Late stage iodination of biologically active agents using a one-pot process from aryl amines

Article abstract of DOI:10.1039/c7ra11860k

A simple and effective one-pot tandem procedure that generates aryl iodides from readily available aryl amines via stable diazonium salts has been developed. The operationally simple procedure and mild conditions allow late-stage iodination of a wide range of aryl compounds bearing various functional groups and substitution patterns. A novel synthetic strategy involving the preparation of nitroaryl compounds followed by a chemoselective tin(ii) dichloride reduction and the use of the one-pot diazotisation-iodination transformation was also developed. The general applicability of this approach was demonstrated with the preparation of a number of medicinally important compounds including CNS1261, a SPECT imaging agent of the N-methyl-d-aspartate (NMDA) receptor and IBOX, a compound used to detect amyloid plaques in the brain.

Full text of DOI:10.1039/c7ra11860k

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Late stage iodination of biologically active agents
using a one-pot process from aryl amines†
Cite this: RSC Adv., 2017, 7, 54881
Nikki L. Sloan,a Sajinder K. Luthra,b Graeme McRobbie,b Sally L. Pimlottc
a
*
and Andrew Sutherland
A simple and effective one-pot tandem procedure that generates aryl iodides from readily available aryl
amines via stable diazonium salts has been developed. The operationally simple procedure and mild
conditions allow late-stage iodination of a wide range of aryl compounds bearing various functional
groups and substitution patterns. A novel synthetic strategy involving the preparation of nitroaryl
compounds followed by a chemoselective tin(II) dichloride reduction and the use of the one-pot
diazotisation–iodination transformation was also developed. The general applicability of this approach
was demonstrated with the preparation of a number of medicinally important compounds including
CNS1261, a SPECT imaging agent of the N-methyl-D-aspartate (NMDA) receptor and IBOX, a compound
used to detect amyloid plaques in the brain.
Received 27th October 2017
Accepted 26th November 2017
DOI: 10.1039/c7ra11860k
rsc.li/rsc-advances
nickel-catalysed Finkelstein reaction of aryl bromides
(Scheme 1a).10,11 Copper-catalysed iododeboronation of aryl
Introduction
boronic acids has also been used for the preparation of aryl
iodides,12 and recently, this transformation has been extended for
the incorporation of radioiodine.13 Another approach that has
received much attention is the Lewis acid activation of N-iodo-
succinimide (NIS) and the subsequent iodination of activated
arenes (Scheme 1b).14,15 Lewis acids such as silver(I) triimide
have been used to tune the NIS activation for clean mono-
iodination of highly activated arenes.14f Despite these advances,
there are still limitations with many of these transformations.
The metal-catalysed iodination of aryl bromides requires elevated
temperatures, while the Lewis acid-NIS method is restricted to
activated arenes.
Aryl iodides are ubiquitous synthetic building blocks, used
routinely in organic chemistry. The reactivity of the carbon–
iodine bond allows facile oxidative addition and subsequent
application as organometallic reagents in cross-coupling reac-
tions.1 Aryl iodides are also found as structural components in
a wide-range of medicinally important compounds, such as
iomazenil (1, Fig. 1),2 a specic ligand for the central-type
benzodiazepine receptor and quinoline-2-carboxamide 2,3
a high affinity agent for the translocator protein (TSPO). Aryl
and heteroaryl iodides in radioiodinated form are routinely
used in single photon emission computed tomography (SPECT)
imaging for the clinical diagnosis of disease and drug devel-
opment.4 For example, [123I]CNS1261 (3) is a SPECT imaging
agent for the N-methyl-D-aspartate (NMDA) receptor,5 while
a radioiodine version of IBOX (4) is used to detect amyloid
plaques in the brain.6
The other traditional approach for the preparation of aryl
iodides involves the conversion of aryl amines to diazonium
The importance of aryl iodides has led to a wide range of
general synthetic approaches. Traditional methods include elec-
trophilic aromatic substitution7 and directed ortho-lithiation–
iodination sequences.8 Current developments and understanding
of transition metal catalysis has allowed the discovery of
many aryl iodination reactions.9 These include the copper- or
aWestCHEM, School of Chemistry, The Joseph Black Building, University of Glasgow,
Glasgow G12 8QQ, UK. E-mail: Andrew.Sutherland@glasgow.ac.uk; Fax: +44 (0)141
330 4888; Tel: +44 (0)141 330 5936
bGE Healthcare, The Grove Centre, White Lion Road, Amersham, HP7 9LL, UK
cWest of Scotland PET Centre, Greater Glasgow and Clyde NHS Trust, Glasgow G12
0YN, UK
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
for all compounds. See DOI: 10.1039/c7ra11860k
Fig. 1 Structures of biologically active aryl iodides.
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showed that while diazonium salt formation was fast, the
subsequent substitution reaction formed phenol 6b as the
major product (Table 1, entry 1). However, phenol formation
could be completely suppressed by cooling the reaction to 10 ꢀC.
Aer a one-hour reaction time, this gave 53% conversion to
iodide 6a (entry 2). Analysis of each step of the process at this
temperature showed that, while diazonium salt formation was
still fast (<15 minutes), iodination required a longer reaction
time. Increasing the overall reaction time up to two hours
showed an increase in conversion to 85% (entry 4). This was
ꢀ
further optimised by initially conducting the reaction at 10 C
and then warming the mixture to room temperature aer 1 hour
(entry 5). This led to the generation of iodide 6a as the sole
product in quantitative conversion.
Using the optimised protocol, the scope of the one-pot
tandem diazotisation–iodination process was explored as
a general method for the iodination of aryl amines (Scheme 2).
The process was found to be compatible with a wide range of
substitution patterns and functional groups and could tolerate
electron-rich or electron-decient substituents. In general, the
majority of substrates investigated all gave the iodides as sole
products, typically in good to high yields. Sterically encumbered
2,6-disubstituted anilines such as 5o and 5p also yielded the
corresponding iodides (6o and 6p), in 67% and 74%, respec-
tively, aer a two-hour reaction time. Only very electron-
decient substrates required further optimisation. Anilines
bearing two strongly electron-decient groups [e.g. 5-amino-2-
chlorobenzoic acid (5r) or 2,4-dinitroaniline (5s)] required
longer reaction times, while 3-aminopyridine (5t) could be
converted to the corresponding iodide 6t in 74% yield but
required more forcing conditions (60 ꢀC). The only amino-
substituted aryl compounds that were found not to react
during this process were heterocyclic ring systems bearing
multiple heteroatoms (e.g. 5u and 5v). The presence of multiple
heteroatoms deactivates the amino group such that diazonium
salt formation under these mild conditions is not possible.
As well as a broad substrate scope, avoiding toxic reagents
and harsh reaction conditions, the other key advantage of this
one-pot tandem approach is a very mild work-up procedure,
Scheme 1 Recently developed approaches for iodination of aryl
compounds.
salts, followed by a Sandmeyer-type reaction with iodide
nucleophiles.16 However, the standard conditions of diazonium
salt formation involves strong acids (e.g. HCl or H2SO4) and the
use of sodium nitrite, which can lead to release of nitrogen
oxides. In addition, various diazonium salts are unstable and
potentially explosive. These issues have restricted the large-
scale application of this approach, particularly for complex
biologically active targets. A number of groups have overcome
the limitations associated with the standard conditions of dia-
zonium salt formation, by using polymer-supported nitrite
reagents.17 It has been shown that these can be used in
combination with mild acidic conditions (e.g. p-TsOH) for the
preparation of thermally stable tosylate diazonium salts.17c,18
Using these advances as a starting point, we were interested
in developing a general one-pot, two-step tandem iodination of
readily available aryl amines via stable diazonium salts. In
addition, we wanted to develop a novel synthetic strategy that
would allow the assembly of biologically relevant compounds,
that could then be used with this mild one-pot procedure for
late-stage iodination.19 Here we report an operationally simple,
one-pot tandem iodination of aryl amines using a polymer
supported nitrite reagent and p-toluenesulfonic acid as the
proton source (Scheme 1c). A general strategy for the prepara-
tion of iodinated medicinal agents using a chemoselective tin(II)
chloride reduction of nitroaryl precursors followed by the one-
pot tandem diazotisation–iodination procedure is also
described.
Table
1 Optimisation of the one-pot diazotisation–iodination of
4-nitroaniline (5a)
Results and discussion
Entry
Temp. (ꢀC)
Time (h)
6aa (%)
6ba (%)
Previous studies have shown that polymer-supported nitrite
reagents can be easily formed by the ion exchange of tetraal-
kylammonium functionalised resins with an aqueous solution
of sodium nitrite.17 In this current study, nitrite supported by
the tetraalkylammonium resin Amberlyst A-26 was prepared
and used to investigate the optimisation of the one-pot diazo-
tisation–iodination of 4-nitroaniline (5a). Initial trials at room
temperature (20 ꢀC) and using acetonitrile as the solvent,
1
2
3
4
5
20
10
10
10
1
1
1.5
2
2
15
53
70
85
>95
60
—
—
—
—
10–20
a
1
Conversion measured by H NMR spectroscopy.
