Tert-butyl nitrite mediated regiospecific nitration of (E)-azoarenes through palladium-catalyzed directed C - H activation

Article abstract of DOI:10.1002/chem.201403325

An efficient protocol for the Pd-catalyzed regiospecific ortho-nitration of (E)-azoarenes has been achieved for the first time using tBuONO as a nitrating agent under atmospheric oxygen. A series of both symmetrical and unsymmetrical azoarenes were nitrated efficiently by this procedure providing excellent chemo- and regioselectivity and compatibility with a broad array of functional groups.

Full text of DOI:10.1002/chem.201403325

DOI: 10.1002/chem.201403325
Communication
&
CÀH Activation
tert-Butyl Nitrite Mediated Regiospecific Nitration of (E)-Azoarenes
through Palladium-Catalyzed Directed CÀH Activation
Biju Majhi, Debasish Kundu, Sabir Ahammed, and Brindaban C. Ranu*[a]
dizing agents like K2S2O8 or PhI(OAc)2. Moreover, the copper-
Abstract: An efficient protocol for the Pd-catalyzed regio-
mediated reaction uses the metal catalyst in stoichiometric
specific ortho-nitration of (E)-azoarenes has been achieved
amount.[10a] Being driven by a need of an efficient method for
for the first time using tBuONO as a nitrating agent under
an access to nitroazoarenes we report here a Pd-catalyzed che-
atmospheric oxygen. A series of both symmetrical and un-
lation directed regiospecific CÀH nitration of azoarenes at the
symmetrical azoarenes were nitrated efficiently by this
ortho position using tert-butyl nitrite as a nitrating agent under
procedure providing excellent chemo- and regioselectivity
atmospheric oxygen in the absence of any other oxidant
and compatibility with a broad array of functional groups.
(Scheme 1).
The azoarenes are of much interest due to their applications as
dyes, indicators, nonlinear optics, photochemical switches and
pharmaceuticals.[1] Thus, functionalization of azoarenes has at-
tracted considerable attention.[2] The CÀH activation directed
Scheme 1. Pd-catalyzed ortho-directed CÀH nitration of azoarenes.
by the azo group has been an important tool in regiospecific
aromatic ring functionalization. The Pd-catalyzed ortho-acyla-
tion, alkoxylation, amination and halogenation of azoarenes in-
volving CÀH activation are a few of the examples reported re-
To standardize the reaction conditions a series of experi-
cently.[3] Surprisingly, although the ÀNO2 functionality possess-
ments were performed with variation of reaction parameters,
es remarkable significance due to its transformation to the
other important functional groups, the nitration of azoarenes
has not yet been explored.
such as catalyst, solvent, temperature and time for a represen-
tative reaction of (E)-1,2-di-p-tolyldiazene and tert-butyl nitrite.
The results are summarized in Table 1. The use of Pd(OAc)2,
PdCl2 or (PPh3)2PdCl2 as catalyst furnished relatively low prod-
uct yields (Table 1, entries 1–3). The best yield of product was
obtained using Pd(CH3CN)2Cl2 (15 mol%) as a catalyst and
4 equivalents of tBuONO as a nitrating agent in 1,4-dioxane at
908C (Table 1, entry 6). 1,4-Dioxane was found to be a more ef-
fective solvent compared to xylene, THF, DMF, NMP and DMSO
Nitration of aromatic compounds through electrophilic aro-
matic substitution is one of the most common processes.[4]
However, this protocol suffers from severe drawbacks such as
harsh reaction conditions, poor regioselectivity, and functional
group intolerance among others. Thus, regioselective nitration
in aromatic systems remains a challenge. Several new strat-
egies such as ipso-nitration,[5] nitrodemetalation of CÀB and CÀ (Table 1, entries 7–11) although CH3CN and dichloroethane pro-
Li bonds,[6] indirect nitration of amines and azides through
ipso-oxidation and nitrodecarboxylation[7] have been devel-
oped. However, transition-metal-catalyzed directed CÀH func-
tionalization is considered one of the effective ways for the re-
gioselective inclusion of a group in an aromatic ring.[8] Liu and
co-workers reported palladium-catalyzed N-donor directed
ortho nitration in the aromatic ring using AgNO2 as a nitrating
agent and K2S2O8 as an oxidizing agent.[9] CuII[10] and RhIII[11] cat-
alyzed directed CÀH nitration have also been developed. How-
ever, most of these protocols involve the use of expensive and
toxic metal nitrites as nitrating agent in combination with oxi-
vided relatively improved yields (Table 1, entries 12 and 13).
