The ruthenium-catalyzed: Meta -selective C-H nitration of various azole ring-substituted arenes

Article abstract of DOI:10.1039/c9ob01930h

The efficient ruthenium-catalyzed meta-selective C_Ar-H nitration of azole ring substituted arenes has been developed. In this work, Ru₃(CO)₁₂ was used as the catalyst, AgNO₂ as the nitro source, HPcy₃⁺·BF₄^- as the ligand, pivalic acid as the additive, and DCE as the solvent, and a wide spectrum of arenes bearing thiazole, pyrazolyl or removable oxazoline directing groups were tolerated in this meta-selective C_Ar-H nitration, affording the nitrated products in moderate to good yields. Moreover, this study reveals a gentler and environmentally friendly way to access meta-nitration arenes compared to the traditional process.

Full text of DOI:10.1039/c9ob01930h

Organic &
Biomolecular Chemistry
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The ruthenium-catalyzed meta-selective C–H
nitration of various azole ring-substituted arenes†
Cite this: Org. Biomol. Chem., 2019,
17, 9065
Dong Zhang,a Di Gao,a Jinlin Cai,a Xiaoyu Wu,a Hong Qin,a Kai Qiao,a
a,b
Chengkou Liu,a Zheng Fang*a and Kai Guo
*
The efficient ruthenium-catalyzed meta-selective CAr–H nitration of azole ring substituted arenes has
−
been developed. In this work, Ru3(CO)12 was used as the catalyst, AgNO2 as the nitro source, HPcy3+·BF4
Received 3rd September 2019,
Accepted 20th September 2019
as the ligand, pivalic acid as the additive, and DCE as the solvent, and a wide spectrum of arenes bearing
thiazole, pyrazolyl or removable oxazoline directing groups were tolerated in this meta-selective CAr–H
nitration, affording the nitrated products in moderate to good yields. Moreover, this study reveals a gentler
and environmentally friendly way to access meta-nitration arenes compared to the traditional process.
DOI: 10.1039/c9ob01930h
rsc.li/obc
ruthenium-catalyzed meta-selective CAr–H sulfonation,7 and
later meta-alkylation was developed by Ackermann,8 and
Introduction
Transition-metal catalyzed C–H functionalization has attracted then meta-bromination was discovered by Greaney9 and
more and more attention for the development of molecular Huang.10 However, the methods used to form meta-selective
syntheses in recent years.1 In recent decades, ortho-selective CAr–N bonds have not been fully established. Nitro arenes
CAr–H functionalization, assisted by transition-metal and are a key class of C–N bond-containing compounds in organic
directing groups, has achieved great success.2 However, the synthesis, medicinal chemistry and material science.11
meta-selective CAr–H functionalization still remains a challenge Moreover, the nitro group can also be easily transformed
owing to the target CAr–H bond which is located away from the into various functional groups such as amines and ketones.12
directing
group.3
Traditionally,
meta-selective
CAr–H More recently, Zhang’s group reported a method for the meta-
functionalization was achieved using the influence of the selective C–H nitration of arenes.13 However, the
meta-directing electron withdrawing groups. Previously, Yu’s4 substrates they used required a pyridine ring which acts as a
and Maiti’s5 groups have developed different approaches to coordinating center and is difficult to remove or transform.
construct various meta-CAr–C, CAr–O, and CAr–I bonds. They Therefore, superior substrates for this ruthenium-catalyzed
both utilized a series of nitrile- or pyridine-templates as the meta-selective CAr–H nitration still require urgent further
remote directing groups to cooperate with the Pd to obtain the exploration.
meta-target products. In addition, norbornene and its deriva-
Owing to their pharmacological activities and fluorescent
tives which were used as transition mediators to assist the Pd properties, aryl-thiazoles are the core structural motifs in func-
catalyzed meta-CAr–H activation to achieve meta-selective aryla- tional organic materials such as organic electroluminescent
tion or alkylation was also reported by Yu’s and Dong’s devices, bioactive compounds and pharmaceuticals.14
groups,6 however, in these methods special substrates and However, compared to the widely used pyridyl directing
complicated directing groups were generally required.
