Unexpected palladium catalyzed O-arylation occurring in 4-(4-fluoro-3-nitrophenyl)-1,2-dimethyl-5-nitro-1H-imidazole series

Article abstract of DOI:10.1016/j.tetlet.2012.07.107

We describe herein a new unexpected palladium-catalyzed O-arylation reaction in fluorinated nitro(o-nitrophenyl)imidazole series involving arylboronic acids under Suzuki-Miyaura cross-coupling reaction conditions.

Full text of DOI:10.1016/j.tetlet.2012.07.107

Tetrahedron Letters 53 (2012) 5393–5397
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Unexpected palladium catalyzed O-arylation occurring in
4-(4-fluoro-3-nitrophenyl)-1,2-dimethyl-5-nitro-1H-imidazole series
⇑
Laura Zink, Kevin Neildé, Maxime D. Crozet, Patrice Vanelle
Aix-Marseille Univ, UMR CNRS 7273: Institut de Chimie Radicalaire, Equipe Pharmaco-Chimie Radicalaire (LPCR), Faculté de Pharmacie, 27 Boulevard Jean Moulin, CS 30064,
13385 Marseille cedex 5, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe herein a new unexpected palladium-catalyzed O-arylation reaction in fluorinated nitro(o-
nitrophenyl)imidazole series involving arylboronic acids under Suzuki–Miyaura cross-coupling reaction
conditions.
Received 14 May 2012
Revised 20 July 2012
Accepted 25 July 2012
Available online 2 August 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Suzuki–Miyaura
O-arylation
Palladium
Nitroimidazole
X-ray spectroscopy
During the course of our research on the chemistry of new safer
antiprotozoal1 agents in 5-nitroimidazole series,2 we observed
what appeared to be palladium-catalyzed O-arylation of an aryl
fluoride.
Indeed, they demonstrated a possible mechanism for the oxida-
tive addition step occurring via the palladium(0) species which, in
the case of electron-deficient aryl fluoride, acts as a nucleophile
and displaces the fluoride in an SNAr manner to form the car-
bon–palladium bond, as suggested by Amatore and others.11 Final-
ly, a Nickel-catalyzed Suzuki–Miyaura reaction of aryl fluorides
was recently described in the literature.12
This report focuses on the unexpected O-arylation of the aryl
fluoride derivative 2 with boronic acids, giving diaryl ether deriva-
tives instead of the expected C–C derivatives during the Suzuki–
Miyaura cross-coupling study. The required starting material13
was obtained by nitration using a mixture of HNO3 60%/H2SO4 of
compound 18b (Scheme 1).
The development of mild conditions for the synthesis of diaryl
ethers has attracted considerable attention, mainly due to their
biological activity.3 Reactions used to generate aryl ethers appear
in the literature, for example the Cu-promoted arylation of alcohol
derivatives with phenylboronic acids known as Chan–Lam cou-
pling,4 the Cu-mediated Ullmann condensation of phenols with
aryl halides,5 and the Buchwald’s palladium-catalyzed C–O cou-
pling of phenols with aryl halides.6 However, to the best of our
knowledge, no example of diaryl ether synthesis using arylboronic
acid and aryl halides under the catalytic effects of palladium spe-
cies has ever been described.
Compound 2, reacted with 4-methoxyphenylboronic acid under
classical Suzuki–Miyaura reaction conditions using Pd(OAc)2/
xantphos catalyst, Cs2CO3 under inert atmosphere in DME at
The Suzuki–Miyaura cross-coupling has proved to be extremely
versatile and is extensively used in natural products and heterocy-
clic synthesis.7 To our knowledge, only
a few examples of
Suzuki–Miyaura cross-coupling in haloimidazole series have been
reported.8 Bromides and chlorides are commonly used as leaving
groups in Suzuki–Miyaura cross-coupling.9 Although aryl fluorides
have long been considered inert to palladium(0)-catalyzed cou-
pling reactions, Yu and Kim described in 2003 an original palla-
dium(0)-catalyzed Suzuki cross-coupling reactivity of highly
electron-deficient aryl fluoride.10
NO2
F
F
HNO3 60%
/ H2SO4
0.25 h
N
N
83%
O2N
O2N
N
N
2
1
⇑
Corresponding author. Tel.: +33 4 91 83 55 73; fax: +33 4 86 13 68 22.
