77 (1H, dd, J 8.7, 4.1, H-3), 7.98 (1H, d, J
8.9, ArH), 8.28 (1H, d, J 8.7, H-4), 8.34 (1H, d, J 8.9, ArH),
9.09 (1H, d, J 4.1, H-2); dC (75 MHz; DMSO-d6) 20.7 (Me),
61.7 (CH2), 119.9 (C), 124.8 (CH), 128.8 (C), 130.7 (CH),
131.7 (CH), 132.6 (CH), 145.1 (C), 145.5 (C), 151.8 (CH),
170.3 (C); m/z (CI) 247 (MHþ, 19%), 189 (24), 188 (28),
187 (100), 173 (16), 171 (17), 61 (40).
3.2.7. 2-Chloro-5-nitroquinoline-6-methanol 16
To a solution of 6-acetoxymethyl-2-chloro-5-nitroquinoline
15 (4.0 g, 14.3 mmol) in 70% aqueous methanol (300 mL) was
added potassium carbonate (7.9 g, 57.0 mmol). The reaction
mixture was stirred at room temperature for 1 h. The methanol
was then removed in vacuo, dichloromethane (100 mL) and
water (50 mL) were added, and the layers were separated.
The organic phase was dried (MgSO4) and concentrated in va-
cuo. The crude product was purified by column chromatogra-
phy eluting with light petroleum/ethyl acetate (4:1) to give the
title compound as an off-white solid (2.72 g, 80%), Rf 0.38
(light petroleum/ethyl acetate 1:1); mp 116e118 ꢀC (from di-
chloromethane/hexane). (Found: C, 50.67; H, 2.98; N, 11.80.
C10H7ClN2O3 requires C, 50.42; H, 2.96; N, 11.74%.) (Found:
Mþ, 238.0138. C10H735ClN2O3 requires 238.0145.) nmax (KBr)/
cmꢂ1 3430 (OH), 1628, 1588, 1525 (NO2), 1364 (NO2), 821;
dH (300 MHz; DMSO-d6) 4.76 (2H, s, CH2), 5.81 (1H, s, OH),
7.79 (1H, d, J 9.0, ArH), 8.07 (1H, d, J 8.9, ArH), 8.25 (1H, d,
J 8.9, ArH), 8.30 (1H, d, J 9.0, ArH); dC (75 MHz; DMSO-d6)
59.6 (CH2), 118.8 (C), 125.4 (CH), 130.7 (CH), 131.8 (CH),
134.5 (CH), 134.8 (C), 144.5 (C), 146.3 (C), 151.6 (C); m/z
(EI) 240/238 (Mþ, 6/16%), 220 (30), 193 (15), 178/176 (39/
87), 166 (44), 163 (53), 162 (80), 161 (17), 151 (23), 150
(27), 149 (54), 141 (65), 129 (75), 128 (96), 127 (95), 102 (50).
3.2.5. 6-Acetoxymethyl-5-nitroquinoline-N-oxide 14
To a solution of 6-acetoxymethyl-5-nitroquinoline 13
(0.43 g, 1.8 mmol) in acetic acid (2 mL) was added hydrogen
peroxide (35%; 0.8 mL). The mixture was heated to 80 ꢀC for
4 h. After cooling, the mixture was poured into water (10 mL)
and neutralised with saturated sodium hydrogen carbonate
solution (35 mL). The aqueous mixture was extracted with di-
chloromethane (3ꢁ60 mL), the combined organic phases were
dried (MgSO4) and concentrated in vacuo. The crude product
was purified by column chromatography eluting with ethyl
acetate/methanol (19:1) to give the title compound as a yellow
solid (0.37 g, 79%), Rf 0.11 (ethyl acetate); mp 101e102 ꢀC
(from ethyl acetate/light petroleum). (Found: Mþ, 262.0590.