The use of 10 mol% of catalyst produced a lower yield of
product (Table 1, entry 5). The increase of the amount of
tBuONO beyond 4 equivalents or Pd catalyst more than
15 mol% did not affect the outcome of the reaction (Table 1,
entries 14 and 16). Use of 3 equivalents of tBuONO led to
a lower yield (Table 1, entry 15). The reaction at a lower tem-
perature (808C) furnished lower yield of product (Table 1,
entry 17). Only trace amount of product was obtained when
the reaction was carried out under argon atmosphere (Table 1,
entry 18). The reaction did not proceed at all in the presence
of 2,2,6,6,-tetramethylpiperidine N-oxide (TEMPO; Table 1,
entry 19). No product was formed in the absence of catalyst
(Table 1, entry 20).
[a] B. Majhi, D. Kundu, Dr. S. Ahammed, Prof. Dr. B. C. Ranu
Department of Organic Chemistry
Indian Association for the Cultivation of Science
Jadavpur, Kolkata-700032 (India)
E-mail: ocbcr@iacs.res.in
Thus, in a general experimental procedure a mixture of
azoarene and tert-butyl nitrite was heated with stirring in 1,4-
dioxane at 908C in the presence of Pd(CH3CN)2Cl2 (15 mol%)
for 20–24 h as required for completion. A wide range of di-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403325.
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versely substituted azoarenes were subjected to nitration with
this procedure. The results are summarized in Table 2. Both
electron donating (ÀOMe, ÀMe, ÀEt) and electron withdrawing
groups (ÀCF3, ÀF, ÀCl, ÀCOAr) on the aromatic ring are com-
patible with the reaction conditions. In every reaction only
ortho-mononitrated product was obtained. When compound
2a was subjected to further CÀH nitration under the same re-
action conditions, no reaction occurred leaving the starting
material (Scheme 2).
Table 1. Standardization of reaction conditions.[a]
Entry
Catalyst
Catalyst
[mol%]
Solvent
T
Yield
[%][b]
[oC]
1
2
3
4
5
6
7
8
9
10
11
12
13
14[c]
15[d]
16
17
18[e]
19[f]
20[g]
Pd(OAc)2
PdCl2
10
10
10
10
10
15
15
15
15
15
15
15
15
15
15
20
15
15
15
–
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
xylene
THF
DMF
NMP
DMSO
110
110
110
110
90
90
90
90
90
90
90
90
90
90
90
90
80
90
90
90
45
39
46
65
70
82
12
15
trace
trace
trace
72
60
82
68
81
71
trace
0
(PPh3)2PdCl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
–
Scheme 2. CÀH nitration of mononitroazoarene.
CH3CN
DCE
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
The nitration of halo-substituted azoarenes provided inter-
esting results. The reaction of azoarenes bearing halogen moi-
eties on the para position of aromatic ring, furnished decreas-
ing yields of CÀH nitrated products with increasing electrone-
gativity of the halogen moieties (I>Br>Cl>F; Table 2, 2l, 2m,
2n and 2o). However, a reverse order was noticed in the nitra-
tion of azoarenes with halogen substituents in the ortho posi-
tions (F>Cl>Br>I; Table 2, 2p, 2q, 2r and 2s). This observa-
tion may be related to the electronic effect of d orbitals of hal-
ogens (Cl, Br, I). The reaction did not proceed at all with ortho-
0
[a] Reaction conditions: azoarene (0.5 mmol), tBuONO (2 mmol), solvent,
catalyst, 20 h, air; [b] yield of isolated product; [c] 8 equiv of tBuONO
used; [d] 3 equiv of tBuONO used; [e] under argon atmosphere; [f] in the
presence of TEMPO (3 equiv); [g] in the absence of catalyst.
Table 2. Pd-catalyzed CÀH nitration of azoarenes.[a]
2a, 77%
2b, 82%
2c, 90%
2d, 80%
2e, 72%
2 f, 92%
2g, 75%
2h, 88%
2i, 76%
2j, 46%
2o, 75%
2k, 56%
2p, 60%
2l, 48%
2m, 57%
2r, 40%[b]
2n, 65%
2s, 0%[b]
2q, 51%[b]
[a] Reaction conditions: azoarene (0.5 mmol), tBuONO (2.0 mmol), Pd(CH3CN)2Cl2 (15 mol%), 1,4-dioxane (3 mL), 908C, 20 h, under air; [b] 24 h.
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the aryl substituted ring to give 6a. Most likely, the Ar group
on the azoarene 5a puts a steric hindrance to nitration in the
proximate phenyl ring and thus nitration occurs exclusively at
the other ring.
However, compound 5b bearing ÀCO-p-tolyl substituent at
the ortho position of the aromatic ring was nitrated at the
ortho position of the unsubstituted ring preferentially to pro-
duce 6b’ as major product along with nitration on the substi-
tuted ring (6b). When reaction of azoarene 5c was performed,
Scheme 3. CÀH nitration of meta-substituted azoarenes.
iodo azoarene as the iodo moiety has the most diffused d orbi-
tal compared to the others. Significantly, in all these Pd-cata-
lyzed reactions only the CÀH nitrations are observed and the
halo groups remained unaffected under the reaction condi-
tions although Pd-catalyzed nitration of aryl halides is very
common.[5d]
Interestingly, azoarenes bearing meta substituents showed
excellent regioselectivity towards CÀH nitration under the reac-
tion conditions (Scheme 3). In both the substrates (3a and 3b)
the nitration occurred at the position para to Me (4a) and Cl
(4b) groups.
