Copper-catalysed regioselective azidation of arenes by C-H activation directed by pyridine

Article abstract of DOI:10.1039/c5ra21963a

A novel and efficient copper-catalysed pyridine directed ortho-azidation of arenes has been developed using safe and stable benzotriazole sulphonyl azide as the azidating agent. A variety of organo azides have been synthesized with electron donor and with

Full text of DOI:10.1039/c5ra21963a

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Copper-catalysed regioselective azidation of arenes by C-H
activation directed by pyridine
Chandra S. Azada and Anudeep K. Narulaa*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A novel and efficient copper-catalysed pyridine directed ortho-
Transition
metal
catalyzed
direct
activation
azidation of arenes has been developed using safe and stable /functionalization of C-H bond is one of the main emerging
benzotriazole sulphonyl azide as azidating agent. A variety of strategies that is currently attracting remarkable effort with
organo azides have been synthesized having electron donor and the challenge to afford alternative environmental friendly and
withdrawing group, thereby the azide products can be easily efficient ways for the construction of C-N bond.8 Therefore it is
transformed into assorted functionalities.
attractive to take advantage of pervasiveness of C-H bond
activation/functionalization for making it much more ideal,
straight forward and step economic azidation process.9 The C-
H azidation reaction is generally accomplished in the presence
of hypervalent iodine because of less acidity and high strength
of C-H bond.10 Kita and Suna used the hypervalent iodine
reagents PhI(TFA)2 and PhI(OAc)2 respectively for electrophilic
azidation.11 Jiao and Tang reported copper catalyzed, amine
directed ortho-azidation of aniline.12 Hao and co-worker
developed the oxidant free copper(II) catalyzed methodology
for ortho-azidation of aniline using azido-benziodoxolone.6a
Punniyamurthy and his group reported the elegant synthesis
of benzimidazole in which aniline schiff’s base regioselectively
azidated with copper(I) and TMSN3.13 However, the hazardous
and toxic azide source, such as NaN3, TMSN3, still used in these
reactions are restricting their synthetic utility.
Organic azides have been identified as important
compounds and are extensively used in organic synthesis as
intermediate or as “masked amine”.1 One of the major utilities
of azides are in the “click chemistry”.2 The cyclo- adduct
products of azides have been explored in all aspects of drug
discovery, ranging from lead discovery to proteomics and DNA
research using bio-conjugation reaction.3 In addition to their
important role in click chemistry, aromatic azides are known
for providing an electro-deficient nitrene species, which are
able to show insertion reaction into a C-H bond.4 The azide
pro-drugs of corresponding amine are often better able to
cross the blood-brain barrier (BBB) than the corresponding
drugs by avoiding enzymatic deamination. The successful
examples reported so far are azide derivatives of cordycepine,
2’-F-ara-ddll, vidarabine, acyclovir, penciclovir and other
related drugs.5 Therefore, the introduction of an azide group
into organic framework are of great importance and interest.6
Recently, the transition metal assisted using 2-pyridyl as a
directing group have received considerable attention, and
presently arenes can be functionalize regioselectively by
diverse groups by this method.14 Wang and coworkers
excellently explored the scope of Cu catalyzed, chelation
assisted C-H activation on azacalix[1]arenes[3]pyridine.15
Literature survey showed, only one procedure, reported by X
Li, described Rh (III) catalyzed efficient mono ortho C-H
azidation of 2-phenyl pyridine.16 Unfortunately, this method
has limited utility because of use of the expensive catalyst and
hazardous and toxic NaN3. In continuum of developing copper
catalyzed novel synthetic methods for the synthesis of
biologically important scaffolds,17 herein the first copper
catalyzed regioselective direct ortho C-H azidation of 2-phenyl
pyridine using benzotriazole sulphonyl azide (BtSO2N3) as azide
source, 1,2,3-trichloropropane (TCP) as solvent and potassium
persufate (K2S2O8) as terminal oxidant is reported. One of the
Literature survey showed that, several methodologies are
available for the synthesis of aliphatic azides, although
methodologies for the synthesis of aryl azides are still very
few. The five classical main methodologies for the synthesis of
aryl azides are (i) nucleophilic aromatic substitution (SNAr) of
activated aryl azide, sulphonates, nitro groups and boronic
acid (ii) diazotisation of aromatic amine, (iii) reaction of
Grignard or lithium reagent with tosylazide, (iv) reaction of aryl
amines with azide transfer reagent and (v) N-nitrosation
reaction of aromatic hydrazines, using nitrosation reagent.7
Even though these reactions are of good synthetic utility, they
suffer from
a prolonged reaction time, harsh reaction
conditions, use of additives, which interfere with the other
functionality present on the substrate.