C12H10N2O5 requires 262.0592.) nmax (KBr)/cmꢂ1 3080,
1739 (C]O), 1569, 1527 (NO2), 1352 (NO2), 1262, 1191,
1055; dH (300 MHz; CDCl3) 2.14 (3H, s, Me), 5.33 (2H, s,
CH2), 7.47 (1H, dd, J 8.9, 6.0, H-3), 7.69 (1H, d, J 8.9, H-
4), 7.85 (1H, d, J 9.0, ArH), 7.98 (1H, d, J 6.0, H-2), 8.92
(1H, d, J 9.0, ArH); dC (75 MHz; CDCl3) 21.0 (Me), 61.8
(CH2), 119.9 (CH), 123.6 (C), 123.7 (CH), 124.1 (CH),
130.0 (CH), 130.6 (C), 136.8 (CH), 141.7 (C), 146.6 (C),
170.6 (C); m/z (EI) 262 (Mþ, 58%), 216 (53), 200 (27), 186
(18), 175 (44), 173 (24), 157 (20), 145 (20), 130 (29), 129
(40), 128 (34), 127 (16), 115 (25), 103 (27), 102 (24), 90 (19).
3.2.8. 5-Nitro-2-phenylquinoline-6-methanol 17a
2-Chloro-5-nitroquinoline-6-methanol16 (0.500 g,2.0 mmol)
was reacted with benzeneboronic acid (0.270 g, 2.2 mmol)
following the general procedure A. The crude product was
purified by column chromatography eluting with light petro-
leum/ethyl acetate (1:1) to give the title compound as a col-
ourless solid (0.470 g, 80%), Rf 0.46 (light petroleum/ethyl
acetate 4:1); mp 154e156 ꢀC (from ethyl acetate/
ethanol). (Found: C, 68.14; H, 4.31; N, 9.95. C16H12N2O3 re-
quires C, 68.56; H, 4.32; N, 9.99%.) (Found: MHþ, 281.0918.
C16H12N2O3þH requires 281.0926.) nmax (KBr)/cmꢂ1 3206
(OH), 2923, 2849, 1597, 1582, 1520 (NO2), 1468, 1354
(NO2), 1071; dH (300 MHz; DMSO-d6) 4.77 (2H, d, J 5.7,
CH2), 5.80 (1H, t, J 5.7, OH), 7.56e7.63 (3H, m, ArH),
8.03 (1H, d, J 8.9, ArH), 8.33 (1H, d, J 8.9, ArH), 8.30e
8.34 (4H, m, ArH); dC (75 MHz; DMSO-d6) 59.7 (CH2),
118.7 (C), 121.6 (CH), 127.8 (CH), 129.4 (CH), 129.6 (CH),
130.7 (CH), 131.6 (CH), 132.9 (CH), 133.7 (C), 137.9 (C),
144.7 (C), 146.7 (C), 157.5 (C); m/z (CI) 281 (MHþ, 59%),
263 (100), 268 (39), 250 (19), 249 (62).
3.2.6. 6-Acetoxymethyl-2-chloro-5-nitroquinoline 15
Sulfuryl chloride (3 mL) was added to 6-acetoxymethyl-5-
nitroquinoline-N-oxide 14 (0.17 g, 0.7 mmol) and the mixture
was heated to 60 ꢀC for 3.5 h. After cooling, dichloromethane
(15 mL) and water (15 mL) were added to the mixture and the
mixture was stirred for 1 h to dissolve any insoluble material.
The layers were separated and the organic phase was dried
(MgSO4) and concentrated in vacuo to give the crude product
as a brown oil (0.12 g, 67%). dH (300 MHz; CDCl3) 2.07 (3H,
s, Me), 5.29 (2H, s, CH2), 7.50 (1H, d, J 8.9, ArH), 7.78 (1H,
d, J 8.9, ArH), 8.11 (1H, d, J 8.6, ArH), 8.14 (1H, d, J 8.6,
ArH). No further characterisation was carried out and the com-
pound was used directly in the next step.