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the translocator protein (TSPO), an important biological target
for the study of focal neuroinammation in diseases such as
brain cancer, stroke and neurodegeneration.3,20 The quinoline-
2-carboxamide core was rapidly assembled by condensation of
aniline (7) with diethyl oxalacetate (8), followed by ring closure
of the resulting imine under acidic conditions (Scheme 3).3
Bromination of 9, followed by a Suzuki–Miyaura reaction with
2-nitrophenylboronic acid completed the preparation of the
4-phenylquinoline scaffold 10, with introduction of the key
nitro group. Hydrolysis of the ethyl ester and coupling with
diethylamine in the presence of HBTU gave the corresponding
diethylamide 11. Following the preparation of 20-nitrophenyl
analogue 11, it was found that chemoselective reduction to the
corresponding aniline could be achieved efficiently under mild
conditions using tin(II) chloride.21 The one-pot tandem diazo-
tisation–iodination process was then optimised for the nal
stage conversion to TSPO affinity agent 2. Due to the bulky
ortho-substituent, the reaction required a temperature of 60 ꢀC
for 16 h to achieve completion. This gave quinoline-2-
carboxamide 2 as the sole product in 67% yield.
The next target was CNS1261 (3), a SPECT imaging agent of
N-methyl D-aspartate (NMDA) receptor activation.5 Again,
a synthetic route to a nitroaryl precursor was developed, before
implementation of the tin(II) chloride reduction and the one-pot
tandem iodination process (Scheme 4). Cyanation and methyl-
ation of 3-nitroaniline (13) under standard conditions, followed
by thermal coupling of the resulting cyanamide 14 with
Scheme 2 Scope of one-pot diazotisation–iodination process. For
each reaction 3 eq. of polymer-supported nitrite/p-TsOH and 2 eq. of
NaI were used. aReaction required 24 h. bReaction required 16 h.
cReaction was performed at 60 ꢀC for 16 h.
involving simple ltration of the polymer-supported nitrite
reagent and an aqueous wash of the organic layer. The
Amberlyst A-26 resin can also be re-used by further ion exchange
reactions with sodium nitrite.
The next stage of this work was the application of this one-
pot, two step method for the synthesis of more complex bio-
logically active aryl iodides. This required the development of
a synthetic strategy where the key amino group was masked
during the early stages of each synthetic route, allowing prep-
aration of the target scaffold, before being released at the
penultimate stage for the nal step iodination. For each target
investigated in this study, it was found that the use of a nitro
group permitted facile synthesis of each biologically active
precursor, which could then be reduced to give the required
amino group for the one-pot process. The rst target was
quinoline-2-carboxamide 2, a high affinity agent (Ki 5 nM) for Scheme 3 Synthesis of TSPO targeting agent 2.
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nitro group, followed by the one-pot tandem diazotisation–
iodination process completed the three-pot synthesis of IBOX
(4). The 53% overall yield achieved for IBOX (4) from 18 using
the tin(II) chloride reduction and the one-pot tandem iodination
process was a signicant improvement on the literature
synthesis.6 This involved reductive hydrogenolysis of 18, fol-
lowed by stepwise diazotisation and iodination of amine 19
under traditional conditions (NaNO2/HCl, then KI), giving 4 in
13% yield.6
Conclusions
In conclusion, a rapid and efficient tandem process has been
developed for the general preparation of aryl iodide compounds
bearing a range of functional groups and substitution patterns.
The mild conditions for diazonium salt formation, the facile
removal of the polymer-supported nitrite reagent and simple
work up and purication allowed the clean and efficient
synthesis of a small library of iodinated compounds. The only
amino-substituted aryl compounds found not to undergo this
transformation were deactivated amino-substituted heterocy-
cles bearing multiple heteroatoms. The process was exemplied
with the preparation of a range of important biologically active
agents, including CNS1261 and IBOX, compounds that are used
to study various neurological diseases. In this part of the study,
a novel strategy was developed to allow the preparation of bio-
logically relevant structures with the amine group masked,
before release of the amine and the late-stage incorporation of
the iodine atom. Nitroaryl precursors were used to prepare the
core structures, before a combination of a highly efficient che-
moselective tin(II) chloride reduction, followed by the one-pot
tandem iodination process allowed rapid access to these
targets. We expect this method to be of general use for the
iodination of a wide range of aryl compounds and are currently
investigating further applications.
Scheme 4 Synthesis of CNS1261 (3).
1-naphthylamine hydrochloride, gave biaryl guanidine 15. Aer
a highly efficient tin(II) chloride reduction of the nitroaryl group,
the one-pot tandem iodination process of meta-substituted
aniline 16 was found to proceed at room temperature resulting
in a 58% yield of CNS1261 (3).
The nal target in this study was IBOX (4), an imaging agent
of amyloid plaques in the brain.6 The same strategy of nitroaryl
precursor formation, followed by reduction and application of
the one-pot process was used for the rapid synthesis of IBOX
(Scheme 5). The benzoxazole ring system of IBOX bearing
a nitro group was formed by condensation of 2-hydroxy-4-
nitroaniline (17) with 4-dimethylaminobenzoic acid in the
presence of boric acid. Efficient tin dichloride reduction of the
Experimental
All reagents and starting materials were obtained from
commercial sources and used as received. All dry solvents were
puried using a PureSolv 500 MD solvent purication system.
All reactions were performed under an atmosphere of argon
unless otherwise mentioned. Brine refers to a saturated solution
of sodium chloride. Flash column chromatography was per-
formed using Fisher matrix silica 60. Macherey-Nagel
aluminium-backed plates pre-coated with silica gel 60 (UV254)
were used for thin layer chromatography and were visualised by
1
staining with KMnO4. H and 13C NMR spectra were recorded
on a Bruker DPX 400 (1H: 400 MHz; 13C: 101 MHz) spectrometer
or a Bruker 500 (1H: 500 MHz; 13C: 126 MHz) spectrometer with
chemical shi values reported in ppm relative to a residual
1
solvent peak and in the solvent stated. Assignment of H NMR
signals is based on COSY experiments. Assignment of 13C NMR
signals is based on HSQC and/or DEPT experiments. All
coupling constants, J, are quoted in Hz. Mass spectra were ob-
tained using a JEOL JMS-700 spectrometer for EI and CI or
a Bruker Microtof-q for ESI. Infrared spectra were obtained neat
Scheme 5 Synthesis of IBOX (4).
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using a Shimadzu IRPrestige-21 spectrometer. Melting points chromatography eluting with 20% ethyl acetate in petroleum
were determined on
apparatus.
a
Reichert platform melting point ether (40–60) gave 4-iodobenzonitrile (6c) as a white solid
(0.080 g, 68%). Spectroscopic data were consistent with the
literature.24 Mp 122–124 ꢀC; dH (400 MHz, CDCl3) 7.36 (2H, d, J
8.6 Hz, 3-H and 5-H), 7.84 (2H, d, J 8.6 Hz, 2-H and 6-H); dC (101
MHz, CDCl3) 100.4 (C), 111.9 (C), 118.3 (C), 133.3 (2ꢁ CH), 138.6
(2ꢁ CH); m/z (EI) 229 (M+. 80%), 102 (100), 84 (95), 69 (31), 49
(38).
4-Iodochlorobenzene (6d).25 The reaction was carried out
according to the general procedure for 4-iodonitrobenzene (6a)
using 4-chloroaniline (5d) (0.050 g, 0.41 mmol), p-toluene-
sulfonic acid monohydrate (0.22 g, 1.2 mmol), polymer-
supported nitrite (0.34 g, containing 1.2 mmol of NO2) and
sodium iodide (0.12 g, 0.79 mmol). The crude material was
puried using ash column chromatography eluting with 5%
ethyl acetate in petroleum ether (40–60) to give 4-iodo-
chlorobenzene (6d) as a white solid (0.058 g, 57%). Mp 55–56 ꢀC
General procedure for preparation of polymer-supported
nitrite17
The polymer-supported nitrite reagent was prepared by the
addition of Amberlyst® A26 hydroxide form resin (1.00 g, 4.00
mmol) to a solution of sodium nitrite (0.55 g, 8.00 mmol) in
water (20 mL). The mixture was stirred at room temperature for
0.5 h. The polymer-supported nitrite was ltered and washed
with water until the pH of the ltrate became neutral. The
content of the polymer-supported nitrite was 3.5 mmol of NO2
per g.17
General procedure for one-pot diazotisation and iodination
4-Iodonitrobenzene (6a).22 To a solution of p-toluenesulfonic (lit.25 54–55 ꢀC); dH (400 MHz, CDCl3) 7.09 (2H, d, J 8.7 Hz, 3-H
acid monohydrate (0.27 g, 1.1 mmol) in acetonitrile (2 mL) was and 5-H), 7.61 (2H, d, J 8.7 Hz, 2-H and 6-H); dC (101 MHz,
added 4-nitroaniline (5a) (0.050 g,ꢀ0.36 mmol). The solution was CDCl3) 91.3 (C), 130.7 (2ꢁ CH), 134.4 (C), 138.9 (2ꢁ CH); m/z (EI)
cooled in a water bath to 10–15 C. Polymer-supported nitrite 238 (M+. 52%), 111 (50), 84 (100), 49 (40).
