Iodine-catalyzed ammoxidation of methyl arenes

Article abstract of DOI:10.1039/c5cc01024a

The development of organic transformation using cheap and readily available substrates under mild conditions will be pivotal for green and sustainable synthetic organic chemistry. Concerning our continued interest in the cyanation reaction, a metal-free direct ammoxidation of readily available methyl arenes leading to nitriles was established under mild conditions. A series of aryl methanes especially heteroaryl methanes (30 examples) were applicable in moderate to good yields with good functionality tolerance.

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ARTICLE TYPE
Iodine-catalyzed ammoxidation of methyl arenes†
Songjin Guo,a Gen Wan,a Song Sun,a Yan Jiang,a Jin-Tao Yua and Jiang Cheng* a, b
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
the combination of I2/TBHP for the transformation of methyl
5
The development of organic transformation from cheap and
readily available substrates under mild conditions will be
pivotal for the green and sustainable synthetic organic
chemistry. Concerning our continued interests in the
cyanation reaction, a metal-free direct ammoxidation of
arenes into nitriles with cheap and readily available
50 ammonium salts as the N atom source (eq 5, Scheme 1). This
procedure is featured with: 1) metal-free procedure with mild
reaction condition; 2) no expensive catalysts or toxic additives
were required.
10 readily available methyl arenes leading to nitriles was
established under mild conditions. A series of aryl methanes
especially heteroaryl methanes (30 examples) were applicable
in moderate to good yields with good functionality tolerance.
The methyl group is one of the most common groups in
15 small-molecule organic compounds.1 Therefore, the
transformation of aromatic methyl as potential functional
group into other target molecules is of great importance.2 In
comparison with the well-developed transition-metal
catalyzed cyanation of aryl halides3 and C-H cyanation
20 reactions,4 the ammoxidation of methyl arenes that are
abundant starting materials is almost the most straightforward
and simplest procedure leading to aryl nitriles in the large
industrial scale, which are not only useful intermediates5 but
also potential pharmaceutical and biologic active molecules.6
25 This ammoxidation procedure represents an ideal process
using O2 as a clean oxidant (eq 1, Scheme 1).7 However, it
suffers from high reaction temperature in the case of
laboratory scale. To circumvent this drawback, Jiao et al.
reported CuSO4-catalyzed conversion of methyl arenes to
30 nitriles utilizing excess amounts of toxic NaN3 as the nitrogen
source and expensive (diacetoxyiodo)-benzene (DIB) as the
oxidant (eq 2, Scheme 1).8 Subsequently, Togo developed a
one-pot two-step procedure for the transformation of methyl
arenes into nitriles by treatment with N-bromosuccinimide
35 (NBS), 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) or
HBr followered by I2 and aqueous ammonium (eq 3, Scheme
1).9 Wang described palladium(II)-catalyzed direct conversion
of methyl arenes into aromatic nitriles with tert-butyl nitrite
as the N source (eq 4, Scheme 1).10 Nevertheless, those
40 reported protocols either required transition metals and toxic
additives, or suffered from multisteps.
55
Scheme 1 Direct transformation of methyl arenes into nitriles.
Our study was initialized with evaluation of the direct
ammoxidation of 1-methylnaphthalene under oxidative
conditions. To our delight, in the presence of (NH4)2CO3, the
60 combination of I2 and TBHP provided the nitrile product 2a in
29% yield in DMSO at 70 oC (Table 1, entry 1). The yield
increased to 58% by replacing (NH4)2CO3 with NH4OAc (Table 1,
entry 2). However, under similar reaction conditions, NH3•H2O,
NH4Cl and NH4Br failed to promote this transformation (Table 1,
65 entries 3 and 5). At last, NH4F was found to be the best choice
and 80% of 1-cyanonaphthalene was isolated (Table 1, entry 6).