E-mail address: patrice.vanelle@univ-amu.fr (P. Vanelle).
Scheme 1. Preparation of starting material 2.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.107

5394
L. Zink et al. / Tetrahedron Letters 53 (2012) 5393–5397
NO2
NO2
NO2
O
Ar
NO2
Ar
HO
F
Ar
B(OH)2
Pd(OAc)2
Xantphos
N
N
N
N
Cs2CO3,
TBAB
O2N
O2N
3 0%
O2N
O2N
N
N
N
N
DME,
N2, 70 ºC
2
10 traces
4 Ar = p-MeO-C6H4
5 Ar = p-Me-C6H4
6 Ar = p-Cl-C6H4
7 Ar = C6H5
60%
53%
30%
79%
18%
37%
8 Ar = o-Me-C6H4
9 Ar = 4-pyridinyl
Scheme 2. Reaction of 2 and boronic acids.
Figure 1. Ortep drawings of 4 and 5.
F
O
MeO
B(OH)2
OMe
Pd(OAc)2
Xantphos
N
N
N
X
O2N
Cs2CO3, TBAB
DME, N2, 70 ºC
N
O2N
1
Scheme 3. Reaction using 1 and 4-methoxyphenylboronic acid.
OH
B(OH)2
OMe
70 °C in the presence of tetrabutylammonium bromide (TBAB),
gave unexpected methoxyphenoxy derivative 4 in 60% yield, and
traces of nitrophenol derivative 10 instead of the expected C–C
coupled derivative 3. Adding 10 equiv of water to the same reac-
tion medium afforded compound 4 in similar yields (51% vs 60%
without addition of water). Thus, the formation of compound 10
could result from a SNAr reaction between compound 2 and, either
carbonate or hydroxide anion as oxygen sources. Then, this reactiv-
ity was confirmed with other boronic acids, giving O-arylated com-
pounds 5–9 in 30–79% yields (Scheme 2).14
F
Pd(OAc)2
Xantphos
NO2
NO2
Cs2CO3, TBAB
DME, N2, 70 ºC
CHO
CHO
11
12 75%
Scheme 4. Reaction using 4-fluoro-3-nitrobenzaldehyde 11 and 4-meth-
oxyphenylboronic acid.
X-ray spectroscopy15 of 4 and 5 (Fig. 1) and HRMS spectrum of
these four compounds confirmed the C–O bond formation.
Since palladium-catalyzed O-arylation had never been de-
scribed with arylboronic acids and electron-deficient aryl fluorides,
additional experiments were performed to further understand the
mechanism of the C–O bond formation.
First, palladium catalysis was investigated by treating 2 and 4-
methoxyphenylboronic acid under our experimental conditions

L. Zink et al. / Tetrahedron Letters 53 (2012) 5393–5397
5395
DME, N2, 70 ºC
0.05 equiv. Pd(OAc)2
1.5 equiv. Cs2CO3
NO2
HO
X
NO2
0.1 equiv. Xantphos
MeO
O
B(OH)2
OMe
1.2 equiv. TBAB
N
N
O2N
10
N
CH2Cl2
O2N
N
X
4
1 equiv. Cu(OAc)2,
2 equiv. Et3N
Scheme 5. Coupling assays of nitrophenol 10 and 4-methoxyphenylboronic acid.
NO2
F
NO2
O
MeO
N
Oxidation
B(OH)2
OMe
OH
Conditions? X
O2N
N
2
N
O2N
OMe
N
4
O-arylation
Scheme 6. Formation hypothesis of 4-methoxyphenol.
but without palladium. After 5 days, this reaction did not produce
any compound 4, but only traces of the nitrophenol derivative 10,
which suggests that palladium plays a key catalytic role in the
reaction.
investigated the possibility of the 4-methoxyphenylboronic acid
being converted into 4-methoxyphenol under the experimental
conditions previously cited, subsequently reacting with substrate
2 via an O-arylation and SNAr mechanism and leading to compound
4 (Scheme 6). However, no trace of methoxyphenol was produced
(confirmed by LC/MS and TLC). Moreover, other oxidation assays
were also performed, but no trace of 4-methoxyphenol was ever
observed.
