One-pot ortho-amination of aryl C-H bonds using consecutive iron and copper catalysis

Article abstract of DOI:10.1039/c9ob00712a

A one-pot approach for ortho-coupling of arenes with non-actived N-nucleophiles has been developed using sequential iron and copper catalysis. Regioselective ortho-activation of anisoles, anilines and phenols was achieved through iron(iii) triflimide catalysed iodination, followed by a copper(i)-catalysed, ligand-assisted coupling reaction with N-heterocycle, amide and sulfonamide-based nucleophiles. The synthetic utility of this one-pot, two-step method for the direct amination of ortho-aryl C-H bonds was demonstrated with the late-stage functionalisation of 3,4-dihydroquinolin-2-ones. This allowed the preparation of a TRIM24 bromodomain inhibitor and a series of novel analogues.

Full text of DOI:10.1039/c9ob00712a

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DOI: 10.1039/C9OB00712A
ARTICLE
One-pot ortho-amination of aryl C-H bonds using consecutive iron
and copper catalysis
Martyn C. Henry, Rochelle McGrory, Réka J. Faggyas, Mohamed A. B. Mostafa and Andrew
Sutherland*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A one-pot approach for ortho-coupling of arenes with non-actived N-nucleophiles has been developed using sequential iron
and copper catalysis. Regioselective ortho-activation of anisoles, anilines and phenols was achieved through iron(III)
triflimide catalysed iodination, followed by a copper(I)-catalysed, ligand-assisted coupling reaction with N-heterocycle,
amide and sulfonamide-based nucleophiles. The synthetic utility of this one-pot, two-step method for the direct amination
of ortho-aryl C-H bonds was demonstrated with the late-stage functionalisation of 3,4-dihydroquinolin-2-ones. This allowed
the preparation of a TRIM24 bromodomain inhibitor and a series of novel analogues.
transformation, it was proposed that the in situ generated
FPdN(SO2Ph)2 formed a dearomatised spiro-cyclopalladium
intermediate that underwent an ortho-nucleophilic amination
with benzenesulfonimide. Alternatively, with ortho-substituted
anilides, this approach enabled the preparation of para-
benzenesulfonimide functionalised arenes.
Introduction
In the last few decades, significant progress in the development
of transition metal catalysed reactions has resulted in
regioselective formation of aryl C-N bonds and the use of these
processes for the general synthesis of pharmaceutically active
compounds, organic materials and natural products.1 Early
methods involved the copper- or palladium-catalysed
amination of aryl (pseudo)halides using Ullmann-Goldberg,
Chan-Evans-Lam or Buchwald-Hartwig methods (Figure 1a).2,3
More recently, procedures have also been developed for the
amination of aryl halides using a combination of iron and copper
catalysis.4 While extensive reaction optimisation has resulted in
highly efficient transformations, a drawback to this approach is
the requirement of pre-functionalised arenes.
To avoid arene ring pre-functionalisation, more recent
strategies have focused on ortho-directed dehydrogenative
coupling of aryl C-H bonds with non-activated amines and
amides using chelating auxiliary groups in the presence of
oxidants such as oxygen or hypervalent iodine compounds.5
This method has found application for the regioselective
substitution of a wide range of arenes, including the ortho-
amination of anilines.5,6 For example, Rodríguez and co-workers
described the efficient copper-catalysed amination of anilines
using the 2-picolinic acid directing group and
(diacetoxyiodo)benzene as the oxidant (Figure 1b).7,8 The
auxiliary group could be removed under basic conditions to
access the ortho-aminated aniline in high overall yield.
Mechanistically distinct, palladium-catalysed ortho-amination
of para-substituted anilides with N-fluorobenzenesulfonimide
(NFSI) has also been described (Figure 1c).9 In this
We recently reported a one-pot para-amination and
amidation of activated arenes using sequential iron and copper
catalysis.10 The process permitted the reaction of para-aryl C-H
bonds with non-activated amines and amides via iron(III)-
triflimide catalysed arene bromination, followed by a copper(I)-
catalysed coupling reaction. However, attempted ortho-
amination of para-substituted anilines using this one-pot, two-
step approach led to inseparable mixtures of the coupled
product and the aniline starting material. Further studies
revealed this was due to competing reduction of the bromide
intermediate during the relatively slow copper-catalysed
Goldberg-type11 amination. As current methods for transition
metal catalysed ortho-amination of arenes requires either aryl
ring pre-functionalisation or the use of chelating auxiliary
groups with strong oxidising conditions and often precious
metals, we were interested in overcoming the issues of the one-
pot iron and copper catalysed method for direct access to ortho-
aminated arenes. Herein, we describe a one-pot intermolecular
ortho-amination of arenes using an iron-catalysed iodination,
followed by
a copper-catalysed, ligand-assisted coupling
reaction (Figure 1d). As well as exploring the scope of this
method for the ortho-amination or amidation of anilines,
anisoles and phenols, we also describe the use of the procedure
for the late-stage amidation of quinolin-2-ones and the
structural diversification of a TRIM24 bromodomain inhibitor.
WestCHEM, School of Chemistry, The Joseph Black Building, University of
Glasgow, Glasgow G12 8QQ, UK. Email: Andrew.Sutherland@glasgow.ac.uk
†Electronic Supplementary Information (ESI) available: 1H and 13C NMR spectra
for all compounds. See DOI: 10.1039/x0xx00000x
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(entry 4). On screening other ligands that facilitateVaiewwAidrtiecleraOnnlginee
of N-arylation reactions,
raDceOmI: 1ic0.1039/Ctr9aOnBs0-N07,1N2’A-
dimethylcyclohexane-1,2-diamine (6) gave the highest
selectivity of 12:1 for 3a versus 1a from the one-pot process
(entry 5).17 Further optimisation revealed that increasing the
amount of pyrazole led to complete suppression of the
reductive pathway and generation of only coupled product 3a
(entry 6). It should be noted that the involvement of Fe3+ during
the first step is crucial for the success of the one-pot process.
When iodination of 1a is performed under the same conditions
as in table 1 (70 °C), but without the presence of iron(III)
chloride, only 40% conversion is observed after 20 h.
Table 1 Optimisation of the one-pot ortho C-H amination process
Figure 1 Selected methods for ortho C-H aryl amination.
Results and Discussion
The study began by the investigation of the one-pot ortho-
amination of para-aminobenzonitrile (1a) with pyrazole (Table
1). Iron(III) chloride and the ionic liquid, [BMIM]NTf2 were used
for the in situ formation of the super Lewis acid, iron triflimide
and the activation of N-bromosuccinimide (NBS) for ortho-
bromination of 1a (entry 1).10,12 Following full conversion to the
bromide (4 h), the copper(I)-catalysed coupling reaction with
pyrazole, using N,N′-dimethylethylenediamine (4) (DMEDA) as
the copper-chelating ligand was investigated. This gave a 2:1
mixture of coupled product 3a and reduced compound 1a.13,14
It was proposed that a more reactive aryl halide bond may
facilitate the coupling reaction over the reduction pathway.
Therefore, the process was repeated using N-iodosuccinimide
(NIS) during the halogenation step (entries 2 and 3). While this
initially resulted in only a modest improvement (entry 2), the
combination of using a lower reaction temperature (130 °C)
during the coupling step gave a 6:1 ratio of 3a and 1a (entry 3).
To further refine the process, alternative ligands were
considered.15 Problems associated with challenging Goldberg-
type coupling reactions are generally due to catalyst
deactivation via competitive N-arylation of the ligand.16 To
overcome this issue, ligands such as diketone 5 that exist in a
delocalised enolate form and are less likely to undergo arylation
have been utilised. The use of diketone 5 during the one-pot
iodination and pyrazole coupling of 1a did lead to coupled
product 3a, but there was no improvement in the product ratio
Entry
1a
Pyrazole (equiv.)
Ligand Temp. (°C)
Ratio (3a:1a)
2:1
1.5
1.5
1.5
1.5
1.5
3
4
4
5
6
6
6
150
150
130
130
130
130
2
3:1
3
6:1
4
5:1
5
12:1
6
3a only
a
The one-pot process was performed via the bromide intermediate using NBS for the
activation step.
Using the optimised conditions, the scope of the one-pot
ortho-amination of a range of activated para-substituted arenes
with pyrazole was explored (Scheme 1). Various anilines were
subjected to the standard one-pot iron-catalysed activation and
copper-catalysed coupling process and gave the ortho-
substituted adducts (3a–3e) cleanly, in good yields (58–71%).
This method allows direct ortho-substitution of unprotected
anilines and despite the use of nucleophilic substrates, only N-
arylation by pyrazole was observed. Extension of the one-pot
process for the ortho N-arylation of anisoles, gave the
corresponding ortho-substituted compounds (3f–3k) in 48–71%
yield. Again, use of the highly regioselective iron-catalysed
mono-iodination reaction led to formation of the ortho-coupled
2 | J. Name., 2012, 00, 1-3
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adducts as the sole products, even using highly reactive arenes for each step. We previously reported that iVoiedwinAartitciloe nOnlionef
DOI: 10.1039/C9OB00712A
with multiple activating groups (e.g. 1i, 1k).
phenols could be improved using the softer Lewis acid, silver
triflimide to activate NIS.18 The use of silver triflimide (7.5 mol%)
was more effective for ortho-iodination of p-cresol (1l);
however, the one-pot process yielded the coupled product 3l in
a moderate 37% yield.