(0.31 g, containing 1.1 mmol of NO2) was added, followed by
4-Iodobromobenzene (6e).26 The reaction was carried out
sodium iodide (0.11 g, 0.54 mmol) in water (0.2 mL). The according to the general procedure for 4-iodonitrobenzene (6a)
reaction mixture was stirred for 1 h then warmed to room using 4-bromoaniline (5e) (0.050 g, 0.28 mmol), p-toluene-
temperature and stirred for 2 h in total. The mixture was ltered sulfonic acid monohydrate (0.17 g, 0.87 mmol), polymer-
from the resin and the resin was washed with diethyl ether (50 supported nitrite (0.25 g, containing 0.87 mmol of NO2) and
mL). The reaction mixture and diethyl ether washings were sodium iodide (0.090 g, 0.58 mmol). Purication by ash
combined and washed with water (50 mL). The aqueous layer column chromatography eluting with 5% diethyl ether in
was then extracted with diethyl ether (3 ꢁ 50 mL). The petroleum ether (40–60) gave 4-iodobromobenzene (6e) as
combined organic layers were dried (MgSO4) and concentrated a white solid (0.063 g, 77%). Mp 91–92 C (lit.26 90 C); dH (400
in vacuo. The crude material was puried using ash column MHz, CDCl3) 7.23 (2H, d, J 8.6 Hz, 3-H and 5-H), 7.54 (2H, d, J
chromatography eluting with 20% ethyl acetate in petroleum 8.6 Hz, 2-H and 6-H); dC (101 MHz, CDCl3) 92.2 (C), 122.4 (C),
ether (40–60) to give 4-iodonitrobenzene (6a) as a pale yellow 133.6 (2ꢁ CH), 139.2 (2ꢁ CH); m/z (EI) 282 (M+. 48%), 155 (32),
solid (0.080 g, 86%). Mp 170–172 ꢀC (lit.22 169–171 ꢀC); dH (400 84 (100), 49 (48).
ꢀ
ꢀ
MHz, CDCl3) 7.91 (2H, d, J 8.0 Hz, 3-H and 5-H), 7.94 (2H, d, J
4-Iodoanisole (6f).27 The reaction was carried out according
8.0 Hz, 2-H and 6-H); dC (101 MHz, CDCl3) 102.8 (C), 125.0 (2ꢁ to the general procedure for 4-iodonitrobenzene (6a) using 4-
CH), 138.8 (2ꢁ CH), 148.0 (C); m/z (CI) 250 (MH+. 60%), 209 (12), methoxyaniline (5f) (0.050 g, 0.40 mmol), p-toluenesulfonic acid
193 (15), 124 (30), 113 (22), 85 (78), 69 (100).
monohydrate (0.23 g, 1.2 mmol), polymer-supported nitrite
4-Iodoacetophenone (6b).23 The reaction was carried out (0.34 g, containing 1.2 mmol of NO2) and sodium iodide (0.12 g,
according to the general procedure for 4-iodonitrobenzene (6a) 0.80 mmol). The crude material was puried using ash column
using 4-aminoacetophenone (5b) (0.050 g, 0.39 mmol), p-tol- chromatography eluting with 5% ethyl acetate in petroleum
uenesulfonic acid monohydrate (0.24 g, 1.1 mmol), polymer- ether (40–60) to give 4-iodoanisole (6f) as a white solid (0.070 g,
supported nitrite (0.32 g, containing 1.1 mmol of NO2) and 71%). Mp 47–48 C (lit.27 49–50 C); dH (400 MHz, CDCl3) 3.78
sodium iodide (0.11 g, 0.74 mmol). The crude material was (1H, s, OCH3), 6.68 (2H, d, J 9.0 Hz, 2-H and 6-H), 7.56 (2H, d, J
puried using ash column chromatography eluting with 20% 9.0 Hz, 3-H and 5-H); dC (101 MHz, CDCl3) 55.5 (CH3), 82.9 (C),
ethyl acetate in petroleum ether (40–60) to give 4-iodoaceto- 116.5 (2ꢁ CH), 138.4 (2ꢁ CH), 159.6 (C); m/z (EI) 234 (M+. 100%),
phenone (5b) as a white solid (0.090 g, 94%). Mp 84–85 ꢀC (lit.23 219 (22), 191 (11), 92 (14).
ꢀ
ꢀ
82–84 ꢀC); dH (400 MHz, CDCl3) 2.57 (3H, s, COCH3), 7.66 (2H, d,
Methyl 3-iodobenzoate (6g).28 The reaction was carried out
J 8.6 Hz, 3-H and 5-H), 7.83 (2H, d, J 8.6 Hz, 2-H and 6-H); dC (101 according to the general procedure for 4-iodonitrobenzene (6a)
MHz, CDCl3) 26.6 (CH3), 101.2 (C), 129.9 (2ꢁ CH), 136.5 (C), using methyl 3-aminobenzoate (5g) (0.050 g, 0.33 mmol),
138.1 (2ꢁ CH), 197.5 (C); m/z (ESI) 269 (MNa+. 80%).
p-toluenesulfonic acid monohydrate (0.19 g, 0.99 mmol),
4-Iodobenzonitrile (6c).24 The reaction was carried out polymer-supported nitrite (0.28 g, containing 0.99 mmol of
according to the general procedure for 4-iodonitrobenzene (6a) NO2) and sodium iodide (0.10 g, 0.66 mmol). Purication by
using 4-aminobenzonitrile (5c) (0.050 g, 0.38 mmol), p-tolue- ash column chromatography eluting with 20% diethyl ether in
nesulfonic acid monohydrate (0.24 g, 1.1 mmol), polymer- petroleum ether (40–60) gave methyl 3-iodobenzoate (6g) as
supported nitrite (0.32 g, containing 1.1 mmol of NO2) and a yellow solid (0.060 g, 71%). Mp 52–53 C (lit.28 54–56 C); dH
sodium iodide (0.11 g, 0.74 mmol). Purication by ash column (400 MHz, CDCl3) 3.91 (3H, s, OCH3), 7.17 (1H, t, J 7.9 Hz, 5-H),
ꢀ
ꢀ
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7.87 (1H, ddd, J 7.9, 1.7, 1.2 Hz, 4-H), 7.99 (1H, ddd, J 7.9, 1.7, (lit.32 31–32 C); dH (400 MHz, CDCl3) 7.15–7.21 (1H, m, ArH),
1.2 Hz, 6-H), 8.37 (1H, t, J 1.7 Hz, 2-H); dC (101 MHz, CDCl3) 52.5 7.30 (1H, dd, J 7.6, 1.5 Hz, ArH), 7.42–7.49 (3H, m, 3ꢁ ArH),
(CH3), 93.9 (C), 128.9 (CH), 130.2 (CH), 132.2 (C), 138.6 (CH), 7.58–7.63 (1H, m, ArH), 7.79–7.83 (2H, m, 2ꢁ ArH), 7.93 (1H, dd,
141.9 (CH), 165.7 (C); m/z (EI) 262 (M+. 28%), 231 (30), 203 (9), 84 J 8.0, 0.8 Hz, ArH); dC (101 MHz, CDCl3) 92.3 (C), 127.9 (CH),
ꢀ
(100), 49 (40).
128.6 (CH), 128.8 (CH), 130.6 (2ꢁ CH), 131.2 (2ꢁ CH), 133.8
3-Iodoacetophenone (6h).29 The reaction was carried out (CH), 135.7 (C), 139.8 (CH), 144.5 (C), 197.3 (C); m/z (ESI) 331
according to the general procedure for 4-iodonitrobenzene (6a) (MNa+. 100%).