3.2.9. 2-(Naphth-2-yl)-5-nitroquinoline-6-methanol 17b
2-Chloro-5-nitroquinoline-6-methanol 16(0.500 g,2.0 mmol)
was reacted with 2-naphthaleneboronic acid (0.400 g,
2.2 mmol) following the general procedure A. The crude
product was purified by column chromatography eluting
with light petroleum/ethyl acetate (1:1) to give the title com-
pound as a colourless solid (0.450 g, 65%), Rf 0.36 (light
petroleum/ethyl acetate 4:1); mp 205e207 ꢀC (from ethyl
acetate/ethanol). (Found: MHþ, 331.1082. C20H14N2O3þH re-
quires 331.1078.) nmax (KBr)/cmꢂ1 3418 (OH), 2958, 1622,
1592, 1537 (NO2), 1365 (NO2); dH (400 MHz; DMSO-d6)

G.D. Couch et al. / Tetrahedron 64 (2008) 2816e2823
2821
4.78 (2H, d, J 5.6, CH2), 5.78 (1H, t, J 5.6, OH), 7.60e7.62
(2H, m, ArH), 7.99e8.05 (2H, m, ArH), 8.10e8.13 (2H, m,
ArH), 8.33e8.40 (2H, m, ArH), 8.47e8.53 (2H, m, ArH),
8.80 (1H, s, ArH); dC (100 MHz; DMSO-d6) 59.3 (CH2),
118.4 (C), 121.5 (CH), 124.4 (CH), 126.7 (CH), 127.4
(CH), 127.4 (CH), 127.6 (CH), 128.6 (CH), 128.9 (CH),
129.3 (CH), 131.2 (CH), 132.5 (CH), 133.0 (C), 133.4 (C),
133.8 (C), 134.9 (C), 144.3 (C), 146.4 (C), 157.4 (C); m/z
(CI) 331 (MHþ, 83%), 330 (26), 314 (37), 313 (100), 298
(14), 297 (24), 270 (13).
152.6 (C), one C unobserved; m/z (EI) 270 (Mþ, 79%), 238
(20), 222 (25), 208 (34), 196 (87), 195 (41), 194 (50), 179
(51), 176 (29), 167 (100), 140 (64), 139 (49).
3.2.13. 6-Bromomethyl-5-nitro-2-phenylquinoline
5-Nitro-2-phenylquinoline-6-methanol
17a
(0.560 g,
2.0 mmol) was treated with phosphorus tribromide (0.2 mL,
2.2 mmol) following the general procedure B. The crude
product was purified by column chromatography eluting
with light petroleum/ethyl acetate (4:1) to give the title com-
pound as a colourless solid (0.651 g, 95%), Rf 0.68 (light
petroleum/ethyl acetate 4:1); mp 156e158 ꢀC (from ethyl
acetate/light petroleum). (Found: C, 56.00; H, 3.25; N,
8.07. C16H11BrN2O2 requires C, 56.00; H, 3.23; N, 8.16%.)
3.2.10. 2-(Naphth-1-yl)-5-nitroquinoline-6-methanol 17c
2-Chloro-5-nitroquinoline-6-methanol16(0.500 g,2.0 mmol)
was reacted with 1-naphthaleneboronic acid (0.400 g,
2.2 mmol) following the general procedure A. The crude prod-
uct was purified by column chromatography eluting with light
petroleum/ethyl acetate (1:1) to give the title compound as a col-
ourless solid (0.525 g, 76%), Rf 0.38 (light petroleum/ethyl
acetate 4:1); mp 202e204 ꢀC (from ethyl acetate/ethanol).
(Found: MHþ, 331.1096. C20H14N2O3þH requires
331.1082.) nmax (KBr)/cmꢂ1 3306 (OH), 3063, 2922, 2863,
1591, 1555, 1524 (NO2), 1356 (NO2), 1080; dH (300 MHz;
DMSO-d6) 4.81 (2H, d, J 5.7, CH2), 5.84 (1H, t, J 5.7, OH),
7.53e7.81 (4H, m, ArH), 8.02e8.17 (5H, m, ArH), 8.37 (1H,
d, J 2.3, ArH), 8.39 (1H, d, J 2.3, ArH); dC (75 MHz;
DMSO-d6) 59.7 (CH2), 118.5 (C), 125.6 (CH), 125.8 (CH),
126.0 (CH), 126.6 (CH), 127.3 (CH), 128.6 (CH), 128.9
(CH), 129.6 (CH), 130.0 (CH), 130.7 (C), 131.2 (CH), 132.9
(CH), 133.8 (C), 134.0 (C), 137.4 (C), 144.7 (C), 146.6 (C),
160.2 (C); m/z (CI) 331 (MHþ, 64%), 330 (18), 314 (36), 313
(100), 300 (33), 298 (26), 285 (16), 271 (13).
(Found: Mþ, 341.9988. C16H BrN2O2 requires 342.0004.)