a.“Hygeia”Centre of Excellence in Pharmaceutical Sciences (CEPS), GGS
Indraprastha Univeristy, Sec. 16-C, Dwarka, New Delhi, 110078 (India) Email:
medchemlab58@gmail.com
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Electronic Supplementary Information (ESI) available: [1H and 13C NMR spectra of
compounds]. See DOI: 10.1039/x0xx00000x
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novel finding is the use of imidazole sulphonyl azide (ImSO2N3)
Journal Name
9
CuOAc (5)
Cu(OTf)2
CuF2
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
BtSO2N3
72c
56
hydrochloride and benzotriazole sulphonyl azide (BtSO2N3) as 10
azide source. These organic azide transfer reagents are 11
relatively stable and safe to handle with a long shelf-life, good 12
solubility in most of the organic and aqueous solvents, which 13
motivated us to use these regents as azide source.18 This 14
BtSO2N3
BtSO2N3
BtSO2N3
BtSO2N3
BtSO2N3
BtSO2N3
35
Cu2O
12
Pd(OAc)2
PdCl2
34
23
manuscript represent
a
new approach to cost-effective 15
Pd(OH)2/C
CuI
traced
52
regioselective aromatic azidation directed by pyridine.
Primarily, a review on reaction parameters, including
16
(NH4)2S2O BtSO2N3
8
catalyst, azide source, oxidant and solvent, was conducted at 17
fixed temperature of 120o C and reaction time 12 h using the 18
azidation of 2-phenylpyridine (1a) as a model substrate. The 19
reported methods from Hao , Wang and Zhu reinvigorated us 20
to use copper as a catalyst in the reaction medium and polar 21
solvent as a reaction medium.6a,15,19 After concernig the 22
importance of haloginated solvents in C-H bond activation, 23
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
None
CuI
air
BtSO2N3
BtSO2N3
traced
66
TBHP
Hgb-H2O2 BtSO2N3
46
Oxone
H2O2
BtSO2N3
BtSO2N3
ImSO2N3
TMSN3
NaN3
67
Tracec,d
78
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
None
62
high boiling TCP was solvent of choice.19a 20
,
Firstly catalyst 24
75
(CuI) loading was studied from 0.75 mol % to 10 mol % and 25
satisfying yield was observed when 5 mol % catalyst was used, 26
excess catalyst did not have profound effect on the yield 27
TfN3
66
TsN3
24
BtSO2N3
BtSO2N3
---
(Table
1
, entries
1
-
5
). In order to find the better catalyst, other 28
a
---
copper salts were also screened. The copper bromide and
Reagent 1 (1mmol and 5 ml/mmol TCP), catalyst other than CuI
b
screened at 5 mol% scale. Isolated yield. c Reaction completed in 24 h
copper chloride led to the formation of 2a in 52 and 44% yield
at 140oC.d Trace amount was spotted on TLC.