groups, it is difficult to utilize thiazole as a directing group,
In contrast, ruthenium catalysts were recently used to because of the high reactivity of the C-4 and C-5 position in
exhibit excellent catalytic properties in meta-selective CAr–H the thiazole ring. Many methods for thiazole C-4 and C-5 posi-
functionalization
using
ortho-directing
group-assisted tion functionalization have been reported in the past (see
cyclometalation. Frost’s group reported pioneering work on Scheme 1a),15 however, only a few methods have been reported
for the ortho-selective C–H functionalization on the aryl com-
ponent of the 2-aryl-thiazoles (see Scheme 1b)16 and the meta-
aCollege of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University,
30 Puzhu Rd S., Nanjing 211816, China. E-mail: guok@njtech.edu.cn,
fzcpu@163.com; Fax: +8625 5813 9935; Tel: +86 25 5813 9926
bState Key Laboratory of Materials-Oriented Chemical Engineering,
Nanjing Tech University, 30 Puzhu Rd S., Nanjing 211816, China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9ob01930h
selective C–H functionalization has never been achieved.
Inspired by the ruthenium-catalyzed meta-selective CAr–H
functionalization reactions and the pioneering work of the
Zhang group, we hypothesized that 2-aryl-thiazoles could be
used as suitable substrates to achieve meta-selective CAr–H
nitration.
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AgNO2 as nitrogen source and DCE as a solvent (Table 1,
entry 1). To improve the reaction efficiency, different
ruthenium catalysts were used in the reaction and Ru3(CO)12
performed better than the others, affording the desired
product 3a in a 15% yield (Table 1, entry 3). Then, a number of
oxidants such as oxone, K2S2O8, Na2S2O8, (NH4)2S2O8 and
PIDA ((diacetoxyiodo)benzene) were tested, the results indi-
cated that none of them could match the efficiency of PIFA
([bis(trifluoroacetoxy)iodo]benzene) (Table 1, entries 4–9). The
effect of the additives was also investigated and unsatisfactory
yields were obtained when PIV-OH was replaced by Bu4NHSO4,
Bu4NOAc, Bu4NBF4, 1-Ad-OH (adamantine methanol), 1-Ad-
COOH (adamantanecarboxylic acid) and MesCOOH (2,4,6-tri-
methylbenzoic acid) (Table 1, entries 10–16). Moreover, the
amounts of Ru3(CO)12, AgNO2 and PIFA were examined as
well; however, no significant improvement was obtained.
Meanwhile, other nitro sources, ligands, temperatures and sol-
vents were also tested as alternatives but the meta-nitration
product 3a was only achieved in low yields (see ESI†).
Therefore, the conditions used in entry 16 were selected as the
best reaction conditions.
Scheme 1 The C–H activations for thiazole and meta-selective
nitration.
Results and discussion
With the optimized reaction conditions established, we first
investigated the scope of the substituted 2-aryl-thiazole sub-
strates 1 to evaluate the generality of the transformation. As
shown in Table 2, a wide range of 2-aryl-thiazoles substrates
bearing both electron-donating and -withdrawing groups were
found to proceed smoothly under the optimized conditions
and afforded the corresponding products in moderate to good
yields. Screening of the substitution effect showed that the
ortho or meta-substituted 2-aryl-thiazoles had a good reaction
activity and gave the corresponding products in 56–88% yields
(3b–d). Furthermore, in the case of 3b we only obtained the
C-3 position nitration product not the C-5 position. This
showed that Ru was selectively inserted into the ortho-C-6(Ar)–
H bond.13 Then, various para-substituted 2-aryl-thiazoles were
examined, the results indicated that all of them performed
well under the standard conditions including the large steric
substituted group tert-butyl and the electron-withdrawing sub-
stituted groups (3e–j). Additionally, biphenyl and naphthyl
substituted thiazoles also participated in the reaction very
well, and the corresponding products 3k and 3l were obtained
in 67% and 61% yields respectively. Furthermore, the sub-
strates bearing methyl and fused benzene on the thiazole ring
were also tested, and most transformations showed good
results and the corresponding products were obtained in
44–72% yields (3m–q). However, the 4-methyl-substituted
2-phenyl-thiazole demonstrated a poor reaction activity (3l,
35% yield).