These unsuccessful results led us to re-examine LC/MS spectra
previously observed under Pd-catalyzed reactions. A mass peak
(m/z 539 [M+H]+) was chosen because of its occurrence throughout
the reactions using different arylboronic acids. Complementary
spectral analysis confirmed the formation of 4,40-[4,40-oxybis(3-ni-
tro-4,1-phenylene)]bis(1,2-dimethyl-5-nitro-1H-imidazole) 13.
We hypothesized that a possible mechanism for the O-arylation
could be via intermediate 13 after a palladium oxidative addition
and a cross-coupling with arylboronic acids, even though, to the
best of our knowledge, no such palladium addition had ever been
described.
In order to propose a mechanism, supposing the in situ forma-
tion of compound 13, we realized a particular assay using the same
reaction conditions and 1 equiv of compound 10. Thus, with
p-chlorophenylboronic acid, the desired product 6 was formed in
30% yield. In order to reinforce the proposed mechanism, com-
pound 13 was synthesized by reaction with aryl fluoride derivative
2 and nitrophenol derivative 10 under base-mediated conditions.16
Then, compound 13 was tested with 4-methoxyphenylboronic acid
under the above experimental conditions. After 48 h, a conversion
of 13 in O-arylated compound 4 (39%), nitrophenol 10 (60%), and
C-arylated compound 3 (traces) were observed, suggesting the pos-
sible mechanism depicted in Scheme 7.
The present work is the first example of a palladium-catalyzed
C–O bond formed from a reaction between an activated phenylflu-
oride derivative and aryl or heteroaryl boronic acids. Initial mech-
anistic studies indicate that the reaction may occur via the
formation of a nitrophenol derivative 10 and a diphenyl ether
As Kim and Yu10 stated that a fluoride has to be activated by
two withdrawing groups in order to react, the roles of the o-nitro
and 5-nitroimidazole groups of substrate 2 were investigated.
We found that the reaction of compound 1 (which does not bear
the o-nitro group on the phenyl ring) and the 4-methoxyphenylbo-
ronic acid did not yield any expected product under our conditions
(Scheme 3).
In the same way, the reaction of the 4-fluoro-3-nitrobenzalde-
hyde 11, bearing an aldehyde as electron-withdrawing group (in-
stead of the 5-nitroimidazole group), only gave nitrophenol 12
under our experimental conditions (Scheme 4).
These two reactions suggest that both the o-nitro and the nitro-
imidazole groups are essential to the formation of the C–O bond.
Furthermore, as the nitrophenol derivative 10 was formed un-
der these experimental conditions, we suggest that substrate 2
gives the nitrophenol derivative 10, which could undergo a cross-
coupling with the boronic acid derivatives.
Indeed, this coupling is known as the Chan–Lam reaction, but
the reaction is copper-promoted. However, when the reactivity of
nitrophenol 10 with 4-methoxyphenylboronic acid was examined
under the previous experimental palladium-catalyzed conditions,
no C–O coupled compound was detected. Another assay involving
classic Chan–Lam copper-promoted conditions4 was also ineffec-
tive (Scheme 5).
Next, we turned our attention to the boron species. Thus, by
replacing arylboronic acids by a boronic ester (4,4,5,5-tetra-
methyl-2-(5-methylthiophen-2-yl)-1,3,2-dioxaborolane) or potas-
sium trifluoroborate (potassium 4-methoxyphenyltrifluoroborate),
no reaction was observed. Furthermore, Lam and co-workers
demonstrated that boronic acids can be oxidized into the corre-
sponding phenol derivatives induced by copper- promoted condi-
tions, or in the presence of 10 equiv water, and we therefore

5396
L. Zink et al. / Tetrahedron Letters 53 (2012) 5393–5397
NO2
NO2
HO
F
Base
N
NO2
N
O
Ar
O2N
O2N
N
N
2
N
10
2
/ Base
O2N
N
NO2
N
Oxidative
addition
NO2
N
O
Pd0
Reductive elimination
NO2
N
N
O2N
NO2
N
13
Ar
II
N
Pd
O
NO2
II
Pd
O
O2N
NO2
N
O2N
N
N
O2N
Ar
N
N
NO2
N
NO2
B-
OH
Transmetallation
N
N
HO OH
+/-
OH
OH
B-
O2N
O2N
HO
OH
Scheme 7. Proposed mechanism of C–O bond formation.