79
11
nmax (KBr)/cmꢂ1 1597, 1539, 1520 (NO2), 1446, 1359 (NO2),
799; dH (300 MHz; CDCl3) 4.58 (2H, s, CH2), 7.43e7.51
(3H, m, ArH), 7.72 (1H, d, J 8.9, ArH), 7.96 (1H, d, J 8.9,
ArH), 8.09e8.15 (3H, m, ArH), 8.23 (1H, d, J 8.9, ArH); dC
(75 MHz; CDCl3) 27.0 (CH2), 119.6 (C), 121.9 (CH), 128.1
(CH), 128.4 (C), 129.5 (CH), 130.8 (CH), 131.2 (CH), 131.9
(CH), 134.1 (C), 138.5 (CH), 146.6 (C), 148.1 (C), 159.5 (C);
m/z (FI) 344/342 (Mþ, 94/100%).
3.2.14. 6-Bromomethyl-5-nitro-2-(thien-2-yl)quinoline
The impure 5-nitro-2-(2-thienyl)quinoline-6-methanol 17d
(0.20 g, 0.7 mmol) was treated with phosphorus tribromide
(0.07 mL, 0.7 mmol) following the general procedure B. The
crude product was purified by column chromatography eluting
with light petroleum/ethyl acetate (4:1) to give the title com-
pound as a bright yellow solid (0.195 g, 61% over 2 steps), Rf
0.67 (light petroleum/ethyl acetate 4:1); mp 179e181 ꢀC
(from chloroform). (Found: MHþ, 348.9631. C14H799BrN2O2
þH requires 348.9646.) nmax (KBr)/cmꢂ1 1596, 1580, 1523
(NO2), 1456, 1445, 1364 (NO2), 1099, 752; dH (300 MHz;
DMSO-d6) 4.95 (2H, s, CH2), 7.35 (1H, dd, J 5.1, 3.8, ArH),
7.93 (1H, d, J 5.1, ArH), 8.07 (1H, d, J 8.9, ArH), 8.20 (1H,
d, J 3.8, ArH), 8.31 (1H, d, J 8.9, ArH), 8.33 (1H, d, J 9.1,
ArH), 8.41 (1H, d, J 9.1, ArH); dC (75 MHz; DMSO-d6) 28.0
(CH2), 118.8 (C), 121.0 (CH), 128.3 (C), 129.3 (CH), 129.3
(CH), 131.7 (CH), 131.8 (CH), 132.2 (CH), 132.8 (CH),
143.6 (C), 146.2 (C), 147.1 (C), 154.1 (C); m/z (CI) 351/349
(MHþ, 14/13%), 271 (25), 270 (16), 269 (100), 253 (7).
3.2.11. 5-Nitro-2-(2-thienyl)quinoline-6-methanol 17d
2-Chloro-5-nitroquinoline-6-methanol16(0.500 g,2.0 mmol)
was reacted with 2-thiophene boronic acid (0.320 g,
2.1 mmol) following the general procedure A. Complete pu-
rification of this compound proved to be difficult, and there-
fore the crude product (0.447 g, 76%) was used in the next
step without further purification or characterisation.
3.2.12. 2-(Fur-2-yl)-5-nitroquinoline-6-methanol 17e
2-Chloro-5-nitroquinoline-6-methanol16(0.500 g,2.0 mmol)
was reacted with 2-furan boronic acid (0.280 g, 2.4 mmol)
following the general procedure A. The crude product was
purified by column chromatography eluting with light petro-
leum/ethyl acetate (7:3) to give the title compound as a pale
yellow solid (0.350 g, 62%), Rf 0.36 (light petroleum/ethyl
acetate 1:1); mp 179e181 ꢀC (from methanol/hexane). (Found:
Mþ, 270.0643. C14H10N2O4 requires 270.0641.) nmax (CHCl3)/
cmꢂ1 3606 (OH), 1602, 1496 (NO2), 1354 (NO2), 1072, 1010;
dH (300 MHz; CDCl3) 2.57 (1H, br s, OH), 4.87 (2H, s, CH2),
6.62 (1H, dd, J 3.5, 1.7, ArH), 7.30 (1H, d, J 3.5, ArH), 7.66
(1H, dd, J 1.4, 0.8, ArH), 7.89 (1H, d, J 8.9, ArH), 7.94 (1H,
d, J 9.1, ArH), 8.21 (1H, dd, J 9.1, 0.8, ArH), 8.27 (1H, d, J
8.9, ArH); dC (75 MHz; CDCl3) 61.5 (CH2), 112.0 (CH),
112.8 (CH), 119.0 (C), 120.0 (CH), 129.6 (CH), 131.5 (CH),
131.9 (C), 133.2 (CH), 145.2 (CH), 147.3 (C), 150.2 (C),
3.2.15. 6-(4-Methylcoumarin-7-yloxyl)methyl-5-nitro-2-
phenylquinoline 18a
7-Hydroxy-4-methylcoumarin (0.093 g, 0.5 mmol) was re-
acted with 6-bromomethyl-5-nitro-2-phenylquinoline (0.200 g,
0.6 mmol) following the general procedure C. The crude
product was stirred in water (50 mL) for 30 min and then fil-
tered. The solid was then stirred in ethyl acetate for 30 min
and then filtered to give the title compound as a colourless
solid (0.200 g, 65%), Rf 0.58 (light petroleum/ethyl acetate
4:1); mp 244e246 ꢀC (from tetrahydrofuran/ethyl acetate).