With these conditions in mind, 2-aryl-thiazole (1a) was chosen
as a model substrate to assess whether meta-selective CAr–H
nitration could be performed with a ruthenium catalyst
(Table 1). Unfortunately, the conversion of 1a was poor and no
meta-nitrated product was detected when the reaction was
carried out at 100 °C for 24 h in the presence of a catalytic
amount of RuCl3 (10 mol%) under an air atmosphere using
Table 1 The optimization of meta-selective CAr–H nitrationa,b
Catalyst
(10 mol%)
Oxidant
(equiv.)
Additive
(equiv.)
Yieldb
(%, 3a)
Entry
1
2
3
4
5
6
7
8
RuCl3
—
—
—
—
—
—
—
—
—
—
—
0%
0%
15%
6%
5%
4%
5%
0%
37%
37%
42%
39%
51%
62%
74%
85%
[RuCl2(p-cymene)]2
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Oxone
K2S2O8
Na2S2O8
(NH4)2S2O8
PIDA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
9
—
10
11
12
13
14
15
16
Bu4NHSO4
Bu4NOAc
Bu4NBF4
1-Ad-OH
1-Ad-COOH
MesCOOH
PIV-OH
After investigating the generality of this meta-selective CAr–
H nitration reaction with respect to a series of substituted
2-aryl-thiazoles, we next studied whether this protocol could
be expanded to substrates with different directing groups. We
first examined the 1-aryl-pyrazol substrates which are also
widely used in medicinal chemistry. As illustrated in Table 3,
different functional group substituted 1-aryl-pyrazols, includ-
ing methyls, halogens, aldehydes and acyls were found to
a Reaction conditions: 1a (0.2 mmol), AgNO2 (1.2 equiv.), catalyst
−
(10 mol%), HPcy3+·BF4 (30 mol%), oxidant (1.2 equiv.) and additives
(0.3 equiv.) in DCE (2 mL) for 24 h at 100 °C in a sealed tube. b Isolated
yield.
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Table 2 Substrate scope for the 2-aryl-thiazolesa,b
Table 3 Substrate scope for the 1-aryl-pyrazolsa,b
a Reaction conditions: 4 (0.2 mmol), AgNO2 (1.2 equiv.), Ru3(CO)12
−
(10 mol%), HPcy3+·BF4 (30 mol%), PIFA (1.2 equiv.) and PIV-OH (0.3
equiv.) in DCE (2 mL) for 24 h at 100 °C in a sealed tube. b Isolated
yield.
a Reaction conditions: 1 (0.2 mmol), AgNO2 (1.2 equiv.), Ru3(CO)12
Table 4 Substrate scope for the 2-aryl-oxazolinesa,b
−
(10 mol%), HPcy3+·BF4 (30 mol%), PIFA (1.2 equiv.) and PIV-OH (0.3
equiv.) in DCE (2 mL) for 24 h at 100 °C in a sealed tube. b Isolated
yield. c 110 °C.
proceed smoothly under the standard nitration conditions
(5a–i), and the corresponding meta-nitration products were
obtained in 53–83% isolated yields. As the oxazoline directing
groups can be easily transformed and removed, 2-aryl-oxazo-
lines were also employed as the substrates and the results are
shown in Table 4. However, owing to the weakly coordinating
activity of the 2-aryl-oxazolines, we could only obtain the
different functional groups substituted meta-nitration products
in 57–72% yields (7a–f) under the conditions of 20 mol%
Ru3(CO)12 and 110 °C. Meanwhile, 2-phenyl-4,5-dihydrooxa-
zole and 2-phenyloxazole were also subjected to the optimized
reaction conditions, but unfortunately this reaction only
afforded the nitration products in trace yields (7g, 7j). This is
mostly due to the different bond angle between the C–Ru
bond and the Ru–N bond in the process of cyclometalation.