Nitrations of unsymmetrically substituted azoarenes pro-
ceeded successfully with excellent regioselectivity (Scheme 4).
Azoarene bearing an aryl substituent at the ortho position of
one aromatic ring (5a) underwent CÀH nitration selectively at
Figure 1. ORTEP diagram of compound 6d in the form of two rotamers.
nitration occurred preferentially
at the methyl substituted ring
to give 6c as a major product.
On the other hand, compound
5d having ÀOMe group on one
of the aromatic rings underwent
nitration preferentially on the
unsubstituted ring giving 6d as
the major product. The struc-
ture of compound 6d was con-
firmed
by
X-ray
analysis
(Figure 1).[12]
Densely substituted azoar-
enes were also nitrated success-
fully (7a, 7b and 7c) to
produce the corresponding
nitro-substituted
(Scheme 5).
products
In general, the reactions are
clean and high yielding. A series
of o-nitroazoarenes including
densely substituted ones were
Scheme 4. Regioselective CÀH nitration of unsymmetrical azoarenes.
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Scheme 7. Possible mechanism for Pd-catalyzed CÀH nitration of azoarenes.
This observation of increased reactivity for electron-donating
groups substituted azoarenes relative to those having elec-
tron-withdrawing moieties, suggests an electrophilic-type acti-
vation manifold. We propose that initially an intermediate A is
formed by the chelation of azoarene and PdII (Scheme 7).[3b]
The reaction may involve either Pd0/PdII or PdII/PdIV catalytic
process.[13] As no external reducing agent or strong base was
used in the reaction medium, the formation of Pd0 in the initial
stage of the reaction is unlikely. It was also observed that a con-
trol experiment with 2 equivalents of Pd(CH3CN)2Cl2 in the ab-
sence of air failed to initiate the reaction. Thus, the reaction
may not follow the Pd0/PdII process. We suggest a CÀH activa-
tion involving a PdII/PdIV pathway towards ortho nitration of
azoarenes. In a first step in situ formed NO2 radical undergoes
chelation with PdII of intermediate A to form a PdIII intermedi-
ate B. Intermediate B then suffers one electron oxidation by
another NO2 radical to form PdIV intermediate C, which on re-
ductive elimination leads to the product with regeneration of
PdII to start the next cycle.
Scheme 5. CÀH nitration of densely substituted azoarenes.
obtained by this procedure and many of them are reported for
the first time. The compounds are obtained in high purity. The
nitration is compatible with several functional groups.
To understand the mechanism we performed a few competi-
tive reactions with a pair of substituted azoarenes (Scheme 6).
We have performed UV experiments for the nitration of 4-
Me azobenzene under the standardized reaction conditions,
which shows an absorbance at 445 nm corresponding to PdIII
intermediate[14] (see the Supporting Information) supporting
our proposed reaction pathway.
In conclusion, we have developed an efficient procedure for
the highly regioselective ortho-nitration of azoarenes by tert-
butyl nitrite with a Pd-catalyzed directed CÀH activation. The
azo-nitroarenes have much potential as useful materials and
pharmaceuticals. The significant features of this protocol are:
1) mild reaction conditions avoiding use of any metal nitrite,
acid and ligand; 2) applicability to a wide range of diversely
substituted azoarenes; 3) excellent regioselectivity; and 4) high
yield of products. In fact, we are not aware of any report for ni-
tration of aromatic systems including azoarenes by CÀH activa-
tion using an organonitrite, and thus this nitration of azoar-
enes by tert-butyl nitrite is significant and constitutes the first
report of its kind. We believe, this method will find useful ap-
plications in organic synthesis.
Scheme 6. Intermolecular competition experiment.
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Acknowledgements
We gratefully acknowledge the financial support from DST,
Govt. of India, New Delhi with an award of J. C. Bose fellowship
to B.C.R. (Grant no. SR/S2/JCB-11/2008). B.M., D.K. and S.A.
thank CSIR, New Delhi for their fellowships. The help from
DBT-funded CEIB program (Project no. BT/01/CEIB/11V/13)
awarded to the Department of Organic Chemistry, IACS, Kolka-
ta, is also acknowledged for Single Crystal X-ray diffraction
data collection.
Keywords: CÀH activation · nitration · o-nitroazoarenes ·
palladium · tert-butyl nitrite
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Received: April 30, 2014
Published online on July 10, 2014
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