(Found: C, 70.99; H, 4.04; N, 6.18. C26H18N2O5 requires
C, 71.23; H, 4.14; N, 6.39%.) (Found: Mþ, 438.1211.
C26H18N2O5 requires 438.1216.) nmax (KBr)/cmꢂ1 2983,

2822
G.D. Couch et al. / Tetrahedron 64 (2008) 2816e2823
2922, 2863, 1724 (C]O), 1617, 1598, 1582, 1470, 1454,
1073; dH (500 MHz; DMSO-d6) 2.40 (3H, s, Me), 5.58
(2H, s, CH2), 6.24 (1H, s, CH), 7.04 (1H, dd, J 8.8, 2.4,
ArH), 7.13 (1H, d, J 2.4, ArH), 7.57e7.62 (3H, m, ArH),
7.73 (1H, d, J 8.8, ArH), 8.13 (1H, d, J 8.8, ArH), 8.31e
8.33 (2H, m, ArH), 8.37 (1H, d, J 9.2, ArH), 8.40 (1H, d,
J 9.2, ArH), 8.42 (1H, d, J 8.8, ArH); dC (125 MHz;
DMSO-d6) 18.4 (Me), 67.0 (CH2), 102.6 (CH), 112.2 (CH),
113.0 (CH), 114.6 (C), 119.1 (C), 122.1 (CH), 127.1 (CH),
127.8 (C), 128.0 (CH), 129.5 (CH), 130.3 (CH), 130.9
(CH), 131.9 (CH), 133.5 (CH), 138.1 (C), 146.1 (C), 147.6
(C), 153.5 (C), 155.2 (C), 158.6 (C), 160.3 (C), 161.2 (C);
m/z (EI) 438 (Mþ, 7%), 264 (22), 263 (100), 246 (15), 219
(18), 205 (66), 204 (74), 176 (20), 148 (27), 147 (44).
peroxide (35%; 9 mL). The mixture was heated to 80 ꢀC for
4 h. After cooling, the mixture was basified with sodium
hydroxide solution (1 M) and extracted with dichloromethane
(3ꢁ60 mL). The combined organic phases were dried
(MgSO4) and concentrated in vacuo to give 6-methyl-5-nitro-
quinoline-N-oxide as a yellow solid (5.91 g, 81%), Rf 0.10
(ethyl acetate); mp 196e198 ꢀC. (Found: Mþ, 204.0534.
C10H8N2O3 requires 204.0535.) nmax (KBr)/cmꢂ1 3050,
2987, 2922, 1622, 1574, 1528, 1355, 1267; dH (300 MHz;
CDCl3) 2.57 (3H, s, Me), 7.43 (1H, dd, J 8.8, 6.1, ArH),
7.60 (1H, d, J 8.8, ArH), 7.66 (1H, d, J 9.0, ArH), 8.54 (1H,
d, J 6.1, ArH), 8.82 (1H, d, J 9.0, ArH); dC (75 MHz;
CDCl3) 18.5 (Me), 119.5 (CH), 122.8 (CH), 123.6 (C),
123.7 (CH), 132.0 (C), 133.0 (CH), 136.2 (CH), 140.7 (C),
147.4 (C); m/z (EI) 204 (Mþ, 73%), 188 (81), 171 (71), 143
(91), 142 (100), 141 (71), 115 (68), 77 (49).