using 3-aminoacetophenone (5h) (0.050 g, 0.40 mmol), p-tol-
5-Chloro-2-iodobenzophenone (6l).33 The reaction was
uenesulfonic acid monohydrate (0.21 g, 1.1 mmol), polymer- carried out according to the general procedure for 4-iodoni-
supported nitrite (0.32 g, containing 1.1 mmol of NO2) and trobenzene (6a) using 2-amino-5-chlorobenzophenone (5l)
sodium iodide (0.11 g, 0.74 mmol). Purication by ash column (0.050 g, 0.22 mmol), p-toluenesulfonic acid monohydrate
chromatography eluting with 20% diethyl ether in petroleum (0.13 g, 0.66 mmol), polymer-supported nitrite (0.19 g, con-
ether (40–60) gave 3-iodoacetophenone (6h) as a colorless oil taining 0.66 mmol of NO2) and sodium iodide (0.070 g, 0.44
(0.060 g, 64%). Spectroscopic data were consistent with the mmol). Purication by ash column chromatography eluting
literature.29 dH (500 MHz, CDCl3) 2.58 (3H, s, COCH3), 7.21 (1H, with 10% diethyl ether in petroleum ether (40–60) gave 5-chloro-
t, J 7.9 Hz, 5-H), 7.86–7.93 (2H, m, 4-H and 6-H), 8.28 (1H, t, J 2-iodobenzophenone (6l) as a yellow solid (0.050 g, 66%). Mp
1.6 Hz, 2-H); dC (126 MHz, CDCl3) 26.7 (CH3), 94.6 (C), 127.6 72–74 C (lit.33 80–82 C); dH (400 MHz, CDCl3) 7.18 (1H, dd, J
(CH), 130.5 (CH), 137.5 (CH), 139.0 (C), 142.0 (CH), 196.7 (C); m/ 8.4, 2.5 Hz, 4-H), 7.28 (1H, d, J 2.5 Hz, 6-H), 7.46–7.52 (2H, m, 2ꢁ
z (EI) 246 (M+. 78%), 231 (100), 203 (48), 181 (20), 84 (80), 76 (56). ArH), 7.61–7.67 (1H, m, ArH), 7.78–7.82 (2H, m, 2ꢁ ArH), 7.84
3,4,5-Trimethoxyiodobenzene (6i).30 The reaction was carried (1H, d, J 8.4 Hz, 3-H); dC (101 MHz, CDCl3) 89.4 (C), 128.6 (CH),
out according to the general procedure for 4-iodonitrobenzene 129.0 (2ꢁ CH), 130.6 (2ꢁ CH), 131.4 (CH), 134.2 (CH), 134.8 (C),
(6a) using 3,4,5-trimethoxyaniline (5i) (0.050 g, 0.29 mmol), p- 135.2 (C), 141.0 (CH), 146.0 (C), 195.9 (C); m/z (EI) 342 (M+.
toluenesulfonic acid monohydrate (0.16 g, 0.82 mmol), 100%), 265 (20), 215 (20), 152 (14), 105 (59), 77 (26), 51 (11).
ꢀ
ꢀ
polymer-supported nitrite (0.23 g, containing 0.82 mmol of
2-Iodo-4-methylanisole (6m).34 The reaction was carried out
NO2) and sodium iodide (0.080 g, 0.55 mmol). The crude according to the general procedure for 4-iodonitrobenzene (6a)
material was puried using ash column chromatography using 2-methoxy-5-methylaniline (5m) (0.050 g, 0.36 mmol), p-
eluting with 20% diethyl ether in petroleum ether (40–60) to toluenesulfonic acid monohydrate (0.21 g, 1.1 mmol), polymer-
give 3,4,5-trimethoxyiodobenzene (6i) as a yellow solid (0.060 g, supported nitrite (0.31 g, containing 1.1 mmol of NO2) and
73%). Mp 84–86 C (lit.30 83–85 C); dH (400 MHz, CDCl3) 3.80 sodium iodide (0.11 g, 0.73 mmol). The crude material was
(3H, s, OCH3), 3.82 (6H, s, 2ꢁ OCH3), 6.87 (2H, s, 2ꢁ ArH); dC puried using ash column chromatography eluting with 20%
(101 MHz, CDCl3) 56.5 (2ꢁ CH3), 61.0 (CH3), 86.2 (C), 115.1 (2ꢁ ethyl acetate in petroleum ether (40–60) to give 2-iodo-4-
CH), 138.4 (C), 154.1 (2ꢁ C); m/z (EI) 294 (M+. 100%), 279 (58), methylanisole (6m) as a white solid (0.070 g, 82%). Spectro-
ꢀ
ꢀ
251 (19), 236 (18), 124 (21), 109 (12), 84 (70), 49 (25).
scopic data were consistent with the literature.34 Mp 28–29 C;
ꢀ
1-Iodo-3,4-methylenedioxybenzene (6j).31 The reaction was dH (500 MHz, CDCl3) 2.26 (3H, s, 4-CH3), 3.85 (3H, s, OCH3), 6.72
carried out according to the general procedure for 4-iodoni- (1H, d, J 8.3 Hz, 6-H), 7.10 (1H, dd, J 8.3, 1.6 Hz, 5-H), 7.60 (1H,
trobenzene (6a) using 3,4-(methylenedioxy)aniline (5j) (0.050 g, d, J 1.6 Hz, 3-H); dC (126 MHz, CDCl3) 20.1 (CH3), 56.6 (CH3),
0.36 mmol), p-toluenesulfonic acid monohydrate (0.21 g, 1.1 85.9 (C), 110.9 (CH), 130.1 (CH), 132.2 (C), 140.0 (CH), 156.2 (C);
mmol), polymer-supported nitrite (0.31 g, containing 1.1 mmol m/z (EI) 248 (M+. 100%), 233 (28), 121 (11), 84 (28), 78 (17).
of NO2) and sodium iodide (0.11 g, 0.73 mmol). Purication
4,5-Dimethoxy-2-iodobenzonitrile (6n).35 The reaction was
by ash column chromatography eluting with 5% ethyl carried out according to the general procedure for 4-iodoni-
acetate in petroleum ether (40–60) gave 1-iodo-3,4- trobenzene (6a) using 2-amino-4,5-dimethoxybenzonitrile (5n)
methylenedioxybenzene (6j) as a pale yellow oil (0.06 g, 69%). (0.050 g, 0.28 mmol), p-toluenesulfonic acid monohydrate
Spectroscopic data were consistent with the literature.31 dH (400 (0.16 g, 0.84 mmol), polymer-supported nitrite (0.24 g, con-
MHz, CDCl3) 5.96 (2H, s, CH2), 6.59 (1H, d, J 8.1 Hz, 5-H), 7.12 taining 0.84 mmol of NO2) and sodium iodide (0.080 g, 0.56
(1H, d, J 1.6 Hz, 2-H), 7.14 (1H, dd, J 8.1, 1.6 Hz, 6-H); dC (101 mmol). Purication by ash column chromatography eluting
MHz, CDCl3) 82.3 (C), 101.5 (CH2), 110.6 (CH), 117.8 (CH), 130.7 with 20% ethyl acetate in petroleum ether (40–60) gave 4,5-
(CH), 148.0 (C), 148.8 (C); m/z (EI) 248 (M+. 100%), 247 (68), 183 dimethoxy-2-iodobenzonitrile (6n) as an orange solid (0.070 g,
(10), 121 (42), 63 (34).
86%). Mp 98–99 ꢀC (lit.35 103–104 ꢀC); dH (400 MHz, CDCl3) 3.87
2-Iodobenzophenone (6k).32 The reaction was carried out (3H, s, OCH3), 3.91 (3H, s, OCH3), 7.02 (1H, s, 3-H), 7.24 (1H, s,
according to the general procedure for 4-iodonitrobenzene (6a) 6-H); dC (101 MHz, CDCl3) 56.4 (CH3), 56.6 (CH3), 88.8 (C), 112.3
using 2-aminobenzophenone (5k) (0.050 g, 0.25 mmol), p-tol- (C), 115.9 (CH), 119.9 (C), 121.7 (CH), 149.5 (C), 153.0 (C); m/z
uenesulfonic acid monohydrate (0.14 g, 0.76 mmol), polymer- (ESI) 312 (MNa+. 100%).
supported nitrite (0.22 g, containing 0.76 mmol of NO2) and
2,4,6-Trimethyliodobenzene (6o).36 The reaction was carried
sodium iodide (0.080 g, 0.51 mmol). The crude material was out according to the general procedure for 4-iodonitrobenzene
puried using ash column chromatography eluting with 5% (6a) using 2,4,6-trimethylaniline (5o) (0.050 mL, 0.37 mmol), p-
diethyl ether in petroleum ether (40–60) to give 2-iodobenzo- toluenesulfonic acid monohydrate (0.21 g, 1.1 mmol), polymer-
ꢀ
phenone (6k) as an orange solid (0.060 g, 79%). Mp 30–31 C supported nitrite (0.32 g, containing 1.1 mmol of NO2) and
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sodium iodide (0.11 g, 0.74 mmol). Purication by ash column ethyl acetate in petroleum ether (40–60) to give 2,4-dini-
chromatography eluting with 20% diethyl ether in petroleum troiodobenzene (6s) as a pale yellow solid (0.040 g, 49%). Mp 88–
ether (40–60) gave 2,4,6-trimethyliodobenzene (6o) as a yellow 89 C (lit.23 88–89 C); dH (500 MHz, CDCl3) 8.11 (1H, dd, J 8.6,
solid (0.061 g, 67%). Mp 29–30 ꢀC (lit.36 29–30 ꢀC); dH (400 MHz, 2.5 Hz, 5-H), 8.31 (1H, d, J 8.6 Hz, 6-H), 8.68 (1H, d, J 2.5 Hz, 3-
CDCl3) 2.25 (3H, s, CH3), 2.44 (6H, s, 2ꢁ CH3), 6.90 (2H, s, 2ꢁ H); dC (126 MHz, CDCl3) 94.9 (C), 120.6 (CH), 127.1 (CH), 143.6
ArH); dC (101 MHz, CDCl3) 20.8 (CH3), 29.7 (2ꢁ CH3), 104.4 (C), (CH), 148.2 (C), 153.4 (C); m/z (EI) 294 (M+. 53%), 201 (10), 84
128.1 (2ꢁ CH), 137.5 (C), 141.9 (2ꢁ C); m/z (EI) 246 (M+. 100%), (100), 49 (58).