Upcroft, J. A.; Dunn, L. A.; Wright, J. M.; Benakli, K.; Upcroft, P.; Vanelle, P.
Antimicrob. Agents Chemother. 2006, 50, 344–347; (i) Crozet, M. D.; Botta, C.;
Gasquet, M.; Curti, C.; Remusat, V.; Hutter, S.; Chapelle, O.; Azas, N.; De Méo,
M.; Vanelle, P. Eur. J. Med. Chem. 2009, 44, 653–659; (j) Dunn, L. A.; Burgess, A.
G.; Krauer, K. G.; Eckmann, L.; Vanelle, P.; Crozet, M. D.; Gillin, F. D.; Upcroft, P.;
Upcroft, J. A. Int. J. Antimicrob. Agents 2010, 36, 37–42; (k) Zink, L.; Crozet, M. D.;
Terme, T.; Vanelle, P. Tetrahedron Lett. 2011, 52, 6991–6996; (l) Juspin, T.; Zink,
L.; Crozet, M. D.; Terme, T.; Vanelle, P. Molecules 2011, 16, 6883–6893; (m)
Dunn, L. A.; Tan, K. S. W.; Vanelle, P.; Juspin, T.; Crozet, M. D.; Terme, T.;
Upcroft, P.; Upcroft, J. A. Parasitol. Res. 2012. http://dx.doi.org/10.1007/s00436-
012-2860-7.
derivative 13 obtained via SNAr reaction, which could have a key
role in the reactivity. Further investigations of the scope and mech-
anism involved here, as well as potential synthetic applications, are
currently in progress and will be reported in due course. We hope
these data will provide useful input for further mechanistic and
computational studies, as well as fueling additional studies of this
mechanism.
Acknowledgments
3. (a) Buckingham, J. Dictionary of Natural Products; University Press: Cambridge,
MA, 1994; (b) Czarnik, A. W. Acc. Chem. Res. 1996, 29, 112–113; (c) Theil, F.
Angew. Chem., Int. Ed. 1999, 38, 2345–2347; (d) Sawyer, J. S. Tetrahedron 2000,
56, 5045–5065; (e) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131–
209; (f) Thomas, A. W.; Ley, S. V. Angew. Chem., Int. Ed. 2003, 42, 5400–5449; (g)
Cristau, P.; Vors, J.-P.; Zhu, J. Tetrahedron 2003, 59, 7859–7870.
4. (a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett.
1998, 39, 2933–2936; (b) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett.
1998, 39, 2937–2940; (c) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.;
Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941–2944.
5. (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382–2384; (b) Ullmann, F. Ber.
Dtsch. Chem. Ges. 1904, 37, 853–857; (c) Ullmann, F.; Sponagel, P. Ber. Dtsch.
Chem. Ges. 1905, 38, 2211–2212; (d) Lindley, J. Tetrahedron 1984, 40, 1433–
1456.
This work is supported by the CNRS and the Universities of Aix-
Marseille. The authors thank the Spectropole team for various ana-
lytical measurements, and M. Giorgi for the X-ray crystal-structure
determinations. We express our thanks to V. Remusat for 1H and
13C NMR spectra recording.
References and notes
1. Ellis, G. P.; Epstein, C.; Fitzmaurice, C.; Golberg, L.; Lord, G. H. J. Pharm.
Pharmacol. 1967, 19, 102–107.
6. (a) Mann, G.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 13109–13110; (b)
Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 3395–3396;
(c) Mann, G.; Hartwig, J. F. Tetrahedron Lett. 1997, 38, 8005–8008; (d) Burgos, C.
H.; Barder, T. E.; Huang, X.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45,
4321–4326.
7. (a) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513–519; (b)
Suzuki, A. Pure Appl. Chem. 1994, 66, 213–222; (c) Miyaura, N.; Suzuki, A. Chem.
