Ruthenium-Catalyzed meta-Selective C?H Nitration of Biologically Important Aryltetrazoles

Article abstract of DOI:10.1002/adsc.202000475

The first example of tetrazole-directed meta-selective C?H nitration is described. This transformation provided a straightforward approach for the synthesis of biologically important m-nitroaryltetrazoles in moderate to excellent yields with good functional group compatibility. In addition, new metallo-β-lactamase inhibitors were obtained by further transformation of the synthesized m-nitroaryltetrazoles. (Figure presented.).

Full text of DOI:10.1002/adsc.202000475

Title: Ruthenium-catalyzed meta-selective C-H nitration of biologically
important aryltetrazoles
Authors: Jian Chen, Tianle Huang, Xinrui Gong, Zhu-jun Yu, Yuesen
Shi, Yu-Hang Yan, Yang Zheng, Xuexin Liu, Guobo Li, and
Yong Wu
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000475
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10.1002/adsc.202000475
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201
Ruthenium-Catalyzed meta-Selective C-H Nitration of
Biologically Important Aryltetrazoles
Jian Chen, Tianle Huang, Xinrui Gong, Zhu-Jun Yu, Yuesen Shi, Yu-Hang Yan, Yang
Zheng, Xuexin Liu, Guo-Bo Li* and Yong Wu*a
a
Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal Chemistry, West China School
of Pharmacy, Sichuan University, Chengdu 610041, P. R. of China
E-mail: wyong@scu.edu.cn (Y. Wu), liguobo@scu.edu.cn (G.-B. Li)
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
particularly the metallo-β-lactamases (MBLs), which
selective C-H nitration is described. This transformation can hydrolyze almost all β-lactam antibiotics.
Abstract. The first example of tetrazole-directed meta-
provided a straightforward approach for the synthesis of
biologically important m-nitroaryltetrazoles in moderate to
excellent yields with good functional group compatibility.
In addition, new metallo-β-lactamase inhibitors were
obtained by further transformation of the synthesized m-
nitroaryltetrazoles.
Recently, we obtained a 5-phenyltetrazole containing
compound, T-01, which showed potent inhibition
against the clinically relevant B1 subclass of MBL
enzymes NDM-1, IMP-1, and VIM-2 (Figure 1b). In
the synthesis of such MBL inhibitors, the
construction of meta-C-N bonds of aryltetrazoles is
one of the key steps. Motivated by the
pharmacophore feature of tetrazole rings and our
continuous interests in C-H activation, we aimed to
develop a new strategy for the synthesis of meta-
nitroaryltetrazoles, with the aim to readily construct
the C-N bond with high regioselectivity and excellent
functional group tolerance.
With the rapid development of direct C-H
functionalization in recent years,[8] several tetrazole
templates have been reported as the directing groups
(DG) to assist the Ru-, Rh- or Pd-catalyzed ortho-C-
H activation (Scheme 1a). For instance, the Murai
group developed a method for ortho-silylation of
aryltetrazoles with triethylsilane,[9] and then the C–H
arylation/olefination reactions of aryltetrazoles were
reported.[10] The Weck group reported an iridium-
catalyzed ortho-H/D and H/T exchange of
Keywords: tetrazole; meta-selective; C-H nitration;
metallo-β-lactamase inhibitors.
Aryltetrazoles make up a class of biologically active
moieties, which have been used for the development
of antimicrobial,[1] antihypertensive,[2] anticancer,[3]
anti-inflammatory and analgesic agents[4]. Notably,
the 5-phenyltetrazole moiety frequently occurs in
clinically useful drugs, such as the loop diuretics
Azosemide, the hypertension drug Losartan, and the
anti-allergic drug Acitazanolast (Figure 1a). In recent
years, this moiety has also been used in the
development of inhibitors targeting β-lactamases,[5]
which are an important class of enzymes that cause
the β-lactam antibiotic resistance.[6] We are interested
in developing new β-lactamase inhibitors,[7]
Scheme 1. C-H activation examples of aryltetrazoles or 2-
phenylpridine
Figure 1. The 5-phenyltetrazole containing drugs and
MBL inhibitors
1
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10.1002/adsc.202000475
Advanced Synthesis & Catalysis
aryltetrazoles.[11] However, tetrazole-directed meta-C-
H activation had not been reported, to the best of our
knowledge.
hexafluoroisopropanol (HFIP) improved the yield
(entry 6 and 7). Next, extensive ligands were
screened (see Supporting Information). PPh3 led to a
better yield of 61% in this model reaction (entry 8).