ꢀ
ꢀ
119 (90), 91 (68), 84 (82), 77 (20).
3-Iodopyridine (6t).40 The reaction was carried out according
1-Iodo-2,4,6-trichlorobenzene (6p).37 The reaction was to the general procedure for 4-iodonitrobenzene (6a) using 3-
carried out according to the general procedure for 4-iodoni- aminopyridine (5t) (0.030 g, 0.32 mmol), p-toluenesulfonic acid
trobenzene (6a) using 1-amino-2,4,6-trichlorobenzene (5p) monohydrate (0.18 g, 0.96 mmol), polymer-supported nitrite
(0.050 g, 0.26 mmol), p-toluenesulfonic acid monohydrate (0.27 g, containing 0.96 mmol of NO2) and sodium iodide
ꢀ
(0.15 g, 0.77 mmol), polymer-supported nitrite (0.22 g, con- (0.10 g, 0.64 mmol). The reaction mixture was heated to 60 C
taining 0.77 mmol of NO2) and sodium iodide (0.080 g, 0.51 and stirred for 16 h. The crude material was puried using ash
mmol). Purication by ash column chromatography eluting column chromatography eluting with 60% ethyl acetate in
with 5% diethyl ether in petroleum ether (40–60) gave 1-iodo- petroleum ether (40–60) to give 3-iodopyridine (6t) as a white
2,4,6-trichlorobenzene (6p) as a white solid (0.060 g, 74%). Mp solid (0.050 g, 74%). Mp 50–51 ꢀC (lit.40 52–53 ꢀC); dH (400 MHz,
53–54 ꢀC (lit.37 53 ꢀC); dH (400 MHz, CDCl3) 7.37 (2H, s, 2ꢁ ArH); CDCl3) 7.11 (1H, dd, J 6.4, 4.6 Hz, 5-H), 8.02 (1H, dt, J 6.4, 1.4 Hz,
dC (101 MHz, CDCl3) 101.7 (C), 127.4 (2ꢁ CH), 135.3 (C), 141.4 4-H), 8.56 (1H, dd, J 4.6, 1.4 Hz, 6-H), 8.84 (1H, d, J 1.4, Hz, 2-H);
(2ꢁ C); m/z (EI) 308 (M+. 83%), 181 (30), 143 (12), 84 (100).
dC (101 MHz, CDCl3) 93.8 (C), 125.5 (CH), 144.6 (CH), 148.2
1-Iodoanthraquinone (6q).38 The reaction was carried out (CH), 155.9 (CH); m/z (EI) 205 (M+. 80%), 139 (44), 84 (78), 44
according to the general procedure for 4-iodonitrobenzene (6a) (100).
using 1-aminoanthraquinone (5q) (0.050 g, 0.22 mmol), p-tol-
Ethyl 4-hydroxyquinoline-2-carboxylate (9).41 Aniline (7)
uenesulfonic acid monohydrate (0.13 g, 0.67 mmol), polymer- (1.11 g, 11.9 mmol), diethyl oxaloacetate (8) (2.50 g, 11.9 mmol)
supported nitrite (0.19 g, containing 0.67 mmol of NO2) and and p-toluenesulfonic acid (2.26 g, 11.9 mmol) in cyclohexane
sodium iodide (0.070 g, 0.45 mmol). The crude material was (50 mL) were stirred vigorously under Dean–Stark conditions for
puried using ash column chromatography eluting with 10% 48 h. Aer cooling to room temperature, the reaction mixture
diethyl ether in petroleum ether (40–60) to give 1-iodoan- was ltered and washed with cyclohexane before concentrating
thraquinone (6q) as a yellow solid (0.040 g, 54%). Mp 201– in vacuo to give the imine as a yellow oil. Neat polyphosphoric
202 ꢀC (lit.38 204–205 ꢀC); dH (400 MHz, CDCl3) 7.40 (1H, t, J acid (ꢂ5 g) was added and the reaction mixture was stirred
7.8 Hz, 3-H), 7.77–7.85 (2H, m, 2ꢁ ArH), 8.25–8.30 (1H, m, ArH), vigorously at 120 ꢀC for 1 h. Aer cooling to room temperature,
8.33–8.38 (1H, m, ArH), 8.41 (1H, dd, J 7.8, 1.2 Hz, ArH), 8.45 a saturated solution of aqueous sodium hydrogen carbonate (75
(1H, dd, J 7.8, 1.2 Hz, ArH); dC (101 MHz, CDCl3) 93.4 (C), 127.0 mL) was slowly added. Chloroform (100 mL) was added and the
(CH), 127.9 (CH), 128.5 (CH), 132.5 (C), 132.8 (C), 134.0 (CH), two layers separated. The aqueous layer was extracted with
134.0 (C), 134.2 (CH), 134.7 (CH), 136.0 (C), 148.8 (CH), 181.7 chloroform (3 ꢁ 100 mL). The organic layers were dried
(C), 182.0 (C); m/z (ESI) 357 (MNa+. 100%).
(MgSO4), ltered and concentrated in vacuo. The crude material
2-Chloro-5-iodobenzoic acid (6r).39 The reaction was carried was puried using ash column chromatography eluting with
out according to the general procedure for 4-iodonitrobenzene 10% methanol in dichloromethane to give ethyl 4-
(6a) using 5-amino-2-chlorobenzoic acid (5r) (0.050 g, 0.29 hydroxyquinoline-2-carboxylate (9) as a yellow solid (1.24 g,
mmol), p-toluenesulfonic acid monohydrate (0.17 g, 0.87 48%). Mp 214–215 C (lit.41 213 C); dH (400 MHz, CDCl3) 1.44
mmol), polymer-supported nitrite (0.25 g, containing (3H, t, J 7.1 Hz, OCH2CH3), 4.48 (2H, q, J 7.1 Hz, OCH2CH3), 7.00
0.87 mmol of NO2) and sodium iodide (0.090 g, 0.58 mmol). The (1H, s, 3-H), 7.38 (1H, t, J 7.6 Hz, ArH), 7.45 (1H, d, J 8.2, Hz,
reaction mixture was stirred at room temperature for 24 h. This ArH), 7.65–7.68 (1H, m, ArH), 8.35 (1H, dd, J 8.2, 0.9 Hz, ArH),
gave 2-chloro-5-iodobenzoic acid (6r) as a white solid (0.070 g, 8.98 (1H, br s, OH); dC (101 MHz, CDCl3) 14.1 (CH3), 63.4 (CH2),
79%). Mp 155–156 ꢀC (lit.39 155.5–156 ꢀC); dH (400 MHz, CDCl3) 111.6 (CH), 118.0 (CH), 124.5 (CH), 126.3 (CH), 126.4 (C), 133.1
7.22 (1H, d, J 8.4 Hz, 3-H), 7.78 (1H, dd, J 8.4, 2.2 Hz, 4-H), 8.32 (CH), 136.5 (C), 139.0 (C), 163.0 (C), 179.7 (C); m/z (ESI) 240
(1H, d, J 2.2 Hz, 6-H); dC (101 MHz, CDCl3) 90.9 (C), 130.2 (C), (MNa+. 100%).
ꢀ
ꢀ
133.2 (CH), 134.9 (C), 141.1 (CH), 142.5 (CH), 168.8 (C); m/z (EI)
Ethyl
4-bromoquinoline-2-carboxylate.42
Ethyl
4-
282 (M+. 100%), 265 (30), 149 (8), 84 (59), 49 (50).
hydroxyquinoline-2-carboxylate (9) (0.840 g, 3.87 mmol) was
2,4-Dinitroiodobenzene (6s).23 The reaction was carried out dissolved in acetonitrile (50 mL) before addition of phosphorus
according to the general procedure for 4-iodonitrobenzene (6a) oxybromide (3.33 g, 11.6 mmol) and potassium carbonate
using 2,4-dinitroaniline (5s) (0.050 g, 0.27 mmol), p-toluene- (1.60 g, 11.6 mmol). The mixture was heated under reux for
sulfonic acid monohydrate (0.16 g, 0.82 mmol), polymer- 2 h. Aer cooling to room temperature, the solution was
supported nitrite (0.23 g, containing 0.82 mmol of NO2) and concentrated in vacuo and water added. The product was
sodium iodide (0.080 g, 0.55 mmol). The reaction mixture was extracted with ethyl acetate (3 ꢁ 100 mL) and the organic layers
stirred at room temperature for 16 h. The crude material was dried (MgSO4), ltered and concentrated in vacuo to give ethyl 4-
puried using ash column chromatography eluting with 40% bromoquinoline-2-carboxylate as a brown solid (1.03 g, 95%).
