ACCEPTED MANUSCRIPT
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Catalysis Communications
Table 1: Optimizing the conditions for direct oxidation of p-toluidine to 1,2-di-p-
tolyldiazene
Scheme 1. Synthesis of azobenzenes and hydrazines from various primary
and secondary amines using copper (I) catalyst.
Metal
catal-
yst
Ligand
(mmol)
Additives
(mmol)
Entry
1b
Medium
-
Temp.
50 oC
Time
24
Yielda
-
Result and Discussions
CuI
bpy(0.2)
TEMPO(0.1)
2b
3b
4b
5b
6b
7b
8b
9c
10c
11c
12c
13c
CuI
CuI
bpy(0.2)
bpy(0.2)
UHP(2)
-
-
50oC
50 oC
24
24
-
-
To optimize the reaction conditions, a series of experiments
(Table 1) were performed using p-toluidine as starting substrate.
The first set (Table 1, Entry, 1-3) of experiments was carried out
using CuI as catalyst, 2, 2′-bipyridyl as ligand and K2CO3 as base
under atmospheric oxygen using variety of oxidants and radical
initiators such as 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO),
urea hydrogen peroxide (UHP) and aqueous tert-butyl
hydroperoxide solution (TBHP). Notably, no reaction has taken
place with complete recovery of starting materials. The second
set (Table 1, Entry 4 and 5) of reactions was performed using 10
mol% of CuI and CuBr, 20 mol% of 2,2′-bipyridyl and AIBN (40
mol%), which resulted in compound 2 in moderate yields of 24%
and 52% respectively. The third set (Table 1, Entries 6-8) of
reactions was executed using 10 mol% of CuBr by varying
ligands such as bipyridyl, 1,4-diazabicyclo[2.2.2]octane
(DABCO), 4-DMAP, N,N,N′,N′-tetramethyl ethylenediamine
(TMEDA) in CH3CN at room temperature. Product 2 was
obtained in excellent yields when DMAP (or) DABCO used as a
ligand (Table 1, Entries 7 and 8). Because DMAP acts as both
ligand and base, the further experiments (Table 1, Entry 9) were
carried out without additional base (i.e. K2CO3) by varying with
the amounts of DMAP. Interestingly, the yield of the product
improved from 52% to 72%, when the reaction was carried out
under nitrogen atmosphere (Table 1, Entry 10) and was better
than that of atmospheric oxygen or oxygen balloon. Furthermore,
in order to obtain the maximum yield of the product different
mole ratios of DMAP were tested (Table 1, Entry 12-13). It was
observed that, 10 mol% of CuBr, 0.3 mmol of AIBN, 1.2 mmol
of 4-DMAP in dry acetonitrile at room temperature under N2
(commercial grade) atmosphere gave compound 2 in 97%
isolated yield. (Table 1, Entry 13). It was noticed that under
atmospheric oxygen, the reaction was not selective (5% of
unidentified products were noticed along with desired product 2
in 88% yield). However when the reaction was performed under
complete degassed acetonitrile and high pure nitrogen conditions
instead of commercial grade N2, it was observed that the reaction
was slower even after 12 h, 10% of starting material was
recovered along with 81% of product 2. The absence of AIBN in
the reaction mixture gave compound 2 in only 10% of isolated
yield even after 24 h.
aqTBHP(4)
CuI
CuBr
CuBr
bpy(0.2)
bpy(0.2)
TMEDA(0.2)
AIBN(0.3).
AIBN(0.4)
AIBN(0.4)
-
-
-
RT
RT
RT
24
8
24
24
52
28
CuBr
CuBr
CuBr
CuBr
CuBr
DABCO(0.2)
DMAP(0.2)
DMAP (0.2)
DMAP (0.2)
DMAP (0.5)
AIBN(0.4)
AIBN(0.4)
AIBN(0.4)
AIBN(0.4)
AIBN(0.4)
-
-
RT
RT
RT
RT
RT
8
8
8
6
8
84
88
52
72
76
-
N2
N2
CuBr
CuBr
DMAP (1.0)
DMAP (1.2)
AIBN(0.3)
AIBN(0.3)
N2
N2
RT
RT
7
6
94
97
a
Note: All the reactions were carried out using 1 mmol of 1, 10 mol% catalyst, 3
mL CH3CN. Where bpy = 2,2'-bipyridyl. bEntry 1-8 K2CO3 (2 mmol) used as base;
cEntry 9-13 without base. Entry 1-9 Reactions were carried out at atmospheric
oxygen.
.
However, in elevated temperature i.e. at 60 °C, high yields (62-
76%) of desired products were obtained. Remarkably, in all the
above cases only azo products were formed selectively and no
by-products (e.g. Ullmann coupled products, N-oxides and
hydroxyl amine compounds) were noticed [20].
Table 2: Cu (I) catalyzed dehydrogenative coupling of primary
anilines
Next, the scope of the newly developed protocol was
extended to other primary aromatic amines to produce a series of
diverse azo compounds under optimized reaction conditions
(Table 2). In case of aromatic amines without any substituent i.e.
aniline, the corresponding azo compound was obtained in
excellent yield (2a). Similarly, the presence of electron donating
groups such as methyl and methoxy substitution at para-position
of aniline gave the corresponding azo compound in excellent
yields (Table 1, Entry 13; Table 2, 2b). This oxidative coupling
was extended to mono and dihalogen substituted anilines (fluoro,
chloro and bromo). In case of fluoro substituted aniline (1c) the
corresponding azobenzene (2c) was obtained in high yield (88%).
However, for chloro (1d), bromo (1e) and 4-bromo-3-fluoro
aniline (1f), the reaction rate was slower and resulted in
reasonable yields of products (2d-2f).
Note: All reactions were carried out using 1 mmol of substrate under above
optimized conditions. aReaction was carried out at room temperature.
bReaction was carried out at 60 °C.
From literature precedence, we proposed the plausible
mechanism for this copper (I) catalyzed dehydrogentative homo
coupling method in Scheme 3. First, Cu(I)Br form coordination