Rev. 1995, 95, 2457–2484; (d) Malleron, J.-L.; Fiaud, J.-C.; Legros, J.-Y. In
Handbook of Palladium Catalysed Organic Reactions; Malleron, J.-L., Fiaud, J.-C.,
2. (a) Vanelle, P.; Crozet, M. P.; Maldonado, J.; Barreau, M. Eur. J. Med. Chem. 1991,
26, 167–178; (b) Jentzer, O.; Vanelle, P.; Crozet, M. P.; Maldonado, J.; Barreau,
M. Eur. J. Med. Chem. 1991, 26, 687–697; (c) Vanelle, P.; Crozet, M. P. Recent Res.
Develop. Org. Chem. 1998, 2, 547–566; (d) Upcroft, J. A.; Campbell, R. W.;
Benakli, K.; Upcroft, P.; Vanelle, P. Antimicrob. Agents Chemother. 1999, 43, 73–
76; (e) Crozet, M. D.; Perfetti, P.; Kaafarani, M.; Vanelle, P.; Crozet, M. P.
Tetrahedron Lett. 2002, 43, 4127–4129; (f) Crozet, M. D.; Perfetti, P.; Kaafarani,
M.; Crozet, M. P.; Vanelle, P. Lett. Org. Chem. 2004, 1, 326–330; (g) Crozet, M. D.;
Rémusat, V.; Curti, C.; Vanelle, P. Synth. Commun. 2006, 36, 3639–3646; (h)

L. Zink et al. / Tetrahedron Letters 53 (2012) 5393–5397
5397
Legros, J.-Y., Eds.; Academic Press: San Diego, 1997; e Suzuki, A. In Metal
Catalysed Cross Coupling Reactions; Diederich, F., Stang, P. J., Eds.; VCH:
Weinheim, 1998; pp 49–97; (f) Stanforth, S. P. Tetrahedron 1998, 54, 263–
303; (g) Suzuki, A. J. Organomet. Chem. 1999, 576, 147–168; (h) Genet, J.-P.;
Savignac, M. J. Organomet. Chem. 1999, 576, 305–317; (i) Kotha, S.; Lahiri, K.;
Kashinath, D. Tetrahedron 2002, 58, 9633–9695; (j) Suzuki, A. J. Organomet.
Chem. 2002, 653, 83–90; k Suzuki, A.; Brown, H. C. In Organic Syntheses via
Boranes; Aldrich: Milwaukee, 2003; vol. 3,; (l) Enguehard-Gueiffier, C; Hübner,
H.; El Hakmaoui, A.; Allouchi, H.; Gmeiner, P.; Argiolas, A.; Melis, M. R.;
Gueiffier, A. J. Med. Chem. 2006, 49, 3938–3947; (m) Véron, J.-B.; Enguehard-
Gueiffier, C.; Snoeck, R.; Andrei, G.; De Clercq, E.; Gueiffier, A. Bioorg. Med. Chem.
2007, 15, 7209–7219.
148.7 (C), 150.9 (C), 154.1 (C). The two C–NO2 groups did not appear in these
conditions. HRMS calcd for C17H13ClN4O5 [M+H]+: 389.0647, found 389.0650.
1,2-Dimethyl-5-nitro-4-(3-nitro-4-phenoxyphenyl)-1H-imidazole (7): Yellow oil.
1H NMR (200 MHz, CDCl3): d 2.52 (s, 3H), 3.93 (s, 3H), 6.99–7.22 (m, 3H), 7.37–
7.45 (m, 3H), 7.94 (dd, J = 2.2 Hz, 8.8 Hz, 1H), 8.45 (d, J = 2.2 Hz, 1H). 13C NMR
(50 MHz, CDCl3) d 14.2 (CH3), 34.3 (CH3), 119.2 (CH), 119.7 (2 ꢀ CH), 125.0
(CH), 126.9 (C), 127.2 (CH), 127.9 (C), 128.7 (C), 130.2 (2 ꢀ CH), 135.1 (CH),
140.5 (C), 148.7 (C), 151.6 (C), 155.2 (C). HRMS calcd for C17H14N4O5 [M+H]+:
355.1036, found 355.1031.
1,2-dimethyl-5-nitro-4-[3-nitro-4-(o-tolyloxy)phenyl]-1H-imidazole (8): Yellow
oil. 1H NMR (200 MHz, CDCl3): d 2.24 (s, 3H), 2.52 (s, 3H), 3.93 (s, 3H), 6.81
(d, J = 8.8 Hz, 1H), 7.01 (dd, J = 1.7 Hz, 7.3 Hz, 1H), 7.15–7.32 (m, 3H), 7.90 (dd,
J = 2.2 Hz, 8.8 Hz, 1H), 8.46 (d, J = 2.2 Hz, 1H). 13C NMR (50 MHz, CDCl3) d 14.2
(CH3), 16.0 (CH3), 34.3 (CH3), 117.3 (CH), 120.4 (CH), 125.7 (CH), 126.1 (C),
127.4 (CH), 127.6 (CH), 130.4 (C), 131.9 (CH), 135.2 (CH), 139.6 (C), 140.7 (C),
148.7 (C), 152.0 (C), 152.6 (C), a C–NO2 group did not found. HRMS calcd for
8. a Li, J. J.; Gribble, G. W. In Palladium in Heterocyclic Chemistry; Li, J. J., Gribble, G.