Using para-methylanisole (1f), the scope of the nucleophile
was next explored (Scheme 1). With the standard one-pot
conditions for anisoles, various sulfonamides and amides were
smoothly coupled, allowing isolation of the ortho-substituted
adducts (3m–3s) in good yields (52–78%). Using weaker, less
nucleophilic N-heterocycles such as imidazole and pyrrole
required a longer reaction time for the copper-catalysed N-
substitution step (36 h), but still gave the ortho-substituted
products 3t and 3u, cleanly. Two limitations were found when
examining the scope of the nucleophile for the one-pot process.
Electron-rich alkylamine nucleophiles such as morpholine gave
low conversion (<10%) to the coupled product. The activity of
the copper catalyst in these processes is likely compromised by
competitive binding with the alkylamine nucleophiles, which
are presence in significantly higher concentration than the
diamine ligand. Hindered heterocyclic nucleophiles such as 3,5-
dimethylpyrazole also gave no coupled product. In this case,
coupling at the ortho-position of an arene with an N-
heterocyclic nucleophile also bearing an adjacent substituent is
too hindered under these conditions for this transformation to
proceed.
A proposed mechanism for the one-pot, two-step process is
shown in scheme 2. The combination of iron(III) chloride and
the [BMIM]NTf2 ionic liquid leads to the formation of the super
Lewis acid, Fe(NTf2)3 7.19,20 The highly delocalised nature of the
triflimide counterion allows effective activation of NIS by Fe3+,
resulting in rapid regioselective, electrophilic aromatic
iodination of the arene ring system. In the second step, addition
of copper(I) iodide and the chelating diamine ligand, trans-N,N’-
dimethylcyclohexane-1,2-diamine (6) results in formation of
1,2-diamine-ligated copper(I) intermediate 8. Mechanistic
studies by the Buchwald and Hartwig groups have shown
subsequent reaction of copper(I) intermediate 8 with the base
and nucleophile generates 1,2-diamine-ligated copper(I)
amidate 9.21 While radical and nonradical pathways have been
proposed for reaction of copper(I) amidate 9 with haloarenes,
the same mechanistic studies using experimental tests for
radical intermediates and DFT calculations have shown that
oxidative addition to 10 occurs without free aryl radical
intermediates.22 Despite this insight, the precise mechanism of
aryl halide activation is still not well-established but Cu(III)-
intermediates such as 10 are calculated to be kinetically
accessible by a concerted oxidative addition or by internal
electron transfer within the coordination sphere of the metal.21a
Fast reductive elimination of 10 then forms the C-N coupled
product and regenerates 1,2-diamine-ligated copper(I)
intermediate 8. As shown by the results above (Scheme 1), the
sequential transformations are highly compatible within the
one-pot halogenation-amination process, leading to the clean
formation of C-N coupled products. It should also be noted that
Scheme 1
One-pot ortho-amination and amidation of arenes. a Iodination step
was complete after 20 h. b Iodination step was done at 40 °C. c Iodination step was
performed using AgNTf2 (7.5 mol%) at 40 °C. d The second step required 36 h.
A limitation of this method was found in the attempted
ortho-substitution of phenols (Scheme 1). Investigation of p-
cresol (1l) as a substrate for the one-pot process yielded less
than 20% of the coupled product with low conversion observed
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during the course of this study, by-products due to an Ullmann- process, re-utilisation of the palladium catalyst during a
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type, bi-aryl coupling were never observed.
hydrogenation reaction resulted in reducDtiOoIn: 1a0n.1d03c9y/Ccl9isOaBt0io0n712toA
give 3,4-dihydroquinolin-2-one 13 in 79% overall yield. N-
Methylation under standard conditions then gave 14 in 92%
yield. Iodination of 14 was found to proceed with lower catalyst
loadings of both iron(III) chloride (2.5 mol%) and [BMIM]NTf2
(7.5 mol%), under milder conditions (40 °C) than the general
process. In addition, despite the potential substitution of either
ortho-site, only iodination of the 6-position was observed by 1H
NMR analysis of the reaction mixture. Subsequent copper(I)-
catalysed coupling with benzenesulfonamide completed the
one-pot transformation and gave TRIM24 inhibitor, 16a in 56%
yield. Application of the one-pot ortho-amidation of 14 for the
late-stage synthesis of novel analogues of 16a was then
explored. Using other sulfonamides, benzamides and
heterocyclic nucleophiles gave coupled products 16b–16f in
good overall yields (51–61%). Overall, the utilisation of both
one-pot processes allowed rapid access to a range of novel
pharmaceutically relevant targets.
NMe3 NO2
NH2
NO2
CO2Me
p-TsOH.H2O
methyl acrylate
MeOH, 60 ºC, 1.5 h
Pd(OAc)2 (5 mol%)
MeO
MeO
NO2
12
11
79% overall
yield
then H2
2.5 bar, 24 h
MeI
NaH, DMF
MeO
N
O
rt, 1.5 h
92%
MeO
N
O
H
Me
14
13
FeCl3 (2.5 mol%)
[BMIM]NTf2
(7.5 mol%)
NIS, toluene
40 ºC, 4 h
R2
HNR1R2
CuI (10 mol%)
I
N
R1
MeO
N
O
6 (20 mol%), Cs2CO3
water, 150 ºC, 20 h
MeO
N
O
Me
Scheme 2
Proposed one-pot Fe(III)- and Cu(I)-catalysed ortho-amidation of 1f.
Me
15
16
Me
H
H
N
Having examined the scope and limitations of the one-pot
ortho-amination process, we wanted to demonstrate the
synthetic utility of this approach for the preparation of
pharmaceutically relevant targets. Palmer and co-workers have
shown that sulfonamide substituted 3,4-dihydroquinolin-2-
ones, such as 16a (Scheme 3) are inhibitors of the bromodomain
containing protein TRIM24, which is implicated in human
cancers.23 It was proposed that use of the one-pot activation
and ortho-amidation process with N-methyl 3,4-
dihydroquinoline-2-one 14 would allow rapid, late-stage access
to 16a and a range of novel analogues. 3,4-Dihydroquinolin-2-
one 14 was prepared via a two pot-process. Initially, 7-methoxy-
3,4-dihydro-1H-quinolin-2-one (13) was prepared via a one-pot
multistep process, that involved formation of the diazonium salt
intermediate of aniline 11 under mild conditions, followed by a
base-free Heck-Matsuda reaction with methyl acrylate to give
cinnamate intermediate 12.24 In the second part of the one-pot
N
S
S
O
O
MeO
O
O
MeO
N
O
O
O
N
O
Me
Me
16b, 56%
16a, 56%
Me
H
N
H
N
O
O
MeO
N
MeO
N
O
Me
Me
16c, 60%
16d, 61%
N
N
N
O
MeO
N
MeO
N
O
Me
16e, 51%a
Me
16f, 60%
Scheme 3: Synthesis and late-stage functionalisation of 3,4-dihydroquinolin-2-one
14. a The second step required 72 h.
4 | J. Name., 2012, 00, 1-3
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mmol) in toluene (0.5 mL). 4-Aminobenzonitrile (1a) (0.059 g,
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DOI: 10.1039/C9OB00712A
0.50 mmol) was added and the mixture was stirred at 70 °C for
5 h. Upon completion of the iodination step, the reaction
mixture was cooled to room temperature and pyrazole (0.10 g,
1.5 mmol), copper(I) iodide (0.0095 g, 0.050 mmol), caesium
carbonate (0.33 g, 1.0 mmol), trans-N,N′-dimethylcyclohexane-
1,2-diamine (6) (16 µL, 0.10 mmol) and water (0.25 mL) were
added. The reaction mixture was degassed under argon for 0.1
h and then heated to 130 °C for 24 h. The reaction mixture was
cooled to room temperature, diluted with ethyl acetate (10 mL),
washed with a 1 M aqueous sodium thiosulfate solution (10
mL). The aqueous layer was extracted with ethyl acetate (3 × 10
mL) and the combined organic layers were washed with brine
(10 mL). The organic phase was dried (MgSO4), filtered and
concentrated in vacuo. Purification by flash column
chromatography (petroleum ether/ethyl acetate, 7:3) gave N-
(2-amino-5-cyanophenyl)-1H-pyrazole (3a) (0.055 g, 60%) as a
colourless oil. Spectroscopic data were consistent with the
literature.26 δH (500 MHz, CDCl3) 5.45 (2H, br s, NH2), 6.50 (1H,
t, J 2.2 Hz, 4’-H), 6.81 (1H, d, J 8.4 Hz, 3-H), 7.39 (1H, dd, J 8.4,
1.9 Hz, 4-H), 7.47 (1H, d, J 1.9 Hz, 6-H), 7.75 (1H, d, J 2.2 Hz, ArH),
7.77 (1H, d, J 2.2 Hz, ArH); δC (126 MHz, CDCl3) 99.7 (C), 107.2
(CH), 117.0 (CH), 119.2 (C), 125.5 (C), 127.3 (CH), 129.7 (CH),
132.2 (CH), 141.2 (CH), 145.0 (C); m/z (ESI) 207 (MNa+. 100%).