To further demonstrate the synthetic effectiveness of this
methodology, a gram-scale reaction was carried out by using
1a (10 mmol, 1.61 g) and AgNO2 (1.2 equiv.) under the stan-
dard reaction conditions (Scheme 2). We were pleased to dis-
cover that product 3a could be obtained in a 75% isolated
yield. Additionally, the nitro group in 3a could be easily
a Reaction conditions: 6 (0.2 mmol), AgNO2 (1.2 equiv.), Ru3(CO)12
−
(20 mol%), HPcy3+·BF4 (30 mol%), PIFA (1.4 equiv.) and PIV-OH (0.3
equiv.) in DCE (2 mL) for 24 h at 110 °C in a sealed tube. b Isolated
yield.
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Scheme 2 The gram scale synthesis and transformation of 3a.
reduced to the usable free amine at a high yield (90%) under a
hydrogen atmosphere. These results suggested that the meth-
odology is an efficient and practical process for the preparation
of meta-nitration and meta-amino arenes.
In order to shed light on the mechanism, some additional
experiments were performed (Scheme 3). First, the substrate
1a was examined in the absence of any ruthenium catalysts
and the corresponding meta-nitration product was not found.
Then, 2-(2,6-dimethylphenyl)thiazole (1s) was subjected to the
optimized reaction conditions, but the meta-nitration product
(3s) was not detected, indicating that the insertion in the
ortho-CAr–H bond of Ru was necessary for this transformation
to occur. Moreover, the treatment of 1a with Tempo (3 equiv.)
was tested under the standard reaction conditions and the
result showed that the formation of 3a was completely sup-
pressed, suggesting the involvement of a radical pathway in
this reaction. Finally, a kinetic isotope effect (KIE) was
observed in an intermolecular competition experiment and
parallel reactions (Scheme 4). First, a 1 : 1 mixture of 4a and
the deuterium labelled substrate 4a-D5 were subjected to the
standard reaction conditions over 8 h. The kH/kD ratio was 1.5
for the experiment between 4a and 4a-D5.
Scheme 4 Kinetic isotope effect experiments.
On the basis of the above described results and previous lit-
erature reports, a plausible mechanistic pathway for the for-
mation of 3a is depicted in Scheme 5. Initially, the Ru3(CO)12
catalyst was oxidized by PIFA to afford the Ru(II) species I.
Then, the coordination-directed ortho-CAr–H insertion of
2-aryl-thiazole 1a with the Ru(II) species produces the metalla-
cycle intermediate II as well as concomitant formation of
CF3COOH.17 Meanwhile, the AgNO2 is also oxidized by PIFA
and then the nitrogen dioxide radical is released to attack the
para position of the C–Ru bond, forming the intermediate
III.18,19 Subsequently, the reductive deprotonation of inter-
mediate III affords the intermediate IV. Finally, owing to the
ligand exchange step between the intermediate IV and
CF3COOH, the target product 3a is obtained and the species I
is also regenerated for the next cycle.
Second, two independent reactions using substrates 4a and
4a-D5 were performed and the kH/kD ratio was determined to
be 1.3, indicating that the meta-C–H bond cleavage probably
occurs during the rate-determining step.
Scheme 3 Control experiments.
Scheme 5 Plausible mechanism.
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8 (a) L. Ackermann, N. Hofmann and R. Vicente, Org. Lett.,
2011, 13, 1875; (b) N. Hofmann and L. Ackermann, J. Am.
Chem. Soc., 2013, 135(15), 5877; (c) J. Li and L. Ackermann,
J. Am. Chem. Soc., 2015, 137(43), 13894.
9 C. J. Teskey and M. F. Greaney, Angew. Chem., Int. Ed., 2015,
54, 11677.