To our surprise, a substantial increase in conversion
was observed by using Cu(NO3)2·3H2O as the nitro
source (entry 9 and 10). When the reaction was
carried out at 80 °C, the yield of 3a notably dropped
(entry 11). Control experiments in the absence of
PhI(TFA)2 or Ru3(CO)12 revealed that these
components were crucial for this transformation
(entry 12 and 13). Further attempts by using simple
RuCl3 as the catalyst failed to realize the nitration
(entry 14). Taken together, the reaction conditions in
entry 10 were selected as the optimal conditions.
Fortunately, meta-C-H functionalizations have
been achieved by using the ortho-metalation strategy,
in which less expensive ruthenium catalysts and
common DGs can be used.[12] Representative
reactions included sulfonation,[13] halogenation,[14]
nitration,[15] carboxylation,[16] alkylation[17] and so on
(Scheme 1b). Compared with the widely used pyridyl
DG, the tetrazole as a DG is relatively challenging, as
it has multiple potential chelating sites that may
deactivate the metal catalysts. We herein report a
method for tetrazole-directed metal-catalyzed meta-
selective C-H nitration.
Scheme 2. Substrate scope of tetrazole as the DG a)
Table 1. Optimization of reaction conditions a)
Yield
Entry Catal.
NO2 source
Solv.
b)
1
2
Ru3(CO)12
AgNO3
AgNO3
DCE
DCE
33%
N.R.
[RuCl2(p-
cymene)]2
Ru(bpy)3Cl2
3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
KNO3
DCE
DCE
DCE
HFIP 55%
Tol N.R.
<5%
N.R.
<5%
4 c)
5 d)
6
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
a) Reaction conditions: 1 (0.2 mmol), Cu(NO3)2·3H2O (0.3
mmol), Ru3(CO)12 (7.5 mol %), PPh3 (30 mmol %),
PhI(TFA)2 (0.22 mmol) in HFIP (2.0 mL) for 24 h at 100
oC in a sealed tube; isolated yields. b) Yield based on the
recovered starting material is listed in parentheses.
7
8 e)
9 e)
10 e)
HFIP 61%
HFIP 7%
Cu(NO3)2·3H2O HFIP 94%
Cu(NO3)2·3H2O HFIP 59%
Cu(NO3)2·3H2O HFIP N.R.
Cu(NO3)2·3H2O HFIP N.R.
Cu(NO3)2·3H2O HFIP N.R.
11e), f) Ru3(CO)12
12 g)
13
Ru3(CO)12
-
With the optimized conditions in hand, we moved
on to extend the scope of 5-aryltetrazole substrates
(Scheme 2). A series of R1 substituted tetrazoles were
first tested. Introduction of various groups on the
tetrazole moiety could proceed smoothly, affording
the corresponding products in moderate to good
yields, although electron-donating groups were likely
more favorable to this transformation (3a-3g).
Interestingly, in the case of the ortho-methyl
substituted 5-aryltetrazole as the substrate, the
corresponding product 3h was produced in 44% yield.
A different preference was observed for the ortho-
methoxy substituted 5-aryltetrazole; meta-C-H
nitration occurred at the less hindered site (C5),
affording the corresponding product 3i, which may
attribute to the different electronic effects.[14b, 15b, 15d]
When a methyl group was introduced to the meta-
position, the desired product 3j was produced in 65%
yield. The para-substituted 5-aryltetrazoles appear to
be more suitable substrates for this reaction (3k-3n,
3q-3r). The substrates bearing a para-CN or CHO
14
RuCl3
a) Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), Catal.
(7.5 mol %), ligand (30 mol %), PhI(TFA)2 (0.22 mmol),
b)
c)
solvent (2.0 mL) in a sealed tube;
Isolated yields;
K2S2O8 as the oxidant; d) Oxone as the oxidant; e) PPh3 as
the ligand; f) 80 oC; g) no oxidant.
Initially, 2-methyl-5-phenyl-2H-tetrazole (1a) was
selected as a model substrate to react with AgNO3 in
DCE at 100 °C for 24 hours in a sealed tube, using
Ru3(CO)12 as the catalyst and PhI(TFA)2 as the
oxidant (Table 1). The desired product 3a was
obtained in a yield of 33% (entry 1). We then tried
other Ru catalysts (entry 2 and 3); however, the
results showed that Ru3(CO)12 remained the best
catalyst for this transformation. Subsequently, we
screened different oxidants, which did not improve
the conversion (entry 4 and 5). Further screening of
reaction
solvents
revealed
that
only
2
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10.1002/adsc.202000475
Advanced Synthesis & Catalysis
substituent retarded the reaction, further indicating
the reaction seems sensitive to the electronic effects
(3o and 3p). The 1-substituted or non-substituted
tetrazoles were also compatible with the catalytic
system, albeit in low yields (3s and 3t).