The reaction efficiency decreased with less amount of TBHP,
shorter reaction time or under N2 (Table 1, entry 6). Blank
experiment confirmed that no reaction took place in the absence
70 of TBHP or I2. Other iodide species such as KI, CuI or Bu4NI
could also catalyze this transformation yet gave moderate yields
(Table 1, entries 7-9). To our surprise, replacing TBHP with
DTBP, TBPB, H2O2, oxone or NaIO4 resulted in no reaction at all
(Table 1, entries 10-14). Further studies revealed that the solvent
75 played a key role in this procedure as no reaction took place in
solvents except DMSO and CH3CN (Table 1, entries 15-21).
Moreover, metal-free oxidative C-H activation via radical
approach has received growing attention and become as a
powerful tool for organic synthesis due to the eco-friendly
45 condition.11 Our interest in cyanation12 and metal-free C-H
activation13 spurred us to explore the more environmentally
friendly methods. Herein, we explored a useful system with
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Table 1 The opimization of reaction conditions.a
20 Figure 1 The ammoxidation of methyl arenes to nitriles.a, b
Entry Ammonium Catalyst Oxidant Solvent
Yield (%)b
1
2
3
4
5
(NH4)2CO3
NH4OAc
NH3·H 2O
NH4Br
I2
I2
I2
I2
I2
TBHP
TBHP
TBHP
TBHP
TBHP
DMSO
DMSO
DMSO
DMSO
DMSO
29
58
< 5
< 5
NH4Cl
14
80(68)c(71)d(75)e
(65)f(60)g(71)h(0)i
60
6
NH4F
I2
TBHP
DMSO
7
NH4F
NH4F
NH4F
NH4F
NH4F
NH4F
NH4F
NH4F
NH4F
NH4F
NH4F
NH4F
NH4F
NH4F
NH4F
KI
CuI
Bu4NI
I2
TBHP
TBHP
TBHP
DTBP
TBPB
H2O2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
8
36
56
0
9
10
11
12
13
14
15
16
17
18
19
20
21
I2
0
a
Reaction conditions: 1 (0.2 mmol), I2 (20 mol%), NH4F (0.8 mmol),
I2
0
o
TBHP (70% in water, 2.4 mmol), DMSO (0.5 mL), at 70 C under O2 for
48 h, sealed tube. b Isolated yields. c 10 mmol scale. d 60 h.
I2
oxone
NaIO4
0
I2
< 5
0
25 Figure 2 The ammoxidation of methyl hetero-arenes to nitriles.a, b
I2
TBHP CH3NO2
I2
TBHP
TBHP
TBHP
TBHP
TBHP
DCE
EtOH
PC
< 5
0
I2
I2
< 5
< 5
9
I2
HMPA
DMAc
I2
I2
TBHP CH3CN
47
a
Reaction conditions: 1a (0.2 mmol), catalyst (20 mol%), ammonium
o
(0.8 mmol), oxidant (2.4 mmol), solvent (0.5 mL), at 70 C under O2 for
b
c
48 h, sealed tube. TBHP (70% in water). Isolated yields. TBHP (1.2
i
d
e
f
g
h
mmol). TBHP (1.6 mmol). TBHP (2.0 mmol). N2. 24 h. 36 h.
Without I2 or TBHP. (TBHP = tert-butyl hydroperoxide, DTBP = di-tert-
butyl peroxide, TBPB = tert-butyl peroxybenzoate, PC = propylene
carbonate, HMPA = hexamethylphosphoramide, DMAc = dimethyl
acetamide).
With the optimized conditions in hand, the scope and limitation
of the methyl arenes were studied, as shown in Figure 1.