Conclusions
In conclusion, we have efficiently achieved the meta-selective
CAr–H nitration of various arenes that bear thiazole, pyrazolyl
or removable oxazoline as directing groups. In this method, we
used Ru3(CO)12 as a catalyst and AgNO2 as a nitro source; these
replaced the traditional nitration reagents H2SO4 and HNO3, 10 Q.-Z. Yu and J.-H. Huang, Angew. Chem., Int. Ed., 2015, 54,
providing a gentler nitration reaction atmosphere. Moreover, 15284.
the approach exhibits good tolerance for a wide range of func- 11 N. Ono, The Nitro Group in Organic Synthesis, Wiley-VCH,
tional groups, and the reaction proceeds smoothly to provide
the corresponding products in moderate to good yields.
New York, 2001.
12 (a) G. A. Olah, Acc. Chem. Res., 1971, 4, 240; (b) H. Feuer and
A. T. Nielson, Nitro Compounds: Recent Advances in Synthesis
and Chemistry, VCH, Weinheim, 1990; (c) A. G. M. Barrett
and G. G. Graboski, Chem. Rev., 1986, 86, 751.
13 Z. Fan, J. Ni and A. Zhang, J. Am. Chem. Soc., 2016, 138,
8470–8475.
Conflicts of interest
There are no conflicts of interest to declare.
14 (a) S. Miwatashi, Y. Arikawa, E. Kotani, M. Miyamoto,
K. Naruo, H. Kimura, T. Tanaka, S. Asahi and S. Ohkawa,
J. Med. Chem., 2005, 48, 5966; (b) Y. Choi, Y. Kawazoe,
K. Murakami, H. Misawa and M. Uesugi, J. Biol. Chem.,
2003, 278, 7320; (c) J. Lee, S. J. Kim, H. Choi, Y. H. Kim,
I. T. Lim, H. Yang, C. S. Lee, H. R. Kang, S. K. Ahn,
S. K. Moon, D.-H. Kim, S. Lee, N. S. Choi and K. J. Lee,
J. Med. Chem., 2010, 53, 6337; (d) T. Suzuki, S. Hisakawa,
Y. Itoh, N. Suzuki, K. Takahashi, M. Kawahata,
K. Yamaguchi, H. Nakagawa and N. Miyata, Bioorg. Med.
Chem. Lett., 2007, 17, 4208; (e) M. S. Alam, L. Liu, Y.-E. Lee
and D.-U. Lee, Chem. Pharm. Bull., 2011, 59, 568;
(f) D. Zwilling, S.-Y. Huang, K. V. Sathyasaikumar,
F. M. Notarangelo, P. Guidetti, H.-Q. Wu, J. Lee, J. Truong,
Y. Andrews-Zwilling, E. W. Hsieh, J. Y. Louie, T. Wu,
K. Scearce-Levie, C. Patrick, A. Adame, F. Giorgini,
S. Moussaoui, G. Laue, A. Rassoulpour, G. Flik, Y. Huang,
J. M. Muchowski, E. Masliah, R. Schwarcz and
P. J. Muchowski, Cell, 2011, 145, 863.
Acknowledgements
The research was supported by the National Key Research and
Development Program of China (2016YFB0301501).
Notes and references
1 (a) J. Yamaguchi, A. D. Yamaguchi and K. Itami, Angew.
Chem., Int. Ed., 2012, 51, 8960–9009; (b) J. Schranck, A. Tlili
and M. Beller, Angew. Chem., Int. Ed., 2014, 53, 9426–9428;
(c) S. De Sarkar, Angew. Chem., Int. Ed., 2016, 55, 10558–
10560.
2 (a) K. M. Engle, T.-S. Mei, M. Wasa and J.-Q. Yu, Acc. Chem.
Res., 2012, 45, 788–802; (b) L. Ackermann, Acc. Chem. Res.,
2014, 47, 281–295; (c) M. Moselage, J. Li and L. Ackermann,
ACS Catal., 2016, 6, 498–525.