N-(2-Amino-5-nitrophenyl)-1H-pyrazole (3b)
N-(2-Amino-5-nitrophenyl)-1H-pyrazole (3b) was synthesised as
described for N-(2-amino-5-cyanophenyl)-1H-pyrazole (3a)
using 4-nitroaniline (1b) (0.070 g, 0.50 mmol) and pyrazole (0.10
g, 1.5 mmol). The iodination step was carried out at 70 °C for 5
h and the N-arylation step at 130 °C for 24 h. Purification by
flash column chromatography (petroleum ether/ethyl acetate,
4:1) gave N-(2-amino-5-nitrophenyl)-1H-pyrazole (3b) (0.073 g,
71%) as a yellow solid. Mp 137–139 °C; νmax/cm−1 (neat) 3319
(NH), 3080 (CH), 1633, 1614, 1527 (C=C), 1494, 1333, 1316, 707;
δH (500 MHz, CDCl3) 5.84 (2H, br s, NH2), 6.52 (1H, t, J 2.0 Hz, 4’-
H), 6.80 (1H, d, J 8.9 Hz, 3-H), 7.78 (1H, d, J 2.0 Hz, ArH), 7.86
(1H, d, J 2.0 Hz, ArH), 8.05 (1H, dd, J 8.9, 2.5 Hz, 4-H), 8.17 (1H,
d, J 2.5 Hz, 6-H); δC (126 MHz, CDCl3) 107.4 (CH), 115.8 (CH),
119.4 (CH), 124.2 (C), 124.4 (CH), 129.8 (CH), 138.1 (C), 141.2
(CH), 146.8 (C); m/z (EI) 204.0654 (M+. C9H8N4O2 requires
204.0647), 174 (20%), 159 (19), 149 (20), 131 (15), 83 (100), 77
(23), 69 (28), 57 (46).
Conclusions
In summary, a one-pot method for the ortho-amination and
amidation of arenes has been developed using sequential iron
and copper catalysis. Regioselective activation of arenes via
iodination, using NIS and the super Lewis acid, iron(III)
triflimide, followed by copper(I)-catalysed, ligand-assisted
coupling with a range of N-nucleophiles gave the ortho-
substituted products in good yields. As well as allowing access
to a range of anisole adducts, this approach also permits direct
ortho-amination of unprotected anilines, without the
requirement of a directing auxiliary group. The selective and
mild nature of this method was further demonstrated by the
late-stage synthesis of a quinolin-2-one inhibitor of the
bromodomain containing protein TRIM24, as well as a series of
novel analogues. Further applications of one-pot iron and
copper-catalysed arene substitution reactions are currently
being investigated.
Experimental
All reagents and starting materials were obtained from
commercial sources and used as received. The synthesis of
compounds 1324 and 1425 were previously described in the
literature. All dry solvents were purified using a solvent
purification system. All reactions were performed in oven-dried
glassware under an atmosphere of argon unless otherwise
stated. Brine refers to a saturated solution of sodium chloride.
Flash column chromatography was performed using silica gel 60
(40–63 m) and neutral aluminium oxide (50–200 μm).
Aluminium-backed plates pre-coated with silica gel 60F254 were
used for thin layer chromatography and were visualised with a
UV lamp or by staining with potassium permanganate. 1H NMR
spectra were recorded on a NMR spectrometer at either 400 or
500 MHz and data are reported as follows: chemical shift in ppm
relative to tetramethylsilane or the solvent as the internal
standard (CDCl3,  7.26 ppm), multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet or overlap of
nonequivalent resonances, integration). 13C NMR spectra were
recorded on an NMR spectrometer at either 101 or 126 MHz
and data are reported as follows: chemical shift in ppm relative
to tetramethylsilane or the solvent as internal standard (CDCl3,
 77.0 ppm), multiplicity with respect to hydrogen (deduced
from DEPT experiments, C, CH, CH2 or CH3). IR spectra were
recorded on a FTIR spectrometer; wavenumbers are indicated
in cm–1. Mass spectra were recorded using electrospray or
electron impact techniques. HRMS spectra were recorded using
a dual-focusing magnetic analyser mass spectrometer. Melting
points are uncorrected.
3-Pyrazol-1’-yl-4-aminobenzophenone (3c)
3-Pyrazol-1’-yl-4-aminobenzophenone (3c) was synthesised as
described for N-(2-amino-5-cyanophenyl)-1H-pyrazole (3a)
using 4-aminobenzophenone (1c) (0.059 g, 0.50 mmol) and
pyrazole (0.10 g, 1.5 mmol). The iodination step was carried out
at 70 °C for 20 h and the N-arylation step at 130 °C for 24 h.
Purification
(dichloromethane/petroleum
by
flash
column
ether,
chromatography
9:1 to
dichloromethane/petroleum ether, 4:1) gave 3-pyrazol-1’-yl-4-
aminobenzophenone (3c) (0.076 g, 64%) as a colourless oil.
νmax/cm−1 (neat) 3360 (NH), 1611 (C=O), 1518, 1396, 1269,
1148; δH (500 MHz, CDCl3) 5.44 (2H, br s, NH2), 6.47 (1H, t, J 2.2
Hz, 4’-H), 6.82 (1H, d, J 8.4 Hz, 5-H), 7.44–7.50 (2H, m, 3’’-H and
5’’-H), 7.56 (1H, tt, J 7.4, 1.3 Hz, 4’’-H), 7.65 (1H, dd, J 8.4, 1.9
Hz, 6-H), 7.72–7.77 (3H, m, 2-H, 2’’-H and 6’’-H), 7.79 (1H, d, J
N-(2-Amino-5-cyanophenyl)-1H-pyrazole (3a)26
Iron(III) chloride (4.0 mg, 0.025 mmol) was dissolved in 1-butyl-
3-methylimidazolium bis(trifluoromethanesulfonyl)imide (22
µL, 0.075 mmol) and stirred for 0.5 h at room temperature and
then added to a suspension of N-iodosuccinimide (0.11 g, 0.50
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2.2 Hz, ArH), 7.81 (1H, d, J 2.2 Hz, ArH); δC (126 MHz, CDCl3) pyrazole (3a) using 3,4-dimethylanisole (1g) (0.070 mL, 0.50
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DOI: 10.1039/C9OB00712A
106.8 (CH), 115.9 (CH), 125.3 (C), 126.1 (CH), 126.9 (C), 128.3 (2 mmol) and pyrazole (0.10 g, 1.5 mmol). The iodination step was
× CH), 129.5 (2 × CH), 129.9 (CH), 131.5 (CH), 131.7 (CH), 138.4 carried out at 70 °C for 5 h and the N-arylation step at 130 °C for
(C), 140.8 (CH), 145.3 (C), 194.6 (C); m/z (ESI) 286.0944 (MNa+. 24 h. Purification by flash column chromatography
C16H13N3NaO requires 286.0951).
N-(2-Amino-5-chlorophenyl)-1H-pyrazole (3d)26
(hexane/diethyl ether, 9:1) gave N-(2-methoxy-4,5-
dimethylphenyl)-1H-pyrazole (3g) (0.068 g, 67%) as a colourless
N-(2-Amino-5-chlorophenyl)-1H-pyrazole (3d) was synthesised oil. νmax/cm−1 (neat) 2932 (CH), 1520, 1466, 1396, 1242, 1188,
as described for N-(2-amino-5-cyanophenyl)-1H-pyrazole (3a) 1034, 748; δH (400 MHz, CDCl3) 2.23 (3H, s, CH3), 2.29 (3H, s,
using 4-chloroaniline (1d) (0.064 g, 0.50 mmol) and pyrazole CH3), 3.82 (3H, s, OCH3), 6.39 (1H, dd, J 2.3, 1.7 Hz, 4’-H), 6.81
(0.10 g, 1.5 mmol). The iodination step was carried out at 70 °C (1H, s, 3-H), 7.47 (1H, s, 6-H), 7.67 (1H, d, J 1.7 Hz, ArH), 7.97
for 5 h and the N-arylation step at 130 °C for 24 h. Purification (1H, d, J 2.3 Hz, ArH); δC (101 MHz, CDCl3) 18.7 (CH3), 19.9 (CH3),
by flash column chromatography (dichloromethane) gave N-(2- 56.1 (CH3), 105.9 (CH), 113.9 (CH), 126.1 (CH), 127.2 (C), 129.2
amino-5-chlorophenyl)-1H-pyrazole (3d) (0.061 g, 63%) as a (C), 131.4 (CH), 136.4 (C), 139.7 (CH), 149.1 (C); m/z (ESI)
brown oil. Spectroscopic data were consistent with the 225.0994 (MNa+. C12H14N2NaO requires 225.0998).
literature.26 δH (500 MHz, CDCl3) 4.75 (2H, br s, NH2), 6.44 (1H, 3-Pyrazol-1’-yl-4-methoxybiphenyl (3h)
t, J 2.2 Hz, 4’-H), 6.74 (1H, d, J 8.5 Hz, 3-H), 7.08 (1H, dd, J 8.5, 3-Pyrazol-1’-yl-4-methoxybiphenyl (3h) was synthesised as
2.4 Hz, 4-H), 7.18 (1H, d, J 2.4 Hz, 6-H), 7.70 (1H, d, J 2.2 Hz, ArH), described for N-(2-amino-5-cyanophenyl)-1H-pyrazole (3a)
7.73 (1H, d, J 2.2 Hz, ArH); δC (126 MHz, CDCl3) 106.8 (CH), 118.2 using 4-methoxybiphenyl (1h) (0.050 g, 0.19 mmol) and
(CH), 122.2 (C), 123.7 (CH), 126.8 (C), 128.2 (CH), 129.8 (CH), pyrazole (0.051 g, 0.75 mmol). The iodination step was carried
139.7 (C), 140.9 (CH); m/z (ESI) 216 (MNa+. 100%).