Scheme 4. MBL inhibitors and their activities.
Scheme 3. Scope of triazole as the DG a)
1,1-diphenylethylene
or
2,6-di-tert-butyl-4-
methylphenol (BHT), the reactions were almost
completely quenched, suggesting that a radical
pathway might be involved (Scheme 5a). More
importantly, we found that the aryltetrazole substrate
bearing two methyl groups to block the two ortho
positions of the phenyl ring failed to get the target
molecule under the standard conditions, supporting
the necessity of the ortho-C-H metalation in the
reaction process (Scheme 5b). We then conducted the
reaction with two substrates 4 and 5, in which the N1
or N4
a) Reaction conditions: 1 (0.2 mmol), Cu(NO3)2·3H2O (0.3
mmol), Ru3(CO)12 (7.5 mol %), PPh3 (30 mol %),
PhI(TFA)2 (0.22 mmol) in HFIP (2.0 mL) for 24 h at 100
oC in a sealed tube. Isolated yields.
We then examined 2-aryl-1,2,3-triazole and 2-aryl-
1,2,4-triazole,[18] which are structurally similar to
aryltetrazoles, as the substrates to react with
Cu(NO3)2·3H2O under the standard conditions
(Scheme 3). To our delight, the corresponding meta-
nitration products 3u and 3v were obtained with
considerable yields. Various triazoles bearing diverse
aryl substituents were also investigated. The 2-
phenytriazoles substituted with electron-donating and
electron-withdrawing groups at ortho-, meta- or para-
positions of the 2-phenyl moiety were compatible
with this transformation, generating the desired
products (3w-3af) in moderate to high yields.
Scheme 5. Mechanistic studies
We used the generated nitrated products to
synthesize new compounds T-02 to T-06, containing
a
metal-binding moiety of (S)-3-mercapto-2-
methylpropanamide. These compounds displayed
potent inhibition against MBL enzymes VIM-2,
NDM-1, and IMP-1 (Scheme 4). In particular, T-03
manifested IC50 values of 0.053, 0.058 and 0.108 μM
to VIM-2, NDM-1, and IMP-1, respectively, which is
more potent than the control compound L-captopril
(Scheme 4). This application may also suggest a
possible strategy to obtain new MBL inhibitor by
incorporating aryltetrazoles and other appropriate
metal binding pharmacophores.[19]
To understand the mechanism of Ru-catalyzed
meta-selective C-H nitration of aryltetrazoles, a
preliminary mechanism study for the reaction was
conducted. With the addition of the radical inhibitor
3
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10.1002/adsc.202000475
Advanced Synthesis & Catalysis
nitrogen atom is removed. Both meta-nitro products 6
and 7 were generated in good yield under the
standard conditions, indicating that both N1 and N4
might be able to coordinate with Ru (Scheme 5c and
5d). Next, ortho-H/D exchange was observed in the
NMR spectrum when treating [D5]-1a or 1a with
Cu(NO3)2·3H2O under the standard conditions,
confirming that the initial ortho-C-H ruthenation was
reversible (Scheme 5e and 5f). Finally, the
competitive and parallel kinetic isotope effects were
measured. The kH/kD and PH/PD values were 1.0 and
1.6, respectively, suggesting that the C-H cleavage of
aryltetrazole was probably not involved in the rate-
limiting step (Scheme 5g and 5h).
group compatibility. Further transformation of the
synthesized m-nitroaryltetrazoles led to new potent
MBL inhibitors. This work will be useful to derive
new m-nitroaryltetrazoles and related derivatives, as
well as the new types of MBL inhibitors.
Experimental Section
Synthesis of Compound 3a; Typical Procedure
Compound 1a (0.2 mmol), Cu(NO3)2·3H2O (0.3 mmol),
Ru3(CO)12 (0.15 mmol), PPh3 (0.06 mmol) and PhI(TFA)2
(0.22 mmol) were charged into a sealed tube, to which was
added HFIP (2.0 mL). The reaction mixture was stirred at
Scheme 6. Proposed mechanism
o
100 C for 24 h. After cooled to room temperature, the
solvent was removed under reduced pressure and the
residue was purified by silica gel chromatography using
PE/EA as the eluent to afford the corresponding compound
3a.
Acknowledgements
We are grateful for financial support from the National NSF of
China (grant number 81573259 and 81874291).
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