respectively, with the recovery of substrate 1a (Table
1, entries
6
and 7). It is interesting to note that Cu(OAc)2 led to the
formation of desired product in 62 % yield and Cu(OAc) gave
72% yield, although it required longer reaction time (24 h) and
Hgb-H2O2, Oxone and H2O2 afford the target molecule in <67%
yield (Table
1 entries 16-21). Afterward the azide source was
higher temp 140oC (Table 1 entries
8 and 9). Other copper salts
screened, NaN3 and ImSO2N3.HCl found to be effective in
yielding product in 75 and 78% respectively, while TMSN3, TfN3
used were found to be less effective in term of effective
conversion, Cu2O gave only 12 % yield and found to be least
and TSN3 gave the targeted molecule in <66% yield (Table
1
effective (Table 1, entries 10-12). Furthermore, considering the
entries 22-26). The higher yield in case of BtSO2N3 may be due
importance of palladium in C-H bond activation, some easily
accessible Pd salts were examined for the purpose. It was
found that Pd(OAc)2 and PdCl2 led to formation of 2a in 34 and
to excellent solubility of azide donor in TCP. The high
stoichiometric ratio of azide source can be explained on the
basis of stability of BtSO2N3, as loss of mass is evidanced at
high temperature in Thermogravimetric (TGA) analysis.18a
Control experiment ascertained that, without the catalyst and
23 % respectively (Table
1 entries 13- 14) . The Pd(OH)2/C was
found to be ineffective as it gave traces of product with
recovery of starting material after 24 h heating at 140oC(Table
oxidant, the product was not formed (Table
1
entries 27-28).
1
entry 15). After confirming the importance and
Table 2. Synthesis of 2-azidoaromatics.a
stoichiometry (5 mol %) of CuI, the oxidants were screened in
which potassium persulphate K2S2O8 displayed superior results
in 1.5 equivalnet stoichiometry, while (NH4)2S2O8, air, TBHP,
Table 1. Optimisation of reaction conditiona
Entry
1.
R’
R
Time
(h)
2
Yield
(%)b
H
H
H
H
H
12
2a
2b
2c
2d
2e
2f
92
84
83
79
81
90
86
82
76
56
52c
52
2.
3.
4.
4-Me 14
5-Cl 12
5-Me 15
Entry
Catalyst
(mol%)
Oxidant
(1.5 equi) (1.5 equi)
Azide
Yieldb
5. 2-OBn
6. 2-Me
7. 2-Cl
H
H
H
H
H
H
H
H
16
12
15
16
12
14
24
24
1
2
3
4
5
6
7
8
CuI (0.75)
CuI (1.5)
CuI (3)
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
BtSO2N3
BtSO2N3
BtSO2N3
BtSO2N3
BtSO2N3
BtSO2N3
BtSO2N3
BtSO2N3
14
43
76
92
91
52
44
62
2g
2h
2i
8. 4-Me
9. 4-OMe
10. 4-CN
CuI (5)
CuI (10)
CuBr (5)
CuCl (5)
Cu(OAc)2 (5)
2j
11. 4-CHO
12. 4-CO2Me
2k
2l
2 | J. Name., 2012, 00, 1-3
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13. 2,5-diMe
d
14.
H
H
H
H
22
18
15
12
2m 32
as of highly activating nature of aniline, on the other hand in
our substrate no such activation is observed as direction is
achieved by pyridine.21
2n
2o
2p
75
81
82
e
15.
16. 3-Br
a
Reaction condition: 1 (1equivalent), CuI ( 5 mol%) , BtSO2N3 (1.5
b
equivalent), K2S2O8 (1.5 equivalent) in TCP ( 5 mL/mmol). Isolated
c
yield. oxidation of aldehyde occurred as identified by TLC and NMR
analysis, and beside 2k the oxidised product (un-azidated) was also
isolated by column chromatography in minor quantity. d2-thienyl. e2-
naphthalenyl
With the optimised relation condition in hand, the
substrate scope and limitation of the reaction was examined in
the presence of 5 mol % of the copper catalyst and the result
are summarised in table 2. 2-Phenylpyridines bearing electron-
donating and halogen group in the pyridine ring were well
endured in the reaction conditions, and the azidation products
Scheme 1. Functionalization of ortho-azide arenes
2a
-
2d were isolated in good to excellent yield (table
). Likewise, smooth and clean reaction was observed for 2-
Phenylpyridines having electron-donating, electron
withdrawing, and halogen group at the different position of
phenyl ring (Table entries ), though substrate with
electron withdrawing group gave the lesser yield, (Table
entries 10 12). The functional group present on the substrate
2 entries
1-4
The synthetic usefulness of azidation product was further
demonstrated by three additional reaction (Scheme 1). As
represented in scheme
treatment with Zn and NH4Cl in reflux EtOH, providing 92%
yield of amino derivative 4a 22
The reduced amine products of
1, reduction of azide (2a) achieved by
2
5-9
2
.
