Metal-free, highly efficient organocatalytic amination of benzylic C-H bonds

Article abstract of DOI:10.1039/c3cc41558a

A new synthetic approach toward direct C-N bond formation through sp ³ C-H activation has been developed under metal-free conditions. Both primary and secondary benzylic C-H substrates could react smoothly with various amines to give only mono-amination products with good to excellent yields. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc41558a

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Metal-free, highly efficient organocatalytic amination
of benzylic C–H bonds†
Cite this: DOI: 10.1039/c3cc41558a
Qicai Xue,a Jin Xie,a Huamin Li,a Yixiang Chenga and Chengjian Zhu*ab
Received 1st March 2013,
Accepted 15th March 2013
DOI: 10.1039/c3cc41558a
www.rsc.org/chemcomm
A new synthetic approach toward direct C–N bond formation
through sp3 C–H activation has been developed under metal-free
conditions. Both primary and secondary benzylic C–H substrates
could react smoothly with various amines to give only mono-
amination products with good to excellent yields.
The C–N bonds are ubiquitous in natural and synthetic bio-
active compounds.1 Direct amination of C–H bonds is one of
the most exciting strategies to synthesize nitrogen-containing
molecules. In recent years, transition-metal-catalyzed C–H
amination has made considerable achievements.2 However,
the presence of heavy metal residues is a problem in the
pharmaceutical industry, and the effects on health have caused
public concern. In this context, the metal-free system ‘‘n-Bu4NI–
TBHP’’ has been the focus of recent interest.3,4 Although some
excellent methodologies for C–O bond formation have been
Scheme 1 Amination of benzylic C–H bonds.
Initially, p-xylene 1a and 1H-benzotriazole 2a were selected
reported,5a–f n-Bu4NI catalyzed C–N bond formation through as the model substrates to optimize the reaction conditions
sp3 C–H activation has not been placed a high value.4a,b As part (Table 1). The oxidative coupling product 3a could be formed
of our ongoing interest in sp3 C–H activation,4e we are inter- using n-Bu4NI as a catalyst. Encouraged by this result, we
ested in developing a novel organocatalyzed sp3 C–H bond investigated different organocatalysts. As shown in Table 1,
amination protocol.
n-Bu4NI showed the best catalytic activity (Table 1, entry 1).
Toluene and xylenes are important chemical raw materials. Other catalysts such as n-Bu4NBr, n-Bu4NCl and n-Bu4NOH gave
The selective amination of C–H bonds is particularly important unsatisfactory results (Table 1, entries 2–4). TBHP was found to
since it can yield industrially important chemicals. To date, play an important role in the process. The use of other
methodologies for direct conversion of benzylic C–H bonds into peroxides, O2 or K2S2O8 instead of TBHP decreased the yields
C–N bonds through sp3 C–H activation are relatively scarce.6,7 dramatically (Table 1, entries 5–8). To our delight, the coupling
Primary benzylic hydrocarbons such as toluene typically afford reaction proceeded smoothly, giving the desired product 3a
low yields, and a large excess of toluene is usually necessary.6d,e with 90% yield, with the use of 10 mol% n-Bu4NI (Table 1,
Herein, we report an n-Bu4NI-catalyzed highly selective benzylic entry 9). In addition, no 3a was observed when either n-Bu4NI
C–H bond amination protocol using TBHP as an oxidant or TBHP was absent (Table 1, entries 10 and 11). Among the
(Scheme 1).
reaction temperatures examined, it turned out that 75 1C was
the most suitable (Table 1, entry 9).
With the optimized conditions in hand (Table 1, entry 9),
different substrates with benzylic C–H bonds were tested
(Table 2). Both xylenes and mesitylene could be successfully
converted to the corresponding products in good to excellent
yields (Table 2, 3a–d). Intriguingly, the benzylic amination was
also highly selective, affording only mono-amination products,
and no multi-amination or aromatic C–H amination products
a State Key Laboratory of Coordination Chemistry, School of Chemistry and
Chemical Engineering, Nanjing University, Nanjing 210093,
People’s Republic of China. E-mail: cjzhu@nju.edu.cn
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Shanghai 200032, People’s Republic of China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc41558a
c
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Table 1 Optimization of reaction conditionsa
electron-donating substituents were converted into the corre-
sponding products with higher yields than electron-withdrawing
substituents (Table 2, 3f–h). 2- or 3-substituted toluenes were
also tolerated in this protocol (Table 2, 3b, 3c, 3i). When
ethylbenzene or indane was employed, the reaction could
proceed smoothly to furnish the C–N coupling products with
excellent yields (Table 2, 3j–k). Moreover, 8-methylquinoline
could also undergo the coupling reaction to provide the desired
products in good yield (Table 2, 3l).
To further explore the potential of our methodology,
a variety of amines were investigated, and the results are
summarized in Table 3. To our delight, benzotriazoles with
different substituents could be converted to the desired pro-
ducts (Table 3, 3m–n) in good to excellent yields. Subsequently,