N-(2-Amino-5-methylphenyl)-1H-pyrazole (3e)26
out at 70 °C for 5 h and the N-arylation step at 130 °C for 24 h.
Purification by flash column chromatography (hexane/diethyl
N-(2-Amino-5-methylphenyl)-1H-pyrazole (3e) was synthesised ether, 7:3) gave 3-pyrazol-1’-yl-4-methoxybiphenyl (3h) (0.077
as described for N-(2-amino-5-cyanophenyl)-1H-pyrazole (3a) g, 61%) as a white solid. Mp 52–54 °C; νmax/cm−1 (neat) 2940
using 4-methylaniline (1e) (0.054 g, 0.50 mmol) and pyrazole (CH), 1528 (C=C), 1489, 1404, 1281, 1250, 1018, 756; δH (500
(0.10 g, 1.5 mmol). The iodination step was carried out at 40 °C MHz, CDCl3) 3.92 (3H, s, OCH3), 6.45 (1H, dd, J 2.3, 1.8 Hz, 4’-H),
for 5 h and the N-arylation step at 130 °C for 24 h. Purification 7.11 (1H, d, J 8.6 Hz, 5-H), 7.32 (1H, tt, J 7.4, 1.2 Hz, 4’’-H), 7.38–
by flash column chromatography (petroleum ether/ethyl 7.44 (2H, m, 3’’-H and 5’’-H), 7.52 (1H, dd, J 8.6, 2.4 Hz, 6-H),
acetate, 7:3) gave N-(2-amino-5-methylphenyl)-1H-pyrazole 7.58–7.63 (2H, m, 2’’-H and 6’’-H), 7.73 (1H, d, J 1.8 Hz, ArH),
(3e) (0.051 g, 58%) as an orange oil. Spectroscopic data were 7.99 (1H, d, J 2.4 Hz, 2-H), 8.08 (1H, d, J 2.3 Hz, ArH); δC (126
consistent with the literature.26 δH (400 MHz, CDCl3) 2.27 (3H, s, MHz, CDCl3) 56.1 (CH3), 106.3 (CH), 112.7 (CH), 123.9 (CH), 126.3
5-CH3), 4.48 (2H, br s, NH2), 6.42 (1H, t, J 2.1 Hz, 4’-H), 6.74 (1H, (CH), 126.8 (2 × CH), 127.1 (CH), 128.8 (2 × CH), 129.9 (C), 131.6
d, J 8.1 Hz, 3-H), 6.96 (1H, dd, J 8.1, 1.3 Hz, 4-H), 7.00 (1H, d, J (CH), 134.5 (C), 139.8 (C), 140.2 (CH), 150.7 (C); m/z (ESI)
1.3 Hz, 6-H), 7.70 (1H, d, J 2.1 Hz, ArH), 7.73 (1H, d, J 2.1 Hz, 273.0992 (MNa+. C16H14N2NaO requires 273.0998).
ArH); δC (101 MHz, CDCl3) 20.3 (CH3), 106.3 (CH), 117.4 (CH), N-(2,5-Dimethoxyphenyl)-1H-pyrazole (3i)
124.7 (CH), 126.6 (C), 127.6 (C), 129.1 (CH), 129.8 (CH), 138.5 N-(2,5-Dimethoxyphenyl)-1H-pyrazole (3i) was synthesised as
(C), 140.5 (CH); m/z (ESI) 174 (MNa+. 100%).
N-(2-Methoxy-5-methylphenyl)-1H-pyrazole (3f)
N-(2-Methoxy-5-methylphenyl)-1H-pyrazole
described for N-(2-amino-5-cyanophenyl)-1H-pyrazole (3a)
using 1,4-dimethoxybenzene (1i) (0.069 g, 0.50 mmol) and
was pyrazole (0.10 g, 1.5 mmol). The iodination step was carried out
(3f)
synthesised as described for N-(2-amino-5-cyanophenyl)-1H- at 70 °C for 5 h and the N-arylation step at 150 °C for 24 h.
pyrazole (3a) using 4-methylanisole (1f) (0.063 mL, 0.50 mmol) Purification by flash column chromatography (petroleum
and pyrazole (0.10 g, 1.5 mmol). The iodination step was carried ether/ethyl acetate, 9:1) gave N-(2,5-dimethoxyphenyl)-1H-
out at 70 °C for 20 h and the N-arylation step at 130 °C for 24 h. pyrazole (3i) (0.067 g, 66%) as a colourless oil. νmax/cm−1 (neat)
Purification by flash column chromatography (hexane/diethyl 2940 (CH), 1597, 1520, 1504, 1211, 1042, 748; δH (400 MHz,
ether, 4:1) gave N-(2-methoxy-5-methylphenyl)-1H-pyrazole CDCl3) 3.82 (6H, br s, 2 × OCH3), 6.42 (1H, dd, J 2.4, 1.9 Hz, 4’-H),
(3f) (0.067 g, 71%) as a colourless oil. νmax/cm−1 (neat) 2936 (CH), 6.83 (1H, dd, J 9.0, 3.1 Hz, 4-H), 6.98 (1H, d, J 9.0 Hz, 3-H), 7.36
1524 (C=C), 1504, 1462, 1283, 1242, 1036, 804, 744; δH (400 (1H, d, J 3.1 Hz, 6-H), 7.70 (1H, d, J 1.9 Hz, ArH), 8.10 (1H, d, J 2.4
MHz, CDCl3) 2.33 (3H, br s, 5-CH3), 3.83 (3H, s, OCH3), 6.41 (1H, Hz, ArH); δC (101 MHz, CDCl3) 55.9 (CH3), 56.7 (CH3), 106.3 (CH),
dd, J 2.4, 1.9 Hz, 4’-H), 6.92 (1H, d, J 8.4 Hz, 3-H), 7.05–7.10 (1H, 110.0 (CH), 113.6 (CH), 114.0 (CH), 130.2 (C), 131.6 (CH), 140.1
m, 4-H), 7.55 (1H, d, J 2.3 Hz, 6-H), 7.69 (1H, dd, J 2.4, 0.4 Hz, (CH), 145.1 (C), 154.1 (C); m/z (ESI) 227.0785 (MNa+.
ArH), 8.03 (1H, dd, J 1.9, 0.4 Hz, ArH); δC (101 MHz, CDCl3) 20.4 C11H12N2NaO2 requires 227.0791).
(CH3), 56.1 (CH3), 106.1 (CH), 112.3 (CH), 125.6 (CH), 128.3 (CH), 2’’-(4-Methoxy-3-pyrazol-1’-ylphenyl)acetic acid (3j)
129.4 (C), 130.8 (C), 131.5 (CH), 139.9 (CH), 149.1 (C); m/z (EI) 2’’-(4-Methoxy-3-pyrazol-1’-ylphenyl)acetic acid (3j) was
188.0942 (M+. C11H12N2O requires 188.0950), 159 (55%), 144 synthesised as described for N-(2-amino-5-cyanophenyl)-1H-
(34).
pyrazole (3a) using 4-methoxyphenylacetic acid (1j) (0.083 g,
0.50 mmol) and pyrazole (0.10 g, 1.5 mmol). The iodination step
was was carried out at 70 °C for 5 h and the N-arylation step at 150
N-(2-Methoxy-4,5-dimethylphenyl)-1H-pyrazole (3g)
N-(2-Methoxy-4,5-dimethylphenyl)-1H-pyrazole
(3g)
synthesised as described for N-(2-amino-5-cyanophenyl)-1H- °C for 24 h. The reaction mixture was cooled to room
6 | J. Name., 2012, 00, 1-3
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temperature, diluted with dichloromethane (10 mL) and (C=C), 1333, 1279, 1250, 750; δH (400 MHz, CDCl3) 2.33 (3H, s,
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extracted with 1 M aqueous sodium hydroxide solution (10 mL). 5-CH3), 6.49 (1H, dd, J 2.4, 2.1 Hz, 4’-H), D6O.9I:51–07.1.00319/(C29HO,Bm00,731-2HA
The aqueous layer was separated and acidified with 1 M and 4-H), 7.18 (1H, br s, 6-H), 7.72 (1H, d, J 2.1 Hz, ArH), 7.99
aqueous hydrochloric acid and extracted into dichloromethane (1H, d, J 2.4 Hz, ArH), 11.11 (1H, s, OH); δC (101 MHz, CDCl3) 20.6
(3 × 30 mL). The combined organic layers were dried (MgSO4) (CH3), 106.7 (CH), 118.3 (CH), 118.7 (CH), 124.5 (C), 126.6 (CH),
and concentrated in vacuo. Trituration with hexane gave 2’’-(4- 128.2 (CH), 128.9 (C), 138.9 (CH), 147.0 (C); m/z (ESI) 197.0684
methoxy-3-pyrazol-1’-ylphenyl)acetic acid (3j) (0.062 g, 53%) as (MNa+. C10H10N2NaO requires 197.0685).