3 (a) R. Sharma, K. Thakur, R. Kumar, I. Kumar and
U. Sharma, Catal. Rev.: Sci. Eng., 2015, 57, 345–405; 15 (a) J. Haemmerle, M. Schnuerch, N. Iqbal, M. D. Mihovilovic
(b) J. Yang, Org. Biomol. Chem., 2015, 13, 1930–1941.
4 D. Leow, G. Li, T.-S. Mei and J.-Q. Yu, Nature, 2012, 486,
518–522.
5 (a) M. Bera, A. Modak, T. Patra, A. Maji and D. Maiti, Org.
Lett., 2014, 16, 5760–5763; (b) M. Bera, A. Maji, S. K. Sahoo
and D. Maiti, Angew. Chem., Int. Ed., 2015, 54, 8515–8519;
and P. Stanetty, Tetrahedron, 2010, 66, 8051–8059;
(b) M. Schnuerch, J. Haemmerle, M. D. Mihovilovic and
P. Stanetty, Synthesis, 2010, 837–843; (c) S. Kirchberg, S. Tani,
K. Ueda, J. Yamaguchi, A. Studer and K. Itami, Angew. Chem.,
Int. Ed., 2011, 50, 2387–2391; (d) J. Haemmerle, M. Schnuerch
and P. Stanetty, Synlett, 2007, 2975–2978.
(c) A. Maji, B. Bhaskararao, S. Singha, R. B. Sunoj and 16 (a) Y. Ping, Z. Chen, Q. Ding and Y. Peng, Synthesis, 2017,
D. Maiti, Chem. Sci., 2016, 7, 3147–3153; (d) T. Patra,
R. Watile, S. Agasti, T. Naveen and D. Maiti, Chem.
Commun., 2016, 52, 2027–2030.
49, 2015–2024; (b) L. Zhang, Z. Liu, H. Li, G. Fang,
B.-D. Barry, T. A. Belay, X. Bi and Q. Liu, Org. Lett., 2011,
13, 6536–6539; (c) C. S. Azad and A. K. Narula, RSC Adv.,
2015, 5, 100223–100227.
6 (a) X.-C. Wang, W. Gong, L.-Z. Fang, R.-Y. Zhu, S. Li,
K. M. Engle and J.-Q. Yu, Nature, 2015, 519, 334–338; 17 (a) Z. Fan, J. Li, H. Lu, D.-Y. Wang, C. Wang, M. Uchiyama
(b) Z. Dong, J.-C. Wang and G.-B. Dong, J. Am. Chem. Soc.,
2015, 137(18), 5887; (c) J. Han and Y.-S. Zhao, Chem.
Commun., 2016, 52, 6903.
7 (a) O. Saidi, J. Marafie, A. E. Ledger, P. M. Liu,
M. F. Mahon, G. Kociok-Kohn, M. K. Whittlesey and
and A. Zhang, Org. Lett., 2017, 19, 3199–3202; (b) Z. Fan,
H. Lu and A. Zhang, J. Org. Chem., 2018, 83, 3245–3251.
18 (a) Y.-K. Liu, S.-J. Lou, D.-Q. Xu and Z.-Y. Xu, Chem. – Eur. J.,
2010, 16, 13590–13593; (b) G. G. Pawar, A. Brahmanandan
and M. Kapur, Org. Lett., 2016, 18, 448–451.
C. G. Frost, J. Am. Chem. Soc., 2011, 133, 19298; 19 (a) V. R. Sabbasani and D. Lee, Org. Lett., 2013, 15, 3954–
(b) A. J. Paterson and C. G. Frost, Chem. Commun., 2015, 51,
12807.
3957; (b) J. Sun, J.-K. Qu, Y.-N. Wu, W.-J. Hao, C. Guo, G. Li,
S.-J. Tu and B. Jiang, Org. Lett., 2017, 19, 754–757.
This journal is © The Royal Society of Chemistry 2019
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