3.2.16. 6-(4-Methylcoumarin-7-yloxyl)methyl-5-nitro-2-
(thien-2-yl)quinoline 18b
(b) Sulfuryl chloride (46 mL) was added to 6-methyl-5-
nitroquinoline-N-oxide (6.5 g, 32.0 mmol) and the mixture
was heated to 60 ꢀC for 3.5 h. After cooling, dichloromethane
(200 mL) and water (200 mL) were added to the reaction mix-
ture and the mixture was stirred for 1 h to dissolve any insoluble
material. The layers were separated and the organic phase was
dried (MgSO4) and concentrated in vacuo. The crude product
was recrystallised from dichloromethane/light petroleum to
give 2-chloro-6-methyl-5-nitroquinoline as a colourless solid
(4.0 g, 56%), Rf 0.60 (light petroleum/ethyl acetate 4:1); mp
171e173 ꢀC (from dichloromethane/light petroleum). (Found:
Mþ, 222.0198. C10H735ClN2O2 requires 222.0196.) nmax
(KBr)/cmꢂ1 3079, 1583, 1515, 1453, 1365, 817; dH
(300 MHz; CDCl3) 2.49 (3H, s, Me), 7.45 (1H, d, J 8.9,
ArH), 7.58 (1H, d, J 8.7, ArH), 8.00 (1H, d, J 8.9, ArH), 8.01
(1H, d, J 8.7, ArH); dC (75 MHz; CDCl3) 18.6 (Me), 119.5
(C), 125.0 (CH), 130.1 (C), 131.8 (CH), 133.5 (CH), 133.5
(CH), 146.5 (C), 147.0 (C), 152.1 (C); m/z (EI) 224/222 (Mþ,
25/55%), 205 (85), 192 (51), 191 (36), 178 (37), 177 (98),
142 (51), 141 (62), 140 (100), 128 (35), 113 (41), 63 (29).
7-Hydroxy-4-methylcoumarin (0.048 g, 0.3 mmol) was
reacted with 6-bromomethyl-5-nitro-2-(2-thienyl)quinoline
(0.100 g, 0.3 mmol) following the general procedure C. The
crude product was purified by stirring in cold tetrahydrofuran
and collecting the solid to give the title compound as a colourless
solid (0.038 g, 30%), mp 240e242 ꢀC (from chloroform/
hexane). (Found: Mþ, 444.0789. C24H16N2O5S requires
444.0780.) nmax (KBr)/cmꢂ1 2923, 2854, 1714 (C]O), 1609,
1529 (NO2), 1472, 1392 (NO2), 1282, 1268, 1074; dH
(300 MHz; DMSO-d6) 2.44 (3H, s, Me), 5.59 (2H, s, CH2),
6.29 (1H, s, ArH), 7.05e7.09 (1H, m, ArH), 7.17e7.15 (1H,
m, ArH), 7.30e7.33 (1H, m, ArH), 7.77 (1H, d, J 8.9, ArH),
7.89 (1H, d, J 4.5, ArH), 8.11e8.17 (2H, m, ArH), 8.30e8.40
(3H, m, ArH); m/z (EI) 444 (Mþ, 11%), 270 (25), 269 (100),
252 (27), 211 (95), 210 (43), 176 (41), 148 (41), 147 (36),
140 (12), 128 (30), 91 (21).
3.3. Chemical reduction reactions
To a solution of 6-(4-methylcoumarin-7-yloxyl)methyl-5-
nitro-2-phenylquinoline 18a (0.004 g, 9.1 mmol) in THF
(5 mL) and acetic acid (0.001 mL, 36.5 mmol) was added zinc
dust (0.002 g, 63.9 mmol) and the reaction mixture heated under
reflux for 16 h. After cooling, the mixture was diluted with wa-
ter (10 mL) and neutralised with saturated sodium hydrogen
carbonate solution (0.5 mL). The mixture was extracted with
dichloromethane (3ꢁ10 mL) and the combined organic phases
were dried (MgSO4) and concentrated in vacuo. The crude
product was purified by column chromatography eluting with
light petroleum/ethyl acetate (9:1) to give 5-amino-6-methyl-
2-phenylquinoline 20 as a bright yellow solid (0.0015 g,
95%) and 4-methyl-7-hydroxycoumarin as a colourless solid
(0.002 g, 95%); both compounds were comparable to authentic
samples.
(c)
A solution of 2-chloro-6-methyl-5-nitroquinoline
(0.350 g, 1.6 mmol) in 1,2-dimethoxyethane (33 mL) was de-
gassed under reduced pressure and flushed with nitrogen.