a white solid. Mp 94–96 °C νmax/cm−1 (neat) 2940 (CH), 1713 N-(2-Methoxy-5-methylphenyl)benzenesulfonamide (3m)
(C=O), 1526 (C=C), 1462, 1410, 1287, 1248, 1180, 1152, 1022, N-(2-Methoxy-5-methylphenyl)benzenesulfonamide (3m) was
760; δH (400 MHz, CDCl3) 3.62 (2H, s, CH2), 3.86 (3H, s, OCH3), synthesised as described for N-(2-amino-5-cyanophenyl)-1H-
6.42 (1H, dd, J 2.3, 1.8 Hz, 4’-H), 6.99 (1H, d, J 8.5 Hz, 5-H), 7.21 pyrazole (3a) using 4-methylanisole (1f) (0.063 mL, 0.50 mmol)
(1H, dd, J 8.5, 2.1 Hz, 6-H), 7.67 (1H, d, J 2.1 Hz, 2-H), 7.73 (1H, and benzenesulfonamide (0.24 g, 1.5 mmol). The iodination
d, J 1.8 Hz, ArH), 8.02 (1H, d, J 2.3 Hz, ArH); δC (101 MHz, CDCl3) step was carried out at 70 °C for 5 h and the N-arylation step at
40.1 (CH2), 56.0 (CH3), 106.3 (CH), 112.4 (CH), 126.4 (CH), 126.9 150 °C for 24 h. Purification by flash column chromatography
(C), 129.1 (CH), 129.2 (C), 131.9 (CH), 139.9 (CH), 150.2 (C), (hexane/diethyl
ether,
1:1)
gave
N-(2-methoxy-5-
175.5 (C); m/z (ESI) 255.0738 (MNa+. C12H12N2NaO3 requires methylphenyl)benzenesulfonamide (3m) (0.084 g, 61%) as a
255.0740).
white solid. Mp 134–136 °C; νmax/cm−1 (neat) 3011 (CH), 1506,
1389, 1327, 1256, 1165, 1090, 1030, 907, 727; δH (400 MHz,
was CDCl3) 2.25 (3H, s, 5-CH3), 3.54 (3H, s, OCH3), 6.59 (1H, d, J 8.3
N-(5-Acetyl-2,4-dimethoxyphenyl)-1H-pyrazole (3k)
N-(5-Acetyl-2,4-dimethoxyphenyl)-1H-pyrazole
(3k)
synthesised as described for N-(2-amino-5-cyanophenyl)-1H- Hz, 3-H), 6.82 (1H, dd, J 8.3, 1.6 Hz, 4-H), 6.98 (1H, br s, NH), 7.34
pyrazole (3a) using 2,4-dimethoxyacetophenone (1k) (0.090 g, (1H, d, J 1.6 Hz, 6-H), 7.36–7.43 (2H, m, 3’-H and 5’-H), 7.48 (1H,
0.50 mmol) and pyrazole (0.10 g, 1.5 mmol). The iodination step t, J 7.4 Hz, 4’-H), 7.71–7.77 (2H, m, 2’-H and 6’-H); δC (101 MHz,
was carried out at 70 °C for 5 h and the N-arylation step at 150 CDCl3) 20.7 (CH3), 55.7 (CH3), 110.5 (CH), 122.4 (CH), 125.4 (C),
°C for 24 h. Purification by flash column chromatography 125.9 (CH), 127.2 (2 × CH), 128.7 (2 × CH), 130.6 (C), 132.8 (CH),
(petroleum ether/ethyl acetate, 4:1) followed by trituration 139.2 (C), 147.7 (C); m/z (ESI) 300.0653 (MNa+. C14H15NNaO3S
with diethyl ether gave N-(5-acetyl-2,4-dimethoxyphenyl)-1H- requires 300.0665).
pyrazole (3k) (0.059 g, 48%) as a white solid. Mp 122–124 °C; N-(2-Methoxy-5-methylphenyl)-4’-
νmax/cm−1 (neat) 2931 (CH), 1659 (C=O), 1605, 1520, 1265, 1227, methylbenzenesulfonamide (3n)
1026, 741; δH (500 MHz, CDCl3) 2.60 (3H, s, COMe), 3.93 (3H, s, N-(2-Methoxy-5-methylphenyl)-4’-methylbenzenesulfonamide
OCH3), 3.99 (3H, s, OCH3), 6.41 (1H, dd, J 2.3, 1.8 Hz, 4’-H), 6.57 (3n) was synthesised as described for N-(2-amino-5-
(1H, s, 3-H), 7.69 (1H, d, J 1.8 Hz, ArH), 7.78 (1H, d, J 2.3 Hz, ArH), cyanophenyl)-1H-pyrazole (3a) using 4-methylanisole (1f)
8.08 (1H, s, 6-H); δC (126 MHz, CDCl3) 31.7 (CH3), 56.0 (CH3), 56.2 (0.063 mL, 0.50 mmol) and p-toluenesulfonamide (0.26 g, 1.5
(CH3), 95.8 (CH), 106.1 (CH), 120.6 (C), 123.4 (C), 128.8 (CH), mmol). The iodination step was carried out at 70 °C for 5 h and
131.3 (CH), 140.2 (CH), 156.7 (C), 159.9 (C), 196.8 (C); m/z (ESI) the N-arylation step at 150 °C for 24 h. Purification by flash
269.0889 (MNa+. C13H14N2NaO3 requires 269.0897).
N-(2-Hydroxy-5-methylphenyl)-1H-pyrazole (3l)
column chromatography (hexane/diethyl ether, 1:1) gave N-(2-
methoxy-5-methylphenyl)-4’-methylbenzenesulfonamide (3n)
An oven-dried microwave vial was flushed with argon and (0.113 g, 78%) as a white solid. Mp 68–70 °C; νmax/cm−1 (neat)
charged with N-iodosuccinimide (0.11 g, 0.50 mmol) and dry 3400 (NH), 2936 (CH), 1595 (C=C), 1508, 1389, 1330, 1252,
toluene (3 mL). To this suspension was added silver 1163, 1123, 1090, 808; δH (400 MHz, CDCl3) 2.25 (3H, s, 4’-CH3),
bis(trifluoromethanesulfonyl)imide (0.015 g, 0.038 mmol) and 2.35 (3H, s, 5-CH3), 3.58 (3H, s, OCH3), 6.60 (1H, d, J 8.4 Hz, 3-H),
p-cresol (1l) (0.053 mL, 0.50 mmol). The reaction mixture was 6.81 (1H, dd, J 8.4, 2.1 Hz, 4-H), 6.95 (1H, br s, NH), 7.18 (2H, d,
stirred at 40 °C for 5 h in the dark. The reaction mixture was J 8.2 Hz, 3’-H and 5’-H), 7.34 (1H, d, J 2.1 Hz, 6-H), 7.63 (2H, d, J
cooled to room temperature and pyrazole (0.10 g, 1.5 mmol), 8.2 Hz, 2’-H and 6’-H); δC (101 MHz, CDCl3) 20.8 (CH3), 21.5 (CH3),
copper(I) iodide (0.0095 g, 0.050 mmol), caesium carbonate 55.7 (CH3), 110.5 (CH), 121.8 (CH), 125.6 (CH), 125.7 (C), 127.2
(0.33 g, 1.0 mmol), trans-N,N′-dimethylcyclohexane-1,2- (2 × CH), 129.3 (2 × CH), 130.6 (C), 136.4 (C), 143.5 (C), 147.5 (C);
diamine (6) (0.16 µL, 0.10 mmol) and water (0.5 mL) were m/z (ESI) 314.0809 (MNa+. C15H17NNaO3S requires 314.0821).
added. The reaction mixture was degassed under argon for 0.1 N-(2-Methoxy-5-methylphenyl)-4’-
h and then heated to 130 °C for 24 h. The reaction mixture was chlorobenzenesulfonamide (3o)
then cooled to room temperature, diluted with ethyl acetate N-(2-Methoxy-5-methylphenyl)-4’-chlorobenzenesulfonamide
(10 mL), washed with a 1 M aqueous sodium thiosulfate (3o) was synthesised as described for N-(2-amino-5-
solution (10 mL). The aqueous layer was extracted with ethyl cyanophenyl)-1H-pyrazole (3a) using 4-methylanisole (1f)
acetate (3 × 10 mL) and the combined organic layers were (0.063 mL, 0.50 mmol) and p-chlorobenzenesulfonamide (0.29
washed with brine (10 mL). The organic phase was dried g, 1.5 mmol). The iodination step was carried out at 70 °C for 5
(MgSO4), filtered and concentrated in vacuo. Purification by h and the N-arylation step at 150 °C for 24 h. Purification by
flash column chromatography (hexane/diethyl ether, 4:1) gave flash column chromatography (hexane/diethyl ether, 1:1) gave
N-(2-hydroxy-5-methylphenyl)-1H-pyrazole (3l) (0.032 g, 37%) N-(2-methoxy-5-methylphenyl)-4’-chlorobenzenesulfonamide
as a colourless oil. νmax/cm−1 (neat) 3036 (OH), 2920 (CH), 1518 (3o) (0.089 g, 55%) as a yellow oil. νmax/cm−1 (neat) 3273 (NH),
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2932 (CH), 1585 (C=C), 1508, 1335, 1252, 1165, 1123, 1086, 752; (1H, br s, NH); δC (101 MHz, CDCl3) 21.0 (CH3), 21.5 (CH3), 55.9
View Article Online
DOI: 10.1039/C9OB00712A
δH (400 MHz, CDCl3) 2.27 (3H, s, 5-CH3), 3.58 (3H, s, OCH3), 6.61 (CH3), 109.8 (CH), 120.4 (CH), 123.9 (CH), 127.0 (2 × CH), 127.6
(1H, d, J 8.3 Hz, 3-H), 6.85 (1H, dd, J 8.3, 2.0 Hz, 4-H), 6.97 (1H, (C), 129.4 (2 × CH), 130.6 (C), 132.5 (C), 142.1 (C), 146.1 (C),
br s, NH), 7.32–7.38 (3H, m, 6-H, 3’-H and 5’-H), 7.67 (2H, d, J 165.1 (C); m/z (ESI) 278.1146 (MNa+. C16H17NNaO2 requires
8.9 Hz, 2’-H and 6’-H); δC (101 MHz, CDCl3) 20.7 (CH3), 55.7 (CH3), 278.1151).
110.5 (CH), 122.6 (CH), 125.0 (C), 126.3 (CH), 128.7 (2 × CH), N-(2-Methoxy-5-methylphenyl)pyrrolidin-2’-one (3s)28
129.0 (2 × CH), 130.7 (C), 137.7 (C), 139.2 (C), 147.8 (C); m/z (ESI) N-(2-Methoxy-5-methylphenyl)pyrrolidin-2’-one (3s) was
334.0265 (MNa+. C14H1435ClNNaO3S requires 334.0275).