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Mp 88–90 ꢀC (lit.42 91–92 ꢀC); dH (500 MHz, CDCl3) 1.49 (3H, t, J diluted in ethyl acetate (20 mL) and washed with a 5% aqueous
7.1 Hz, OCH2CH3), 4.56 (2H, q, J 7.1 Hz, OCH2CH3), 7.74 (1H, solution of lithium chloride (3 ꢁ 20 mL), followed by brine (20
ddd, J 8.4, 6.9, 1.2 Hz, 6-H), 7.83 (1H, ddd, J 8.4, 6.9, 1.2 Hz, 7-H), mL). The organic layer was dried (MgSO4), ltered and
8.23 (1H, dd, J 8.4, 1.2 Hz, 5-H), 8.31 (1H, dd, J 8.4, 1.2 Hz, 8-H), concentrated in vacuo. The crude material was puried using
8.46 (1H, s, 3-H); dC (126 MHz, CDCl3) 14.5 (CH3), 62.7 (CH2), ash column chromatography eluting with 60% ethyl acetate in
125.2 (CH), 126.8 (CH), 129.0 (C), 130.0 (CH), 131.2 (CH), 131.4 petroleum ether (40–60) to give 4-(20-nitrophenyl)-N,N-
(CH), 135.3 (C), 148.1 (C), 148.2 (C), 164.5 (C); m/z (CI) 280 (MH+. diethylquinoline-2-carboxamide (11) as a colorless oil (0.055 g,
100%), 202 (20), 81 (17), 69 (24).
54%). nmax/cmꢃ1 (neat) 2974 (CH), 1630 (C]O), 1528, 1346,
Ethyl 4-(20-nitrophenyl)quinoline-2-carboxylate (10).3 Ethyl 4- 1275, 1098, 766; dH (400 MHz, CDCl3) 1.27 (3H, t, J 7.2 Hz,
bromoquinoline-2-carboxylate (0.500 g, 1.79 mmol) was dis- NCH2CH3), 1.32 (3H, t, J 7.2 Hz, NCH2CH3), 3.40–3.72 (4H, m,
solved in N,N0-dimethylformamide (25 mL) before addition of 2- 2ꢁ NCH2CH3), 7.42 (1H, dd, J 8.4, 1.2 Hz, ArH), 7.47–7.53 (2H,
nitrophenylboronic acid (0.360 g, 2.14 mmol), tetrakis(- m, 2ꢁ ArH), 7.55 (1H, s, 3-H), 7.66–7.80 (3H, m, 3ꢁ ArH), 8.16–
triphenylphosphine)palladium(0) (0.210 g, 0.180 mmol) and 8.24 (2H, m, 2ꢁ ArH); dC (101 MHz, CDCl3) 13.1 (CH3), 14.6
potassium phosphate (0.450 g, 2.14 mmol). The reaction (CH3), 40.7 (CH2), 43.7 (CH2), 119.9 (CH), 124.6 (CH), 124.9
mixture was stirred at 120 ꢀC for 24 h, before addition of 2- (CH), 126.4 (C), 128.1 (CH), 129.9 (CH), 130.2 (CH), 130.5 (CH),
nitrophenylboronic acid (0.360 g, 2.14 mmol) and potassium 132.5 (CH), 132.9 (C), 133.5 (CH), 145.9 (C), 146.9 (C), 148.8 (C),
phosphate (0.450 g, 2.14 mmol) and further stirring at 120 C 154.4 (C), 168.5 (C); HRMS (ESI) m/z 372.1303 (MNa+.
ꢀ
for 24 h. Aer cooling to room temperature, the reaction
mixture was diluted in ethyl acetate (50 mL) and washed with
a 5% aqueous solution of lithium chloride (3 ꢁ 50 mL) followed (12).
C
20H19N3O3Na requires 372.1319).
4-(20-Aminophenyl)-N,N-diethylquinoline-2-carboxamide
4-(20-Nitrophenyl)-N,N-diethylquinoline-2-carboxamide
by brine (50 mL). The organic layer was dried (MgSO4), ltered (11) (0.050 g, 0.15 mmol) was dissolved in ethanol (2 mL)
and concentrated in vacuo. The crude material was puried before addition of tin(II) chloride dihydrate (0.18 g, 0.77 mmol).
using ash column chromatography eluting with 40% ethyl The solution was stirred under reux for 16 h. Aer cooling to
acetate in petroleum ether (40–60) to give ethyl 4-(20- room temperature, the reaction was quenched by addition of
nitrophenyl)quinoline-2-carboxylate (10) as
a yellow solid a saturated aqueous solution of sodium hydrogen carbonate
(0.510 g, 88%). Mp 149–150 C (lit.3 156–157 ꢀC); dH (500 MHz, and the product was extracted with ethyl acetate (3 ꢁ 5 mL). The
CDCl3) 1.49 (3H, t, J 7.1 Hz, OCH2CH3), 4.51–4.63 (2H, m, organic layers were dried (MgSO4), ltered and concentrated in
OCH2CH3), 7.44–7.48 (2H, m, 2ꢁ ArH), 7.57 (1H, ddd, J 8.4, 7.0, vacuo. The crude material was puried using ash
1.6 Hz, ArH), 7.72 (1H, ddd, J 8.6, 8.0, 1.6 Hz, ArH), 7.77–7.82 column chromatography eluting with 1% methanol in dichloro-
(2H, m, 2ꢁ ArH), 8.07 (1H, s, 3-H), 8.26 (1H, dd, J 8.0, 1.0 Hz, methane to give 4-(20-aminophenyl)-N,N-diethylquinoline-2-
ArH), 8.40 (1H, d, J 8.6 Hz, ArH); dC (126 MHz, CDCl3) 14.5 (CH3), carboxyamide (12) as a colorless oil (0.045 g, 91%). nmax/cmꢃ1
62.6 (CH2), 120.5 (CH), 124.6 (CH), 125.1 (CH), 127.7 (C), 129.3 (neat) 3348 (NH), 2973 (CH), 1620 (C]O), 1486, 1451, 1275, 1099,
(CH), 130.1 (CH), 130.5 (CH), 131.6 (CH), 132.5 (CH), 132.8 (C), 750; dH (500 MHz, CDCl3) 1.27 (3H, t, J 7.2 Hz, NCH2CH3), 1.32
133.6 (CH), 146.5 (C), 147.8 (C), 148.0 (C), 148.7 (C), 165.3 (C); m/ (3H, t, J 7.2 Hz, NCH2CH3), 3.42–3.67 (6H, m, 2ꢁ NCH2CH3 and
z (EI) 322 (M+. 25%), 278 (52), 250 (100), 205 (41), 190 (31), 130 NH2), 6.83 (1H, dd, J 8.2, 1.2 Hz, ArH), 6.88 (1H, td, J 8.2, 1.2 Hz,
ꢀ
(30), 84 (39).
ArH), 7.14 (1H, dd, J 8.2, 1.2 Hz, ArH), 7.28 (1H, td, J 8.2, 1.2 Hz,
4-(20-Nitrophenyl)-N,N-diethylquinoline-2-carboxamide (11). ArH), 7.53 (1H, ddd, J 8.2, 7.2, 1.2 Hz, ArH), 7.64 (1H, s, 3-H), 7.71–
Ethyl 4-(20-nitrophenyl)quinoline-2-carboxylate (10) (0.380 g, 7.78 (2H, m, 2ꢁ ArH), 8.17 (1H, d, J 8.2 Hz, ArH); dC (126 MHz,
1.18 mmol) was dissolved in 50% aqueous ethanol (20 mL) CDCl3) 13.1 (CH3), 14.6 (CH3), 40.5 (CH2), 43.6 (CH2), 115.9 (CH),
before addition of ground sodium hydroxide (0.190 g, 4.72 118.6 (CH), 121.4 (CH), 122.7 (C), 126.2 (CH), 126.7 (C), 127.6
mmol). The mixture was stirred under reux for 16 h. Aer (CH), 129.9 (CH), 130.2 (CH), 130.4 (CH), 130.8 (CH), 143.9 (C),
cooling to room temperature, the ethanol was removed in vacuo 147.3 (C), 147.4 (C), 155.0 (C), 168.8 (C); HRMS (ESI) m/z 320.1743
and the water layer acidied (pH 4) with 1 M hydrochloric acid (MH+. C20H22N3O requires 320.1757).