W., Eds.; Tetrahedron Organic Chemistry Series No. 26; Elsevier: Oxford
Amsterdam, 2007; b Crozet, M. D.; Zink, L.; Rémusat, V.; Curti, C.; Vanelle, P.
Synthesis 2009, 3150–3156.
9. Smith, G. B.; Dezeny, G. C.; Hugues, D. L.; King, A. O.; Verhoeven, T. R. J. Org.
Chem. 1994, 59, 8151–8156.
C
18H16N4O5 [M+H]+: 369.1193, found 369.1190.
4-[4-(1,2-dimethyl-5-nitro-1H-imidazol-4-yl)-2-nitrophenoxy]pyridine
(9):
10. Kim, Y. M.; Yu, S. J. Am. Chem. Soc. 2003, 125, 1696–1697.
11. (a) Amatore, C.; Pfluger, F. Organometallics 1990, 9, 2276–2282; (b) Jutand, A.;
Mosleh, A. Organometallics 1995, 14, 1810–1817.
Brown powder, mp 235 °C (i-PrOH). 1H NMR (200 MHz, CDCl3): d 2.55 (s,
3H), 3.96 (s, 3H), 6.48 (d, J = 7.8 Hz, 2H), 7.34 (d, J = 7.8 Hz, 2H), 7.55 (d,
J = 8.3 Hz, 1H), 8.22 (dd, J = 2.0 Hz, 8.3 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H). 13C NMR
(50 MHz, CDCl3) d 14.2 (CH3), 34.4 (CH3), 119.1 (2 ꢀ CH), 127.4 (CH), 128.3
(CH), 134.1 (C), 135.4 (CH), 136.1 (C), 138.7 (C), 139.4 (2 ꢀ CH), 144.1 (C), 149.1
(C), 178.7 (C), a C–NO2 group did not found. HRMS calcd for C16H13N5O5
[M+H]+: 356.0989, found 356.0990.
12. (a) Tobisu, M.; Xu, T.; Shimasaki, T.; Chatani, N. J. Am. Chem. Soc. 2011, 133,
19505–19511; (b) Paulose, T. A. P.; Wu, S.-C.; Olson, J. A.; Chau, T.; Theaker, N.;
Hassler, M.; Quail, J. W.; Foley, S. R. Dalton Trans. 2012, 41, 251–260.
13. Synthesis and data of compound 2: 1.83 mL of nitric acid 60% was added
dropwise to a two neck flask placed on a cold water bath and containing 1
(4.25 mmol, 1 equiv) solubilized in concentrated sulphuric acid (18.3 mL). The
reaction progress was monitored by TLC analysis. After 45 min at room
temperature, the mixture is poured into cold H2O. The precipitate was filtered
off, washed with a solution of Na2CO3 1 M, H2O, and dried with EtOH and
petroleum ether. The filtrate was extracted by CHCl3 after neutralization by
Na2CO3, and the organic layer was dried (Na2SO4), filtered, and evaporated
under reduced pressure. Compound 2 was isolated in 83% yield. 4-(4-Fluoro-3-
nitrophenyl)-1,2-dimethyl-5-nitro-1H-imidazole (2): Yellow powder, mp 179 °C
(i-PrOH). 1H NMR (200 MHz, CDCl3): d 2.54 (s, 3H), 3.94 (s, 3H), 7.26–7.39 (m,
1H), 8.05–8.13 (m, 1H), 8.53–8.58 (m, 1H). 13C NMR (50 MHz, CDCl3): d 14.2
(CH3), 34.3 (CH3), 118.0 (d, J = 21.2 Hz, CH), 127.6 (d, J = 2.2 Hz, CH), 128.9 (d,
J = 4.4 Hz, C), 136.6 (d, J = 9.2 Hz, CH), 139.8 (C), 148.8 (C), 153.1 (C), 158.4 (C).