N-(2-Methoxy-5-methylphenyl)methanesulfonamide (3p)
synthesised as described for N-(2-amino-5-nitrophenyl)-1H-
pyrazole (3a) using 4-methylanisole (1f) (0.063 mL, 0.50 mmol)
N-(2-Methoxy-5-methylphenyl)methanesulfonamide (3p) was and pyrrolidin-2-one (0.11 mL, 1.5 mmol). The iodination step
synthesised as described for N-(2-amino-5-cyanophenyl)-1H- was carried out at 70 °C for 5 h and the N-arylation step at 150
pyrazole (3a) using 4-methylanisole (1f) (0.063 mL, 0.50 mmol) °C for 24 h. Purification by flash column chromatography (ethyl
and methanesulfonamide (0.14 g, 1.5 mmol). The iodination acetate) gave N-(2-methoxy-5-methylphenyl)pyrrolidin-2’-one
step was carried out at 70 °C for 5 h and the N-arylation step at (3s) (0.053 g, 52%) as a colourless oil. Spectroscopic data were
150 °C for 24 h. Purification by flash column chromatography consistent with the literature.28 δH (500 MHz, CDCl3) 2.12–2.20
(petroleum ether/ethyl acetate, 7:3) gave N-(2-methoxy-5- (2H, m, 4’-H2), 2.28 (3H, s, 5-CH3), 2.54 (2H, t, J 7.8 Hz, 3’-H2)
methylphenyl)methanesulfonamide (3p) (0.061 g, 57%) as a 3.73 (2H, t, J 7.0 Hz, 5’-H2), 3.79 (3H, s, OCH3), 6.84 (1H, d, J 8.9
colourless oil. νmax/cm−1 (neat) 3267 (NH), 2934 (CH), 1508 Hz, 3-H), 7.04–7.07 (2H, m, 4-H and 6-H); δC (126 MHz, CDCl3)
(C=C), 1387, 1323, 1252, 1161, 1121, 1028, 970, 760; δH (500 18.9 (CH2), 20.4 (CH3), 31.2 (CH2), 50.0 (CH2), 55.8 (CH3), 112.1
MHz, CDCl3) 2.30 (3H, s, 5-CH3), 2.94 (3H, s, SO2CH3), 3.85 (3H, (CH), 126.9 (C), 129.1 (CH), 129.2 (CH), 130.4 (C), 152.7 (C),
s, OCH3), 6.74 (1H, br s, NH), 6.80 (1H, d, J 8.3 Hz, 3-H), 6.92 (1H, 175.2 (C); m/z (ESI) 228 (MNa+. 100%).
dd, J 8.3, 1.9 Hz, 4-H), 7.33 (1H, d, J 1.9 Hz, 6-H); δC (126 MHz, N-(2-Methoxy-5-methylphenyl)imidazole (3t)29
CDCl3) 20.8 (CH3), 39.0 (CH3), 55.9 (CH3), 110.6 (CH), 121.7 (CH), N-(2-Methoxy-5-methylphenyl)imidazole (3t) was synthesised
125.7 (C), 125.9 (CH), 131.0 (C), 147.5 (C); m/z (ESI) 238.0502 as described for N-(2-amino-5-cyanophenyl)-1H-pyrazole (3a)
(MNa+. C9H13NNaO3S requires 238.0508).
using 4-methylanisole (1f) (0.063 mL, 0.50 mmol) and imidazole
(0.10 g, 1.5 mmol). The iodination step was carried out at 70 °C
was for 5 h and the N-arylation step at 150 °C for 36 h. Purification
N-(2-Methoxy-5-methylphenyl)benzamide (3q)27
N-(2-Methoxy-5-methylphenyl)benzamide
(3q)
synthesised as described for N-(2-amino-5-cyanophenyl)-1H- by flash column chromatography (ethyl acetate/methanol, 9:1)
pyrazole (3a) using 4-methylanisole (1f) (0.063 mL, 0.50 mmol) gave N-(2-methoxy-5-methylphenyl)imidazole (3t) (0.049 g,
and benzamide (0.18 g, 1.5 mmol). The iodination step was 51%) as a colourless oil. Spectroscopic data were consistent
carried out at 70 °C for 5 h and the N-arylation step at 150 °C for with the literature.29 δH (500 MHz, CDCl3) 2.33 (3H, s, 5-CH3),
24 h. Purification by flash column chromatography 3.80 (3H, s, OCH3), 6.94 (1H, d, J 8.4 Hz, 3-H), 7.09 (1H, d, J 1.8
(hexane/diethyl
ether,
4:1)
gave
N-(2-methoxy-5- Hz, 6-H), 7.14 (1H, dd, J 8.4, 1.8 Hz, 4-H), 7.15–7.24 (2H, m, 5’-H
methylphenyl)benzamide (3q) (0.091 g, 75%) as a colourless oil. and 4’-H), 7.79 (1H, br s, 2’-H); δC (126 MHz, CDCl3) 20.4 (CH3),
Spectroscopic data were consistent with the literature.27 δH 55.9 (CH3), 112.4 (CH), 120.3 (CH), 126.1 (CH), 126.2 (C), 128.7
(500 MHz, CDCl3) 2.33 (3H, s, 5-CH3), 3.87 (3H, s, OCH3), 6.78 (CH), 129.2 (CH), 130.7 (C), 137.8 (CH), 150.4 (C); m/z (ESI) 189
(1H, d, J 8.3 Hz, 3-H), 6.86 (1H, dd, J 8.3 Hz, 2.1 Hz, 4-H), 7.44– (MH+. 100%).
7.55 (3H, m, 3’-H, 4’-H and 5’-H), 7.86–7.90 (2H, m, 2’-H and 6’- N-(2-Methoxy-5-methylphenyl)pyrrole (3u)
H), 8.38 (1H, d, J 2.1 Hz, 6-H), 8.52 (1H, br s, NH); δC (126 MHz, N-(2-Methoxy-5-methylphenyl)pyrrole (3u) was synthesised as
CDCl3) 21.0 (CH3), 55.9 (CH3), 109.8 (CH), 120.5 (CH), 124.1 (CH), described for N-(2-amino-5-nitrophenyl)-1H-pyrazole (3a) using
127.0 (2 × CH), 127.5 (C), 128.7 (2 × CH), 130.6 (C), 131.6 (CH), 4-methylanisole (1f) (0.063 mL, 0.50 mmol) and pyrrole (0.10
135.3 (C), 146.1 (C), 165.1 (C); m/z (ESI) 264 (MNa+. 100%).
N-(2-Methoxy-5-methylphenyl)-4’-methylbenzamide (3r)
mL, 1.5 mmol). The iodination step was carried out at 70 °C for
5 h and the N-arylation step at 150 °C for 36 h. Purification by
N-(2-Methoxy-5-methylphenyl)-4’-methylbenzamide (3r) was flash column chromatography (hexane/diethyl ether, 9:1) gave
synthesised as described for N-(2-amino-5-cyanophenyl)-1H- N-(2-methoxy-5-methylphenyl)pyrrole (3u) (0.035 g, 37%) as a
pyrazole (3a) using 4-methylanisole (1f) (0.063 mL, 0.50 mmol) colourless oil. νmax/cm−1 (neat) 2931 (CH), 1512 (C=C), 1483,
and p-toluamide (0.10 g, 1.5 mmol). The iodination step was 1327, 1242, 1070, 1024, 723; δH (400 MHz, CDCl3) 2.32 (3H, s, 5-
carried out at 70 °C for 5 h and the N-arylation step at 150 °C for CH3), 3.79 (3H, s, OCH3), 6.30 (2H, t, J 2.2 Hz, 3’-H and 4’-H), 6.91
24 h. Purification by flash column chromatography (1H, d, J 8.2 Hz, 3-H), 6.97 (2H, t, J 2.2 Hz, 2’-H and 5’-H), 7.05
(hexane/diethyl
ether,
4:1)
gave
N-(2-methoxy-5- (1H, dd, J 8.2, 2.1 Hz, 4-H), 7.10 (1H, d, J 2.1 Hz, 6-H); δC (101
methylphenyl)-4’-methylbenzamide (3r) (0.098 g, 77%) as a MHz, CDCl3) 20.4 (CH3), 56.0 (CH3), 108.7 (2 × CH), 112.4 (CH),
white solid. Mp 56–58 °C; νmax/cm−1 (neat) 3429 (NH), 2920 122.0 (2 × CH), 126.4 (CH), 127.7 (CH), 130.0 (C), 130.5 (C), 150.6
(CH), 1670 (C=O), 1530 (C=C), 1477, 1423, 1248, 1223, 1138, (C); m/z (ESI) 210.0892 (MNa+. C12H13NNaO requires 210.0889).