Pd(dppf)Cl2 (0.192 g, 0.26 mmol) was added and the system
was degassed again. The solution was stirred for 10 min. Potas-
sium carbonate (0.906 g, 6.6 mmol) was added, which was fol-
lowed by benzeneboronic acid (0.160 g, 1.3 mmol) and the
mixture was heated under reflux for 24 h. After cooling, the
mixture was diluted with ether (70 mL) and washed with water
(3ꢁ20 mL). The organic phase was dried (MgSO4) and concen-
trated in vacuo. The crude product was purified by column chro-
matography eluting with light petroleum/ethyl acetate (4:1) to
give 6-methyl-5-nitro-2-phenylquinoline as a colourless solid
(0.291 g, 84%), Rf 0.70 (light petroleum/ethyl acetate 4:1);
mp 102e104 ꢀC (from light petroleum/ethyl acetate). (Found:
MHþ, 265.0977. C16H12N2O2þH requires 265.0977.) nmax
(KBr)/cmꢂ1 2924, 2848, 1599, 1517 (NO2), 1490, 1471, 1369
(NO2); dH (400 MHz; CDCl3) 2.56 (3H, s, Me), 7.48e7.56
(3H, m, ArH), 7.60 (1H, d, J 8.7, ArH), 7.98e8.01 (1H, m,
ArH), 8.16e8.18 (3H, m, ArH), 8.21 (1H, d, J 8.7, ArH); dC
(100 MHz; CDCl3) 18.2 (Me), 119.3 (C), 121.1 (CH), 127.6
3.4. Independent synthesis of 5-amino-6-methyl-2-
phenylquinoline 20
(a) To a solution of 6-methyl-5-nitroquinoline (6.7 g,
35.6 mmol) in acetic acid (37 mL) was added hydrogen

G.D. Couch et al. / Tetrahedron 64 (2008) 2816e2823
2823
4. Skelly, J. V.; Knox, R. J.; Jenkins, T. C. Mini Rev. Med. Chem. 2001, 1,
293e306.
(CH), 128.7 (C), 129.0 (CH), 130.0 (CH), 130.8 (CH), 131.9
(CH), 132.6 (CH), 138.5 (C), 146.6 (C), 146.7 (C), 157.9 (C);
m/z (CI) 265 (MHþ, 100%), 235 (12).
5. Wardman, P. Curr. Med. Chem. 2001, 8, 739e761.
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(d) A stirred solution of 6-methyl-5-nitro-2-phenylquino-
line (0.150 g, 0.57 mmol) and palladium on carbon (10%;
0.030 g, 0.03 mmol) in methanol (15 mL) was placed under
a hydrogen atmosphere for 16 h at room temperature. The
crude reaction mixture was filtered through Celite and the fil-
trate was concentrated in vacuo. The crude product was puri-
fied by column chromatography eluting with dichloromethane/
ethyl acetate (1:0 to 9:1 elution) to give the title compound as
a bright yellow solid (0.122 g, 92%), Rf 0.46 (light petroleum/
ethyl acetate 1:1); mp 154e156 ꢀC (from dichloromethane/
hexane). (Found: MHþ, 235.1228. C16H14N2þH requires
235.1235.) nmax (CHCl3)/cmꢂ1 3487 (NH), 3410 (NH),
2970, 1623, 1592, 1564, 1406, 1368; dH (400 MHz; CDCl3)
2.35 (3H, s, Me), 4.11 (2H, br s, NH2), 7.43e7.47 (1H, m,
ArH), 7.46 (1H, d, J 8.5, ArH), 7.50e7.54 (2H, m, ArH),
7.61 (1H, d, J 8.5, ArH), 7.77 (1H, d, J 8.8, ArH), 8.14e
8.17 (2H, m, ArH), 8.20 (1H, d, J 8.8, ArH); dC (100 MHz;
CDCl3) 17.6 (Me), 116.7 (C), 117.0 (C), 117.3 (CH), 119.6
(CH), 127.5 (CH), 128.8 (CH), 129.2 (CH), 129.9 (CH),
133.2 (CH), 139.0 (C), 139.5 (C), 147.7 (C), 156.0 (C); m/z
(ES) 235 (MHþ, 100%).
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Acknowledgements
We thank the EPSRC and Morvus Technology Ltd for an
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