Generally, substrates bearing electron-donating groups as well as
1- and 2-methyl naphthalenes provided the cyanation products in
good to excellent yields. For example, 2f, 2j and 2k were isolated
in 71%, 81% and 83% yields, respectively. For 1,4-xylene and
1,3,5-mesitylene, mono-cyanated compound was obtained as the
5
10 major product (2g and 2h) and only a trace of di-cyanated
compound was detected by GC-MS. However, for the substrates
possessing electron-withdrawing groups, moderate yields were
obtained. Notably, the chloro, bromo and iodo groups survived
well under this procedure although with elongated time, which
15 provided potential handle for further functionalization. To further
evaluate the practicability of this procedure, the reactions were
conducted on a 10 mmol scale, and the desired products 2a, 2f
and 2p were obtained in a comparable yield.
a
Reaction conditions: 1 (0.2 mmol), I2 (20 mol%), NH4F (0.8 mmol),
o
TBHP (70% in water, 2.4 mmol), DMSO (0.5 mL), at 70 C under O2 for
b
c
48 h, sealed tube. Isolated yields. 1 (0.2 mmol), KI (20 mol%), NH4F
30 (0.8 mmol), TBHP (2.0 mmol), DMSO (1.0 mL), at 70 oC under O2 for 12
h. d 48 h. e 60 h. f 112 h. g DMSO 1.0 mL. h 10 mmol scale.
Next, the scope of heteroaromatic substrates was investigated,
as shown in Figure 2. To our delight, the methyl in quinoline and
isoquinoline ran smoothly under the standard procedure. For 2,6-
35 dimethyl quinoline, the mono-ammoxidation product 3i was
2
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selectively isolated in 49% yield, where the 6-methyl kept intact.
Particularly, methyl quinoxaline provided the cyanation product
ammonium and aldehyde affords nitrile. However, benzyl amine
and benzyl alcohol may be formed via the nucleophilic attack of
3f in 56% yield. Notably, benzoxazole and benzothiophene were 35 ammonia or water to benzylic carbocation. They can convert to
proper reaction partners, albeit the cyanation products 3k and 3l
were isolated in moderate yields. Meanwhile, 6-methyl-2,3-
dihydrobenzo[b][1,4]dioxine worked well, providing the
cyanation product 3m in 58% yield.
the target cyanation product as confirmed in eq 2, Scheme 2.14
In conclusion, we have developed a mild method for the direct
conversion of methyl arenes into nitriles. The procedure did not
require expensive catalysts or toxic additives. In combination
5
More experiments were conducted to gain some insights into 40 with the ubiquity of methyl group, it represents a facile and green
the mechanism. Firstly, the addition of 2.0 equivalents of
methodology leading to nitriles.
10 TEMPO (2,2,6,6-tetramethylpiperidinyloxy) inhibited the
reaction, indicating that a radical intermediate might be involved
in this transformation (eq 1, Scheme 2). Secondly, some potential
We thank the National Natural Science Foundation of China
(nos.
21272028
and
21202013),
“Innovation
&
Entrepreneurship Talents” Introduction Plan of Jiangsu
intermediates were subjected to the standard procedure. Amide 45 Province, Jiangsu Key Laboratory of Advanced Catalytic
provided no cyanation product, ruling out the possibility of
15 serving as the intermediate (eq 2, Scheme 2). However, benzyl
amine, alcohol and iodide as well as aromatic aldehyde all ran
smoothly to produce the nitrile in good yields (eq 2, Scheme 2).
Materials & Technology (BM2012110), State Key Laboratory
of Coordination Chemistry of Nanjing University, Jiangsu
Province Key Laboratory of Fine Petrochemical Engineering,
and the Priority Academic Program Development of Jiangsu
50 Higher Education Institutions for financial support.
Notes and references
a
School of Petrochemical Engineering, Jiangsu Key Laboratory of
Advanced Catalytic Materials &Technology, and Jiangsu Province Key
Laboratory of Fine Petrochemical Engineering, Changzhou University, 1
55 Gehu Road, Changzhou, 213164, P. R. China. E-mail:
jiangcheng@cczu.edu.cn
b State Key Laboratory of Coordination Chemistry, Nanjing University,
22 Hankou Road, Nanjing, 210093, P. R. China.
†
Electronic supplementary information (ESI) available: Detailed
60 synthetic procedures and characterization of new compounds. See DOI:
10.1039/c0sc00419g
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