1030, 799; δH (400 MHz, CDCl3) 2.33 (3H, s, 5-CH3), 2.41 (3H, s, N-Methyl-6-benzenesulfonamide-7-methoxy-3,4-dihydro-1H-
4’-CH3), 3.87 (3H, s, OCH3), 6.78 (1H, d, J 8.2 Hz, 3-H), 6.85 (1H, quinolin-2-one (16a)
dd, J 8.2, 2.0 Hz, 4-H), 7.27 (2H, d, J 8.1 Hz, 3’-H and 5’-H), 7.78 N-Methyl-6-benzenesulfonamide-7-methoxy-3,4-dihydro-1H-
(2H, d, J 8.1 Hz, 2’-H and 6’-H), 8.38 (1H, d, J 2.0 Hz, 6-H), 8.50 quinolin-2-one (16a) was synthesised as described for N-(2-
8 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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ARTICLE
amino-5-cyanophenyl)-1H-pyrazole (3a) using N-methyl-7- Hz, 4-H2), 2.89 (2H, dd, J = 9.2, 6.8 Hz, 3-H2), 3.37 (3H, s, NCH3),
View Article Online
methoxy-3,4-dihydro-1H-quinolin-2-one (14) (0.0500 g, 0.262 3.95 (3H, s, OCH3), 6.57 (1H, s, NH), 7.47–D7O.5I:910(3.1H03,9m/C,94O’-BH0,0571’-2HA
mmol), benzenesulfonamide (0.122 g, 0.780 mmol), iron(III) and 6’-H), 7.87–7.91 (2H, m, 3’-H and 7’-H), 8.37 (1H, s, 8-H),
chloride (1.01 mg, 0.00625 mmol) and [BMIM]NTf2 (6.00 L, 8.42 (1H, s, 5-H); δC (101 MHz, CDCl3) 24.9 (CH2), 29.6 (CH3), 32.0
0.0196 mmol). The iodination step was carried out at 40 °C for (CH2), 56.2 (CH3), 98.3 (CH), 118.4 (C), 119.5 (CH), 122.6 (C),
4 h and the N-arylation step at 150 °C for 20 h. Purification by 127.0 (2 × CH), 128.8 (2 × CH), 131.8 (CH), 135.1 (C), 136.8 (C),
flash column chromatography (ethyl acetate/hexane, 7:3) gave 147.6 (C), 165.1 (C), 170.4 (C); m/z (ESI) 333.1200 (MNa+.
N-methyl-6-benzenesulfonamide-7-methoxy-3,4-dihydro-1H-
C18H18N2O3 requires 333.1210).
quinolin-2-one (16a) (0.0510 g, 56%) as a white solid. Mp 185– N-Methyl-6-(4’-methylbenzamide)-7-methoxy-3,4-dihydro-
188 °C; νmax/cm−1 (neat) 3252 (NH), 2967 (CH), 1665 (C=O), 1H-quinolin-2-one (16d)
1616, 1518, 1332, 1171, 1146, 1115, 1092, 1061, 934, 763; δH N-Methyl-6-(4’-methylbenzamide)-7-methoxy-3,4-dihydro-1H-
(400 MHz, CDCl3) 2.61 (2H, dd, J 9.2, 6.8 Hz, 4-H2), 2.83 (2H, dd, quinolin-2-one (16d) was synthesised as described for N-
J 7.6, 6.8 Hz, 3-H2), 3.29 (3H, s, NCH3), 3.55 (3H, s, OCH3), 6.33 methyl-6-benzenesulfonamide-7-methoxy-3,4-dihydro-1H-
(1H, s, 8-H), 6.76 (1H, br s, NH), 7.35 (1H, s, 5-H), 7.39–7.44 (2H, quinolin-2-one (16a) using N-methyl-7-methoxy-3,4-dihydro-
m, 3’-H and 5’-H), 7.52 (1H, tt, J 7.2, 1.2 Hz, 4’-H), 7.70–7.74 (2H, 1H-quinolin-2-one (14) (0.0500 g, 0.262 mmol) and p-toluamide
m, 2’-H and 6’-H); δc (101 MHz, CDCl3) 24.6 (CH2), 29.6 (CH3), (0.106 g, 0.783 mmol). The iodination step was carried out at 40
31.8 (CH2), 55.8 (CH3), 98.7 (CH), 118.6 (C), 120.0 (C), 122.5 (CH), °C for 4 h and the N-arylation step at 150 °C for 20 h. Purification
127.2 (2 × CH), 128.7 (2 × CH), 132.8 (CH), 138.8 (C), 139.3 (C), by flash column chromatography (dichloromethane/diethyl
149.8 (C), 170.4 (C); m/z (ESI) 369.0873 (MNa+. C17H18N2NaO4S ether, 3:2) gave N-methyl-6-(4’-methylbenzamide)-7-methoxy-
requires 369.0879).
N-Methyl-6-(p-toluenesulfonamide)-7-methoxy-3,4-dihydro-
1H-quinolin-2-one (16b)
3,4-dihydro-1H-quinolin-2-one (16d) (0.0520 g, 61%) as a white
solid. Mp 164–166 °C; νmax/cm−1 (neat) 3428 (NH), 2955 (CH),
1663 (C=O), 1614, 1533, 1472, 1427, 1350, 1265, 1244, 1206,
1126, 1061, 745; δH (500 MHz, CDCl3) 2.43 (3H, s, 4’-CH3), 2.62–
N-Methyl-6-(p-toluenesulfonamide)-7-methoxy-3,4-dihydro-
1H-quinolin-2-one (16b) was synthesised as described for N- 2.66 (2H, m, 4-H2), 2.86–2.90 (2H, m, 3-H2), 3.37 (3H, s, NCH3),
methyl-6-benzenesulfonamide-7-methoxy-3,4-dihydro-1H- 3.94 (3H, s, OCH3), 6.56 (1H, s, 8-H), 7.29 (2H, d, J 8.2 Hz, 3’-H
quinolin-2-one (16a) using N-methyl-7-methoxy-3,4-dihydro- and 5’-H), 7.78 (2H, d, J 8.2 Hz, 2’-H and 6’-H), 8.36 (1H, s, 5-H),
1H-quinolin-2-one (14) (0.0500 g, 0.262 mmol) and p- 8.39 (1H, br s, NH); δc (126 MHz, CDCl3) 21.5 (CH3), 24.9 (CH2),
toluenesulfonamide (0.134 g, 0.780 mmol). The iodination step 29.6 (CH3), 32.0 (CH2), 56.2 (CH3), 98.3 (CH), 118.3 (C), 119.4
was carried out at 40 °C for 4 h and the N-arylation step at 150 (CH), 122.7 (C), 127.0 (2 × CH), 129.4 (2 × CH), 132.3 (C), 136.6
°C for 20 h. Purification by flash column chromatography (ethyl (C), 142.3 (C), 147.6 (C), 165.1 (C), 170.5 (C); m/z (ESI) 347.1364
acetate/hexane, 7:3) gave N-methyl-6-(p-toluenesulfonamide)- (MNa+. C19H20N2NaO3 requires 347.1366).
7-methoxy-3,4-dihydro-1H-quinolin-2-one (16b) (0.0530 g, N-Methyl-6-(2-pyrrolidinone)-7-methoxy-3,4-dihydro-1H-
56%) as a white solid. Mp 162–164 °C; νmax/cm−1 (neat) 3255 quinolin-2-one (16e)
(NH), 2924 (C-H), 1661 (C=O), 1512, 1342, 1150; δH (400 MHz, N-Methyl-6-(2-pyrrolidinone)-7-methoxy-3,4-dihydro-1H-
CDCl3) 2.38 (3H, s, CH3), 2.61 (2H, dd, J = 9.2, 7.2 Hz, 4-H2), 2.82 quinolin-2-one (16e) was synthesised as described for N-
(2H, dd, J = 9.2, 6.8 Hz, 3-H2), 3.29 (3H, s, NCH3), 3.59 (3H, s, methyl-6-benzenesulfonamide-7-methoxy-3,4-dihydro-1H-
OCH3), 6.35 (1H, s, NH), 6.79 (1H, s, 8-H), 7.20 (2H, d, J = 8.5 Hz, quinolin-2-one (16a) using N-methyl-7-methoxy-3,4-dihydro-
4’-H and 6’-H), 7.34 (1H, s, 5-H), 7.62 (2H, d, J = 8.5 Hz, 3’-H and 1H-quinolin-2-one (14) (0.0500 g, 0.262 mmol) and 2-
7’-H); δC (101 MHz, CDCl3) 21.5 (CH3), 24.6 (CH2), 29.6 (CH3), 31.8 pyrrolidinone (59.3 μL, 0.780 mmol). The iodination step was
(CH2), 55.9 (CH3), 98.8 (CH), 118.5 (C), 120.3 (C), 122.0 (CH), carried out at 40 °C for 4 h and the N-arylation step at 150 °C for
127.2 (2 × CH), 129.4 (2 × CH), 136.4 (C), 138.5 (C), 143.6 (C), 72 h. Purification by flash column chromatography
149.5 (C), 170.4 (C); m/z (ESI) 383.1022 (MNa+. C18H20N2O4S (methanol/ethyl acetate, 1:20 to methanol/ethyl acetate, 1:10)
requires 383.1036).