-
ortho-N-heterocyclic are useful starting material in the
synthesis of bi-dentate nitrogen ligands, e.g. N-tosyl derivative
of 4a was an effective bi-dentate ligand for fluorination.23
Recently, Driver and co-workers reported the conversion of 2a
into carboline 4b by using [Rh2(esp)2] as a catalyst.24 α-
carbolines are known as antiviral agents, inhibitors of ApoB-
100-associated lipoprotein production for cholesterol
lowering, and more recently, as inhibitors of CDK1 kinase as
provide suitable site for further functionalization. Additionally,
the efficiency of the reaction was confirmed by the successful
azidation of di-substituted, fused and heterocyclic ring system
(Table
2 entries 13-15). The longer reaction time and low yield
are in agreement of steric hindrance caused by di-substitution.
In the case of unsymmetrical m-Bromo substrate azidation
occurred exclusively at the least hindered position (table
2
entry 16).
potential anticancer agents.25
The 2a was successfully
converted into pyrido[1,2-b]indazole (4c) by heating at 125o C
in 1,4-Dioxane.16 Pyrido[1,2-b]indazole core is well described
as tubulin binding anticancer agents.26 A click reaction of 2a
and phenylacetylene afford triazole 4d in 81% yield, which
could be used as a precursor to N-hetrocyclic carbene ligand.27
Moreover 5a which is known to be an apoptosis inducer can
be synthesize using developed methodology using 3d as a
starting material.28 The active core of compound 5b (PTP
Inhibitor) can be synthesize by developed methodology
(Scheme 2).29
Figure 1. C-H bond azidation of arenes with different directing
Group.
Undoubtedly, a suitable directing group was essential to
obtain both high yield and high efficacy for ortho-C-H azidation
of arenes. The chelating group appeared to be important for
the ortho C-H azidation of arenes because no reaction was
observed for 3- and 4-phenylpyridine (Figure 1, 3a and 3b).
Other common directing groups, including pyrimidine,
pyrazole and thiazole, could be similarly active to direct ortho
C-H azidation, nevertheless relative lower yield and longer
reaction times are expected as comparison to 2-
Scheme 2. Application of methodology in phamaceutical
chemistry.
phenylpyridines (Figure 1, 3c-e). In all cases, no di azidation
product was formed. Yu and co-worker got the di substitution
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On the basis of reported investigations and our results, effective, safe, and operative finding provided as easy access
the reaction mechanism was hypothesised.6a,16,30 Initially, the for additional chemical modifications of the
2-(2-
reaction is performed using 2,2,6,6-tetramethyl-1- azidophenyl)pyridine derivatives.
piperidinyloxy (TEMPO) as radical scavengers, and it was
found that azidation reaction was completely inhibited,
suggesting radical mechanism pathway So it is postulated that,
firstly 2-phenylpyridine was co-ordinated to copper iodide to
form 6a, which on reaction with BtSO2N3 converted into Cu(III)
possessing SO2Bt, N3 and iodine in presence of K2S2O8 as
oxidant (6b). The iodide might be responsible for stabilising
the variation in oxidation state of Cu as iodine itself showed
variable oxidation states. The 6b converted into radical cation
6c by single electron transfer (SET) in which intramolecular
azide transfer takes place to form 6d radical. Another SET
resulting the formation of 6e with the elimination of
Acknowledgements
CSA acknowledges GGS Indraprastha University, New Delhi for
financial assistance and TRC Lab for providing analytical data.
CSA also acknowledge Dr A K Saxena (Emeritus Scientist) CSIR-
Central Drug Research Institute, India for valuable suggestions
in the preparation of current manuscript.
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DOI: 10.1039/C5RA21963A
Copper-catalysed regioselective azidation of arenes by C-H activation
directed by pyridine
Chandra S. Azad and Anudeep K. Narula*