A C–NO2 group did not appear in these conditions. Anal. Calcd for C11H9FN4O4:
C, 47.15; H, 3.24; N, 19.99. Found C, 47.34; H, 3.33; N, 19.79.
4-(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)-2-nitrophenol (10): Orange oil. 1H
NMR (200 MHz, CDCl3): d 2.53 (s, 3H), 3.93 (s, 3H), 7.22 (d, J = 8.8 Hz, 1H),
8.05 (dd, J = 2.2 Hz, 8.8 Hz, 1H), 8.63 (d, J = 2.2 Hz, 1H), 10.75 (s, 1H). 13C NMR
(50 MHz, CDCl3): d 14.2 (CH3), 34.3 (CH3), 119.6 (CH), 124.5 (C), 126.6 (CH),
127.6 (C), 133.2 (C), 138.6 (CH), 140.8 (C), 148.7 (C), 155.6 (C). HRMS calcd for
C
11H10N4O5 [M+H]+: 279.0724, found 279.0725.
15. Crystal data for compound 4: C18H16N4O6, M = 384.35, triclinic, a = 7.3800(2) Å,
b = 9.2849(2) Å, c = 13.6130(4) Å,
a = 90.672(1)°, b = 105.679(1)°, c = 94.599(1)°,
V = 894.66(4) Å3, T = 293(2) K, space group Pı, Z = 2, 14055 reflections
¯
measured, 4399 independent reflections (Rint = 0.04). The final R1 values were
0.066 (I > 2r r(I)). The final R1
(I)). The final wR(F2) values were 0.2022 (I > 2
values were 0.1023 (all data). The final wR(F2) values were 0.2494 (all data).
CCDC 877509 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge at www.cdcc.cam.ac.uk/data_
request/cif of from the Cambridge Crystallographic Data Centre, 12, Union
Road, Cambridge CB2 1EZ, UK; fax: +44 (1223) 336033; email: deposit@ccdc.
cam.ac.uk.
14. General synthesis and data of compounds 4, 5, 6, 7, 8, 9, 10: To a two neck flask,
0.36 mmol (1 equiv) of 2 was dissolved in DME (15 mL). 0.43 mmol, (1.2 equiv)
of the appropriate arylboronic acid was added with 0.54 mmol (1.5 equiv) of
Cs2CO3, 0.018 mmol (0.05 equiv) of Pd(OAc)2, 0.036 mmol (0.1 equiv) of
Xantphos, and 0.43 mmol (1.2 equiv) of TBAB. The mixture was stirred under
inert atmosphere at 70 °C during 48 h until disappearance of the starting
material. After cooling, the DME was evaporated under reduced pressure and
the residue was purified by column chromatography with a mixture of CH2Cl2–
MeCN (95–5) as eluent. 4-[4-(4-Methoxyphenoxy)-3-nitrophenyl]-1,2-dimethyl-
5-nitro-1H-imidazole (4): Yellow crystals, mp 109 °C (i-PrOH).1H NMR
(200 MHz, CDCl3): d 2.52 (s, 3H), 3.83 (s, 3H), 3.92 (s, 3H, 6.99–6.95 m, 3H),
7.07 (d, J = 9.2 Hz, 2H), 7.90 (dd, J = 2.2 Hz, 8.8 Hz, 1H), 8.43 (d, J = 2.2 Hz, 1H).
13C NMR (50 MHz, CDCl3): d 14.1 (CH3), 34.3 (CH3), 55.6 (CH3), 115.2 (2 ꢀ CH),
117.9 (CH), 121.4 (2 ꢀ CH), 121.6 (C), 126.1 (C), 127.2 (CH), 135.1 (CH), 139.8
(C), 140.6 (C), 148.0 (C), 148.7 (C), 152.6 (C), 157.0 (C). HRMS calcd for
Crystal data for compound 5: C18H16N4O5, M = 368.35, triclinic, a = 7.4586(2) Å,
b = 9.5297(2) Å, c = 12.8344(4) Å,
a = 83.826(1)°, b = 75.061(1)°, c = 86.635(1)°,
V = 875.85(4) Å3, T = 293(2) K, space group Pı, Z = 2, 10098 reflections
¯
measured, 4275 independent reflections (Rint = 0.042). The final R1 values
were 0.0682 (I > 2r r(I)). The final
(I)). The final wR(F2) values were 0.1831 (I > 2
R1 values were 0.0983 (all data). The final wR(F2) values were 0.2232 (all data).