solution. The product was extracted with dichloromethane (3 ꢁ
4-(2-Iodophenyl)-N,N-diethylquinoline-2-carboxamide (2).3
50 mL), washed with water (2 ꢁ 50 mL), dried (MgSO4), ltered The reaction was carried out according to the general procedure
and concentrated in vacuo to give 4-(20-nitrophenyl)quinoline-2- for 4-iodonitrobenzene (6a) using 4-(2-aminophenyl)-N,N-
carboxylic acid as a brown solid (0.320 g, 92%), which was used diethylquinoline-2-carboxamide (12) (0.040 g, 0.12 mmol), p-
without further purication. 4-(20-Nitrophenyl)quinoline-2- toluenesulfonic acid monohydrate (0.070 g, 0.38 mmol),
carboxylic acid (0.0900 g, 0.300 mmol) was dissolved in N,N0- polymer-supported nitrite (0.11 g, containing 0.38 mmol of
dimethylformamide (10 mL), before addition of triethylamine NO2) and sodium iodide (0.038 g, 0.25 mmol). The reaction
(61.0 mL, 0.440 mmol) and N,N,N0,N0-tetramethyl-O-(1H- mixture was heated to 60 ꢀC and stirred for 16 h. The crude
benzotriazol-1-yl)uronium hexauorophosphate (0.120 g, 0.320 material was puried using ash column chromatography
mmol). The mixture was stirred at room temperature for 1 h and eluting with 40% ethyl acetate in petroleum ether (40–60) to give
then heated to 50 ꢀC, with the addition of diethylamine (30.0 mL, 4-(2-iodophenyl)-N,N-diethylquinoline-2-carboxamide (2) as
0.440 mmol). The reaction mixture was stirred at 50 ꢀC for 16 h. a pale yellow solid (0.037 g, 67%). Mp 58–59 ꢀC (lit.3 64–66 ꢀC);
Water was added and the mixture stirred for an additional 1 h. dH (500 MHz, CDCl3) 1.25 (3H, t, J 7.1 Hz, NCH2CH3), 1.33 (3H, t,
Aer cooling to room temperature, the reaction mixture was J 7.1 Hz, NCH2CH3), 3.38–3.60 (2H, m, NCH2CH3), 3.63 (2H, q, J
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7.1 Hz, NCH2CH3), 7.18 (1H, td, J 7.8, 1.6 Hz, 40-H), 7.33 (1H, dd, combined organic layers were dried (MgSO4), ltered and
J 7.8, 1.6 Hz, 5-H), 7.44–7.55 (4H, m, 3-H, 6-H, 50-H and 60-H), concentrated in vacuo. The crude material was puried using
7.75 (1H, ddd, J 8.4, 7.8, 1.6 Hz, 7-H), 8.01 (1H, dd, J 7.8, 1.6 Hz, ash column chromatography eluting with 1% methanol and
30-H), 8.19 (1H, d, J 8.4 Hz, 8-H); dC (126 MHz, CDCl3) 13.1 (CH3), 1% triethylamine in dichloromethane to give N-(1-naphthyl)-N0-
14.7 (CH3), 40.6 (CH2), 43.6 (CH2), 98.5 (C), 120.8 (CH), 125.9 (3-nitrophenyl)-N0-methylguanidine (15) as a viscous oil (0.20 g,
(CH), 126.5 (C), 127.6 (CH), 128.3 (CH), 130.1 (CH), 130.1 (CH), 84%). nmax/cmꢃ1 (neat) 3485 (NH), 3386 (NH), 2924 (CH), 1631,
130.2 (CH), 130.3 (CH), 139.5 (CH), 142.6 (C), 147.2 (C), 151.3 1567, 1522 (NO), 1482, 1379, 1345 (NO), 1234, 960, 854, 783, 771,
(C), 154.5 (C), 168.7 (C); m/z (EI) 430 (M+. 25%), 359 (84), 331 732, 684; dH (400 MHz, CDCl3) 3.60 (3H, s, NCH3), 7.02 (1H, dd, J
(91), 294 (23), 203 (100), 176 (26), 149 (26), 72 (78), 69 (31).
7.2, 1.0 Hz, 20-H), 7.39–7.58 (5H, m, 5ꢁ ArH), 7.72 (1H, ddd, J
N-(3-Nitrophenyl)cyanamide.43 Cyanogen bromide (0.12 g, 8.1, 2.1, 1.0 Hz, 6-H), 7.79–7.86 (1H, m, ArH), 8.03 (1H, ddd, J
1.08 mmol) in diethyl ether (5 mL) was added dropwise to 8.1, 2.1, 1.0 Hz, 4-H), 8.07–8.13 (1H, m, ArH), 8.23 (1H, t, J
a stirred solution of 3-nitroaniline (13) (0.10 g, 0.72 mmol) in 2.1 Hz, 2-H); dC (101 MHz, CDCl3) 39.0 (CH3), 117.5 (CH), 120.1
ꢀ
diethyl ether (5 mL) at 0 C. The reaction mixture was heated (CH), 120.6 (CH), 122.8 (CH), 124.0 (CH), 125.4 (CH), 126.2 (CH),
under reux for 24 h. Aer cooling to room temperature, the 126.5 (CH), 128.1 (CH), 128.6 (C), 130.2 (CH), 131.9 (CH), 134.9
reaction mixture was ltered and washed with ethyl acetate. The (C), 145.9 (C), 146.5 (C), 149.1 (C), 150.1 (C); HRMS (ESI) m/z
ethyl acetate washings were washed with 10% hydrochloric acid 321.1333 (MH+. C18H17N4O2 requires 321.1346).
(2 ꢁ 10 mL), water (10 mL) and brine (10 mL). The organic layer
was dried (MgSO4), ltered and concentrated in vacuo to give (3- The reaction was carried out according to the procedure for 4-
N-(1-Naphthyl)-N0-(3-aminophenyl)-N0-methylguanidine (16).
nitrophenyl)cyanamide as a yellow solid (0.056 g, 46%). Mp (20-aminophenyl)-N,N-diethylquinoline-2-carboxyamide
(12)
133–135 C (lit.43 133–135 C); dH (400 MHz, CD3OD) 7.38 (1H, using
N-(1-naphthyl)-N0-(3-nitrophenyl)-N0-methylguanidine
ꢀ
ꢀ
ddd, J 8.1, 2.2, 0.8 Hz, 6-H), 7.59 (1H, t, J 8.1 Hz, 5-H), 7.81 (1H, t, (15) (0.23 g, 0.73 mmol) and tin(II) chloride dihydrate (0.82 g, 3.6
J 2.2 Hz, 2-H), 7.91 (1H, ddd, J 8.1, 2.2, 0.8 Hz, 4-H); dC (126 MHz, mmol) in ethanol (10 mL). The reaction mixture was stirred
CD3OD) 110.8 (CH), 112.1 (C), 118.5 (CH), 122.1 (CH), 132.1 under reux for 16 h to give N-(1-naphthyl)-N0-(3-aminophenyl)-
(CH), 141.7 (C), 150.6 (C); m/z (EI) 163 (M+. 100%), 117 (32), 90 N0-methylguanidine (16) as a brown solid (0.12 g, 95%). Mp 96–
(61), 57 (27).
98 ꢀC; nmax/cmꢃ1 (neat) 3322 (NH), 3200 (NH), 3051, 1618, 1599,
Sodium 1580, 1560, 1491, 1383, 1275, 1227, 970, 781, 750; dH (400 MHz,
N-Methyl-N-(3-nitrophenyl)cyanamide
(14).44
hydride in 60% mineral oil (0.930 g, 2.33 mmol) was washed CDCl3) 3.50 (3H, s, NCH3), 6.53 (1H, ddd, J 7.9, 2.2, 0.9 Hz, 4-H),
with hexane (3 ꢁ 10 mL) and dried. This was then added to (3- 6.63 (1H, t, J 2.2 Hz, 2-H), 6.70 (1H, ddd, J 7.9, 2.2, 0.9 Hz, 6-H),
nitrophenyl)cyanamide (0.190 g, 1.17 mmol) in THF (3 mL) and 7.05 (1H, dd, J 7.4, 1.1 Hz, 20-H), 7.15 (1H, t, J 7.9 Hz, 5-H), 7.40
heated under reux for 2 h. The reaction mixture was cooled to (1H, dd, J 8.4, 7.4 Hz, 30-H), 7.43–7.49 (2H, m, 2ꢁ ArH), 7.52 (1H,
0
ꢀC and methyl iodide (0.186 mL, 2.91 mmol) was added br d, J 8.4 Hz, 40-H), 7.78–7.84 (1H, m, ArH), 8.13–8.19 (1H, m,
dropwise. The reaction mixture was warmed to room tempera- ArH); dC (101 MHz, CDCl3) 39.0 (CH3), 113.4 (CH), 113.5 (CH),
ture and stirred for 16 h. The reaction mixture was then diluted 116.7 (CH), 118.4 (CH), 122.5 (CH), 124.1 (CH), 125.2 (CH), 126.0
with methanol (5 mL) and water (10 mL) and extracted with (CH), 126.4 (CH), 128.0 (CH), 129.2 (C), 130.6 (CH), 134.9 (C),
chloroform (3 ꢁ 10 mL). The combined organic layers were 145.5 (C), 145.7 (C), 148.0 (C), 151.2 (C); HRMS (EI) m/z 290.1528
dried (MgSO4), ltered and concentrated in vacuo. Purication (M+. C18H18N4 requires 290.1531).
by ash column chromatography eluting with 1% methanol in
N-(1-Naphthyl)-N0-(3-iodophenyl)-N0-methylguanidine
(3).