three benzimidazoles were examined (Table 3, 3o–q). They
could also react with primary benzylic C–H bonds. Benzimid-
azole bearing electron-withdrawing groups showed lower
activity. Notably, various purine derivatives could react with
p-xylene smoothly in good to high yields (Table 3, 3r–t).
2-Amino-6-chloropurine could also be tolerated in this proto-
col, and only an N-9 substituted product was detected. The
phthalimide was also highly selective, affording only the
benzylic amination product as demonstrated in this protocol
(Table 3, 3u), its coupled with aryl sp2 C–H bond when using
PhI(OAc)2 as an oxidant.6d Moreover, saccharin and sulfonamide
Entry
Catalyst (mol%)
Oxidantb
T (1C)
Yieldc (%)
1
2
3
4
5
6
7
8
n-Bu4NI (20)
n-Bu4NBr (20)
n-Bu4NCl (20)
n-Bu4NOH (20)
n-Bu4NI (20)
n-Bu4NI (20)
n-Bu4NI (20)
n-Bu4NI (20)
n-Bu4NI (10)
—
n-Bu4NI (10)
n-Bu4NI (10)
n-Bu4NI (10)
n-Bu4NI (10)
TBHP
TBHP
TBHP
TBHP
H2O2
DTBP
75
75
75
75
75
75
75
75
75
75
75
60
90
120
91
Trace
N.D.d
N.D.
N.D.
Trace
N.D.
N.D.
90
N.D.
N.D.
57
87
79
e
O2
K2S2O8
TBHP
TBHP
—
TBHP
TBHP
TBHP
9
10
11
12
13
14d
a
Reaction conditions: 1a (1.5 mmol), 2a (0.3 mmol), oxidant (0.9 mmol),
b
75 1C, 12 h, air. TBHP: tert-butyl hydroperoxide 70% in water, H2O2
c
d
30% in water, DTBP: di-tert-butyl peroxide 98%. Isolated yield. Not
e
detected. Under an oxygen atmosphere (1.0 atm).
were detected. To our delight, it was found that toluene was
still very effective in our catalytic system and can give a good
result (Table 2, 3e). Subsequently, substrates with various
functional groups were examined. Toluene substrates bearing
Table 3 Scope of aminesa
Table 2 Scope of benzyl C–H substratesa
a
Standard reaction conditions: 1a (1.5 mmol), 2 (0.3 mmol), n-Bu4NI
a
Standard reaction conditions: 1 (1.5 mmol), 2a (0.3 mmol), n-Bu4NI
(10 mol%), TBHP (0.9 mmol, 70% in water), 75 1C, 12 h, air. Yields are
for the isolated products. 3n = 5-Chlorobenzotriazole (see ESI). 3q =
b
c
(10 mol%), TBHP (0.9 mmol, 70% in water), 75 1C, 12 h, air. Yields are
for the isolated products.
Methyl benzimidazole-5-carboxylate (see ESI).
c
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benzylic C–H substrates with unmodified amines. Various
amination products were obtained with good to excellent yields
using TBHP (70% in water) as an environmentally benign
oxidant. This method affords a facile metal-free approach for
synthesis of imidazole and purine nucleoside derivatives. The
possible mechanistic pathway is also proposed on the basis of
control experiments.
Scheme 2 A gram scale amination of p-xylene. Reaction conditions: 1a (75 mmol),
2a (15 mmol), n-Bu4NI (1.5 mmol), TBHP (45 mmol, 70% in water), 75 1C, 12 h, air.
We gratefully acknowledge the National Natural Science
Foundation of China (21172106, 21074054), the National
Basic Research Program of China (2010CB923303) and the
Research Fund for the Doctoral Program of Higher Educa-
tion of China (20120091110010) for their financial support.
J. Xie thanks the academic scholarship for doctoral candidates
of MOE.
Notes and references
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Scheme 3 Plausible mechanism.
3 For recent review see: M. Uyanik and K. Ishihara, ChemCatChem,
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could also undergo the oxidation reaction to provide the
desired products with high efficiency (Table 3, 3v–w).
To demonstrate the practicability of this protocol, the
n-Bu4NI-catalyzed reaction was scaled-up to the gram scale.
A gram scale amination of p-xylene was easily performed under
standard reaction conditions to furnish the desired product in
88% isolated yield (Scheme 2).
To probe the reaction mechanism, several control experi-
ments were conducted (see ESI†). When a radical inhibitor,
BHT (2,6-di-tert-butyl-4-methylphenol), was introduced into the
reaction mixture, the formation of the desired product 3e
was completely suppressed. Furthermore, replacing n-Bu4NI
with I2 led to no product. Interestingly, the reaction pro-
ceeded smoothly by the combined use of n-Bu4NOH and I2,
affording the desired product 3e in 76% yield. Based on the
similar results reported by Yu et al.5e and Ishihara et al.,5a we
suppose that the active hypoiodite [n-Bu4N]+[IO]À or iodite
[n-Bu4N]+[IO2]À plays an important role in the sp3 C–H amine
reactions. Additionally, the benzyl radical intermediate was
trapped by a radical scavenger, TEMPO (2,2,6,6-tetra-methyl-
piperidine-N-oxyl), and the oxyamination product was isolated
in 62% yield.
Based on the above results, a plausible mechanism is
proposed in Scheme 3. Initially, n-Bu4NI is oxidized by TBHP
to generate the active iodine species ammonium hypoiodite 4
or iodite 5 (Scheme 3a). Subsequently 4 or 5 induces the
homolysis of a benzyl C–H bond to give the benzyl radical
A,5e which is then oxidized by active iodine species to form the
benzyl cation B (Scheme 3b).6e,8 Finally, the nucleophilic reac-
tion of amine 2 with the benzyl cation B forms the desired
product 3 (Scheme 3c).
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In conclusion, we have reported a novel n-Bu4NI catalyzed
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c
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Chem. Commun.