N-Methyl-6-benzamide-7-methoxy-3,4-dihydro-1H-quinolin-
2-one (16c)
gave N-methyl-6-(2-pyrrolidinone)-7-methoxy-3,4-dihydro-1H-
quinolin-2-one (16e) (0.0360 g, 51%) as a white solid. Mp 188–
190 °C; νmax/cm−1 (neat) 2970 (CH), 1667 (C=O), 1612, 1520,
1450, 1420, 1350, 1281, 1057; δH (400 MHz, CDCl3) 2.15–2.23
N-Methyl-6-benzamide-7-methoxy-3,4-dihydro-1H-quinolin-2-
one (16c) was synthesised as described for N-methyl-6- (2H, m, 4’-H2), 2.55 (2H, t, J = 8.4 Hz, 5’-H2), 2.64 (2H, dd, J = 9.2,
benzenesulfonamide-7-methoxy-3,4-dihydro-1H-quinolin-2- 6.8 Hz, 4-H2), 2.83 (2H, dd, J = 9.2, 6.8 Hz, 3-H2), 3.36 (3H, s,
one (16a) using N-methyl-7-methoxy-3,4-dihydro-1H-quinolin- NCH3), 3.73 (2H, t, J = 7.2 Hz, 3’-H2), 3.86 (3H, s, OCH3), 6.57 (1H,
2-one (14) (0.0500 g, 0.262 mmol) and benzamide (0.094 g, s, 8-H), 7.05 (1H, s, 5-H); δC (101 MHz, CDCl3) 18.9 (CH2), 24.4
0.780 mmol). The iodination step was carried out at 40 °C for 4 (CH2), 29.7 (CH3), 31.1 (CH2), 31.8 (CH2), 50.0 (CH2), 56.0 (CH3),
h and the N-arylation step at 150 °C for 20 h. Purification by 100.0 (CH), 118.4 (C), 121.6 (C), 127.6 (CH), 140.8 (C), 154.2 (C),
flash column chromatography (dichloromethane/ethyl acetate, 170.5 (C), 175.4 (C); m/z (ESI) 297.1214 (MNa+. C15H18N2NaO3
4:1) gave N-methyl-6-benzamide-7-methoxy-3,4-dihydro-1H- requires 297.1210).
quinolin-2-one (16c) (0.0480 g, 60%) as a white solid. Mp 168– N-Methyl-6-pyrazole-7-methoxy-3,4-dihydro-1H-quinolin-2-
170 °C. νmax/cm−1 (neat) 3428 (NH), 2941 (CH), 1661 (C=O), one (16f)
1530, 1124, 1059; δH (400 MHz, CDCl3) 2.65 (2H, dd, J = 9.2, 7.2
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
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Organic & Biomolecular Chemistry
Page 10 of 11
ARTICLE
Journal Name
Chem., 2010, 12, 276. (g) N. Panda, A. K. Jena, VSi.ewMAorthiclaepOantlirnae
and S. R. Rout, Tetrahedron Lett., 2011, 52, 1924.
For recent reviews, see: (a) M.-L. LouilDlaOtIa: 1n0d.1F0.39W/C.9POaBtu00re71a2uA,
Chem. Soc. Rev., 2014, 43, 901. (b) J. Jiao, K. Murakami and K.
Itami, ACS Catal., 2016, 6, 610. (c) Y. Park, Y. Kim and S. Chang,
Chem. Rev., 2017, 117, 9247. (d) M. C. Henry, M. A. B. Mostafa
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Á. M. Martinez, N. Rodriguez, R. G. Arrayás and J. C. Carretero,
Chem. Commun., 2014, 50, 2801.
N-Methyl-6-(1H-pyrazole)-7-methoxy-3,4-dihydro-1H-quinolin-
2-one (16f) was synthesised as described for N-methyl-6-
benzenesulfonamide-7-methoxy-3,4-dihydro-1H-quinolin-2-
one (16a) using N-methyl-7-methoxy-3,4-dihydro-1H-quinolin-
2-one (14) (0.0500 g, 0.262 mmol) and pyrazole (0.531 g, 0.780
mmol). The iodination step was carried out at 40 °C for 4 h and
the N-arylation step at 150 °C for 20 h. Purification by flash
column chromatography (ethyl acetate/hexane, 7:3) gave N-
methyl-6-(1H-pyrazole)-7-methoxy-3,4-dihydro-1H-quinolin-2-
one (16f) (0.0400 g, 60%) as a white solid. Mp 168–170 °C;
νmax/cm−1 (neat) 2947 (CH), 1667 (C=O), 1620, 1528, 1466, 1350,
1188, 1134, 1034; δH (400 MHz, CDCl3) 2.66 (2H, dd, J = 9.2, 6.8
Hz, 4-H2), 2.89 (2H, dd, J = 9.2, 6.8 Hz, 3-H2), 3.40 (3H, s, NCH3),
3.89 (3H, s, OCH3), 6.42 (1H, dd, J = 2.3, 1.7 Hz, 4’-H), 6.65 (1H,
s, 8-H), 7.54 (1H, s, 5-H), 7.69 (1H, d, J = 1.7 Hz, 3’-H), 7.99 (1H,
d, J = 2.3 Hz, 5’-H); δC (101 MHz, CDCl3) 24.4 (CH2), 29.7 (CH3),
31.8 (CH2), 56.4 (CH3), 100.1 (CH), 106.2 (CH), 118.8 (C), 124.3
(CH), 124.5 (C), 131.4 (CH), 140.0 (CH), 140.2 (C), 150.5 (C),
170.4 (C); m/z (ESI) 280.1052 (MNa+. C14H15N3NaO2 requires
280.1056)
5
6
7
8
9
Q. Li, S.-Y. Zhang, G. He, Z. Ai, W. A. Nack and G. Chen, Org.
Lett., 2014, 16, 1764.
K. Sun, Y. Li, T. Xiong, J. Zhang and Q. Zhang, J. Am. Chem. Soc.,
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10 M. A. B. Mostafa, E. D. D. Calder, D. T. Racys and A. Sutherland,
Chem. Eur. J., 2017, 23, 1044.
11 I. Goldberg, Ber. Dtsch. Chem. Ges., 1906, 39, 1691.
12 (a) D. T. Racys, C. E. Warrilow, S. L. Pimlott and A. Sutherland
Org. Lett., 2015, 17, 4782. (b) M. A. B. Mostafa, R. M. Bowley,
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J. Org. Chem., 2019, 84, 346.
13 Analysis of the one-pot amination of 1a by 1H NMR
spectroscopy showed that full conversion to the bromide
intermediate was achieved during the first step. Hence,
recovery of 1a at the end of the copper-catalysed amination
step is due to reduction of the bromide intermediate and not
returned unreacted aniline.
Conflicts of interest
There are no conflicts to declare.
14 In previous studies (see reference 10), control experiments
showed that the presence of the ionic liquid has no effect on
the copper-catalysed C-N bond forming step.
Acknowledgements
15 G. Evano, N. Blanchard and M. Toumi, Chem. Rev., 2008, 108,
3054.
16 (a) A. Shafir and S. L. Buchwald, J. Am. Chem. Soc., 2006, 128,
8742. (b) A. Shafir, P. A. Lichtor and S. L. Buchwald, J. Am.
Chem. Soc., 2007, 129, 3490.
17 Buchwald and co-workers have suggested that the success of
cyclic diamine ligands for Goldberg-type coupling reactions
may be due to an increase of the stability constant of the
catalytically active copper-nucleophile complex: (a) A.
Klapars, J. C. Antilla, X. Huang and S. L. Buchwald, J. Am. Chem.
Soc., 2001, 123, 7727. (b) A. Klapars, X. Huang and S. L.
Buchwald, J. Am. Chem. Soc., 2002, 124, 7421.
18 D. T. Racys, S. A. I. Sharif, S. L. Pimlott and A. Sutherland, J.
Org. Chem., 2016, 81, 772.
19 (a) M. Earle, B. J. McAuley, A. Ramani, K. Seddon and J.
Thompson, WO 02072260, 2002. (b) M. J. Earle, U. Hakala, B.
J. McAuley, M. Nieuwenhuyzen, A. Ramani, K. R. Seddon,
Chem. Commun., 2004, 1368.
Financial support from the EPSRC (studentship to M.C.H.,
EP/M508056/1), the University of Glasgow (studentship to
R.J.F) and the Ministry of Higher Education and Scientific
Research, Omar Al-Mukhtar University, Libya (studentship to
M.A.B.M.) is gratefully acknowledged.
Notes and references
1
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Ricci, Ed. Amino Group Chemistry: From Synthesis to the Life
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Ley and A. W. Thomas, Angew. Chem. Int. Ed., 2003, 42, 5400.
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McGowan, Chem. Soc. Rev., 2014, 43, 3525. (d) K. Okano, H.
Tokuyama and T. Fukuyama, Chem. Commun., 2014, 50,
13650.
2
20 S. Antoniotti, V. Dalla and E. Duñach, Angew. Chem. Int. Ed.,
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21 For example, see: (a) J. W. Tye, Z. Weng, A. M. Johns, C. D.
Incarvito and J. F. Hartwig, J. Am. Chem. Soc., 2008, 130, 9971.
(b) E. R. Strieter, B. Bhayana and S. L. Buchwald, J. Am. Chem.
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22 E. Sperotto, G. P. M. van Klink, G. van Koten and J. G. de Vries,
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3
4
For reviews of palladium-catalysed aryl amination, see: (a) M.
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