dichloromethane gave N-methyl-N-(3-nitrophenyl)cyanamide The reaction was carried out according to the general procedure
(14) as a white solid (0.190 g, 91%). Spectroscopic data were for 4-iodonitrobenzene (6a) using N-(1-naphthyl)-N0-(3-amino-
consistent with the literature.43 Mp 106–107 C; dH (400 MHz, phenyl)-N0-methylguanidine (16) (0.061 g, 0.21 mmol), p-tolue-
ꢀ
CDCl3) 3.44 (3H, s), 7.48 (1H, ddd, J 8.2, 2.3, 0.9 Hz, 6-H), 7.57 nesulfonic acid monohydrate (0.12 g, 0.62 mmol), polymer-
(1H, t, J 8.2 Hz, 5-H), 7.86 (1H, t, J 2.3 Hz, 2-H), 7.95 (1H, ddd, J supported nitrite (0.18 g, containing 0.62 mmol of NO2) and
8.2, 2.3, 0.9 Hz, 4-H); dC (126 MHz, CDCl3) 37.2 (CH3), 109.4 sodium iodide (0.062 g, 0.41 mmol). The reaction mixture was
(CH), 112.7 (C), 118.2 (CH), 121.0 (CH), 130.8 (CH), 142.0 (C), stirred at room temperature for 16 h. Purication by ash
149.3 (C); m/z (EI) 177 (M+. 100%), 152 (67), 131 (74), 104 (61), 90 column chromatography eluting with 60–100% ethyl acetate in
(26), 77 (60), 63 (25), 50 (18).
petroleum ether gave N-(1-naphthyl)-N0-(3-iodophenyl)-N0-
N-(1-Naphthyl)-N0-(3-nitrophenyl)-N0-methylguanidine (15). methylguanidine (3) as a viscous oil (0.049 g, 58%). nmax/cmꢃ1
1-Naphthylamine (0.13 g, 0.75 mmol) was dissolved in diethyl (neat) 3482 (NH), 3385 (NH), 3053, 2924 (CH), 1624, 1557, 1474,
ether (1 mL) and converted to its hydrochloride salt by dropwise 1376, 1266, 1233, 943, 782, 693; dH (400 MHz, CDCl3) 3.53 (3H, s,
addition of aqueous hydrochloric acid (1 M) in diethyl ether (1 NCH3), 7.03 (1H, dd, J 7.2, 1.1 Hz, 20-H), 7.13 (1H, t, J 8.0 Hz, 5-
mL) to give a pink precipitate. This was ltered and dried. This H), 7.35 (1H, ddd, J 8.0, 2.0, 0.9 Hz, 6-H), 7.41 (1H, dd, J 8.1,
was added to N-methyl-N-(3-nitrophenyl)cyanamide (14) (0.13 g, 7.2, Hz, 30-H), 7.44–7.49 (2H, m, 2ꢁ ArH), 7.52 (1H, br d, J 8.1 Hz,
0.75 mmol) under argon and the neat reaction mixture was 40-H), 7.58 (1H, ddd, J 8.0, 2.0, 0.9 Hz, 4-H), 7.73 (1H, t, J 2.0 Hz,
stirred at 160 ꢀC for 3 h. Aer cooling to room temperature, the 2-H), 7.79–7.85 (1H, m, ArH), 8.09–8.16 (1H, m, ArH); dC (101
reaction mixture was diluted with dichloromethane (10 mL) and MHz, CDCl3) 39.2 (CH3), 94.6 (C), 117.9 (CH), 122.6 (CH), 124.1
washed with 0.1 M sodium hydroxide (10 mL). The aqueous (CH), 125.3 (CH), 126.1 (CH), 126.2 (CH), 126.5 (CH), 128.1 (CH),
layer was extracted with dichloromethane (3 ꢁ 10 mL). The 129.0 (C), 131.1 (CH), 134.9 (C), 135.5 (CH), 135.9 (CH), 145.9
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(C), 146.2 (C), 150.5 (C); HRMS (ESI) m/z 402.0445 (MH+. CDCl3) 3.08 (6H, s, 2ꢁ NCH3), 6.77 (2H, d, J 9.0 Hz, 30-H and 50-
C
18H17IN3 requires 402.0462).
H), 7.43 (1H, d, J 8.4 Hz, 4-H), 7.60 (1H, dd, J 8.4, 1.4 Hz, 5-H),
2-(40-Dimethylaminophenyl)-6-nitrobenzoxazole (18). 4- 7.86 (1H, d, J 1.4 Hz, 7-H), 8.08 (2H, d, J 9.0 Hz, 20-H and 60-H); dC
(Dimethylamino)benzoic acid (0.530 g, 3.25 mmol), 5-nitro-2- (101 MHz, CDCl3) 40.3 (2ꢁ CH3), 86.5 (C), 111.9 (2ꢁ CH), 113.8
aminophenol (17) (0.500 g, 3.25 mmol) and boric acid (C), 119.5 (CH), 120.7 (CH), 129.5 (2ꢁ CH), 133.5 (CH), 142.7 (C),
(0.200 g, 3.25 mmol) in p-xylene (50 mL) were stirred under 151.5 (C), 152.7 (C), 164.6 (C); m/z (ESI) 387 (MNa+. 100%).
Dean–Stark conditions for 72 h. Aer cooling to room temper-
ature, the reaction mixture was ltered and washed with p-
xylene (100 mL) before concentrating in vacuo. Water (20 mL)
Conflicts of interest
was added to the residue and the mixture made basic (pH 9–10) There are no conicts to declare.
with 1 M sodium hydroxide solution. The aqueous layer was
extracted with dichloromethane (3 ꢁ 20 mL) and the organic
Acknowledgements
layers were combined, dried (MgSO4), ltered and concentrated
in vacuo. The crude material was puried using ash column Financial support from Medical Research Scotland (studentship
chromatography eluting with 40% ethyl acetate in petroleum to N. L. S.), G.E. Healthcare Ltd and the University of Glasgow is
ether
(40–60)
to
give
2-(40-dimethylaminophenyl)-6- gratefully acknowledged.
nitrobenzoxazole (18) as an orange solid (0.485 g, 54%). Mp
215–217 C; nmax/cmꢃ1 (neat) 3422, 3315, 2924 (CH), 1615 (C]
ꢀ
Notes and references
C), 1510, 1491, 1357, 822; dH (500 MHz, CDCl3) 3.10 (6H, s, 2ꢁ
NCH3), 6.75 (2H, d, J 9.1 Hz, 30-H and 50-H), 7.69 (1H, d, J 8.7 Hz,
4-H), 8.10 (2H, d, J 9.1 Hz, 20-H and 60-H), 8.26 (1H, dd, J 8.7,
2.1 Hz, 5-H), 8.37 (1H, d, J 2.1 Hz, 7-H); dC (126 MHz, CDCl3) 40.2
(2ꢁ CH3), 106.7 (CH), 111.7 (2ꢁ CH), 112.5 (C), 118.5 (CH),
120.9 (CH), 130.1 (2ꢁ CH), 144.2 (C), 148.6 (C), 149.9 (C), 153.3
(C), 168.9 (C); HRMS (EI) m/z 283.0956 (M+. C15H13N3O3 requires
283.0957).
2-(40-Dimethylaminophenyl)-6-aminobenzoxazole (19). The
reaction was carried out according to the procedure for 4-(20-
aminophenyl)-N,N-diethylquinoline-2-carboxyamide (12) using
2-(40-dimethylaminophenyl)-6-nitrobenzoxazole (18) (0.12 g,
0.42 mmol) and tin(II) chloride dihydrate (0.48 g, 2.1 mmol) in
ethanol (10 mL). The reaction mixture was stirred under
reux for 16 h. The crude material was puried using ash
column chromatography eluting with 1–5% methanol
in dichloromethane to give 2-(40-dimethylaminophenyl)-6-
aminobenzoxazole (19) as an orange solid (0.089 g, 83%). Mp
186–187 ꢀC; nmax/cmꢃ1 (neat) 3430 (NH), 3314 (NH), 2916 (CH),
1613 (C]C), 1508, 1489, 1356, 1126, 949, 820; dH (500 MHz,
CDCl3) 3.05 (6H, s, 2ꢁ NCH3), 6.65 (1H, dd, J 8.4, 2.1 Hz, 5-H),
6.75 (2H, d, J 9.0 Hz, 30-H and 50-H), 6.84 (1H, d, J 2.1 Hz, 7-H),
7.45 (1H, d, J 8.4 Hz, 4-H), 8.03 (2H, d, J 9.0 Hz, 20-H and 60-H); dC
(126 MHz, CDCl3) 40.3 (2ꢁ CH3), 96.8 (CH), 111.8 (2ꢁ CH),
112.8 (CH), 115.0 (C), 119.4 (CH), 128.6 (2ꢁ CH), 135.3 (C), 144.1
(C), 151.9 (C), 152.1 (C), 162.6 (C); HRMS (CI) m/z 254.1289
(MH+. C15H16N3O requires 254.1293).
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