CCDC 877510 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge at www.cdcc.cam.ac.uk/
data_request/cif of from the Cambridge Crystallographic Data Centre, 12,
Union Road, Cambridge CB2 1EZ, UK; fax:
deposit@ccdc.cam.ac.uk.
+ 44 (1223) 336033; email:
16. Synthesis and data of compound 13: A mixture of compound 10 (0.23 mmol) in
DMSO in the presence of KOH (0.23 mmol, 1 equiv) was added slowly to an
excess of 2 (0.46 mmol, 2 equiv) and heated at 80 °C by conventional oil-bath
heating. Appearance of compound 13 was monitored by LC/MS. After 7 days,
the mixture was poured into cold H2O and extracted with CHCl3. The organic
layers were washed with brine, dried over Na2SO4 and evaporated under
reduced pressure. The compound was isolated (34% yield) after purification by
column chromatography using a mixture of acetone–CHCl3 (50–50) as eluent.
4,40-[4,40-Oxybis(3-nitro-4,1-phenylene)]bis(1,2-dimethyl-5-nitro-1H-imidazole)
(13): Orange oil. 1H NMR (200 MHz, CDCl3): d 2.54 (s, 6H), 3.94 (s, 6H), 7.15 (d,
J = 8.7 Hz, 2H), 8.06 (dd, J = 2.2 Hz, 8.7 Hz, 2H), 8.56 (d, J = 2.2 Hz, 2H). 13C NMR
C
18H16N4O6 [M+H]+: 385.1143, found 385.1144.
1,2-Dimethyl-5-nitro-4-[3-nitro-4-(p-tolyloxy)phenyl]-1H-imidazole (5): Yellow
crystals, mp 94 °C (i-PrOH). 1H NMR (200 MHz, CDCl3): d 2.36 s, 3H, 2.52 s, 3H,
3.92 s, 3H, 6.95–7.02 m, 3H), 7.20 (d, J = 8.5 Hz, 2H), 7.91 (dd, J = 2.1 Hz, 8.5 Hz,
1H), 8.43 (d, J = 2.1 Hz, 1H). 13C NMR (50 MHz, CDCl3): d 14.1 (CH3), 20.8 (CH3),
34.3 (CH3), 118.7 (CH), 119.8 (2 ꢀ CH), 126.4 (C), 127.2 (CH), 130.6 (2 ꢀ CH),
134.9 (CH), 135.1 (C), 140.2 (C), 140.6 (C), 148.7 (C), 152.1 (C), 152.7 (C). A C–
NO2 group did not appear in these conditions. HRMS calcd for C18H16N4O5
[M+H]+: 369.1193, found 369.1191.
4-[4-(4-Chlorophenoxy)-3-nitrophenyl]-1,2-dimethyl-5-nitro-1H-imidazole (6):
Yellow oil. 1H NMR (200 MHz, CDCl3): d 2.53 (s, 3H), 3.94 (s, 3H), 7.00–7.06
(m, 3H), 7.33–7.39 (m, 2H), 7.97 (dd, J = 2.1 Hz, 8.8 Hz, 1H), 8.45 (d, J = 2.1 Hz,
1H). 13C NMR (50 MHz, CDCl3): d 14.1 (CH3), 34.3 (CH3), 119.6 (CH), 120.8
(2 ꢀ CH), 127.4 (CH), 127.5 (C), 130.2 (2 ꢀ CH), 135.3 (CH), 140.2 (C), 140.8 (C),
(50 MHz, CDCl3):
d
14.1 (2 ꢀ CH3), 34.3 (2 ꢀ CH3), 120.5 (2 ꢀ CH), 127.6
(2 ꢀ CH), 129.1 (2 ꢀ C), 135.0 (2 ꢀ C), 135.7 (2 ꢀ CH), 139.8 (2 ꢀ C), 140.6
(2 ꢀ C), 148.8 (2 ꢀ C), 149.3 (2 ꢀ C). HRMS calcd for
C
22H18N8O9 [M+H]+:
539.1270, found 539.1270.