Oxidative coupling of methylamine with an aminyl radical: Direct amidation catalyzed by I2/TBHP with HCl

Article abstract of DOI:10.1039/c4cc00621f

Oxidative coupling of methylamines with an aminyl radical to construct amides was developed in the presence of an I₂/TBHP catalyst under acidic conditions via the two cleavages of the sp³ C-N bond of aryl-methylamines and the sp² C-N bond of N-substituted formamides respectively. This transition-metal-free protocol provides a novel synthetic tool for the construction of N-substituted amides and a series of arylamides can be easily obtained with good yields. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc00621f

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Oxidative coupling of methylamine with an aminyl
radical: direct amidation catalyzed by I2/TBHP
with HCl†
Cite this: Chem. Commun., 2014,
50, 4085
Received 24th January 2014,
Accepted 24th February 2014
Lingfeng Gao, Haoming Tang and Zhiyong Wang*
DOI: 10.1039/c4cc00621f
www.rsc.org/chemcomm
Oxidative coupling of methylamines with an aminyl radical to
construct amides was developed in the presence of an I2/TBHP
catalyst under acidic conditions via the two cleavages of the sp3 C–N
bond of aryl-methylamines and the sp2 C–N bond of N-substituted
formamides respectively. This transition-metal-free protocol provides
a novel synthetic tool for the construction of N-substituted amides
and a series of arylamides can be easily obtained with good yields.
Amides are prevalent structural units that are found in biologically
relevant molecules, such as proteins, natural products, pharma-
ceuticals, and functional materials.1 As a result, the construction of
amide bonds has attracted considerable attention and a series of
efficient methods have been developed.2,3 The traditional synthetic
approach is the coupling of carboxylic acid with an amine via
various activating reagents of carboxylic acid. Usually, a stoichio-
metric amount of activating reagents leads to low atom efficiency
and great environmental pollution (Scheme 1a).2a Other alterna-
tives, such as the hydration of nitriles,4 rearrangement of oximes,5
and acylation of amines,6 the cross-coupling of formamides with
aryl/alkyl halides,7 the modified Staudinger reaction,8 carbonyl-
Scheme 1 Typical pathways for the N,N-dimethyl-substituted amide
synthesis.
ation of alkenes or alkynes,9 have also proven to be efficient methods respectively (Scheme 1c(2)).10f,11c On the other hand, very recently, our
for the construction of the amide bond. In recent years, with the aim group reported a novel protocol for the synthesis of cyanobenzene via
to construct an amide bond in a clean atom-economical manner, an oxidation of arylmethylamine by using an I2–TBHP–pyridine
transition metal (Ru, Rh, Pd, Au and Cu) catalyzed oxidative coupling catalyst (Scheme 1c(3)).12a Herein, as a logical extension of our two
between alcohols/aldehydes and amines also provided elegant and direct syntheses of benzamides, and encouraged by our previous work
direct access to amides.10 Moreover, there are some new develop- on I2/TBHP catalysis,12 we developed a metal-free oxidative coupling of
ments of metal-free oxidative coupling between alcohols/aldehydes aryl-methylamine with N-substituted formamide with good to excel-
and various amines sources (Scheme 1b).11
lent yield under mild conditions. To the best of our knowledge, this is
With the aim to construct an amide bond in a clean synthetic the first example of direct amidation via oxidative coupling of
method, our group has developed two new protocols for the direct arylmethylamine with N-substituted formamides in one step.
synthesis of benzamide from alcohol by using a Au/DNA nanohybrid
Based on the reaction conditions of our previous amidation of
catalyst (Scheme 1c(1)) and I2/TBHP (tert-butyl hydroperoxide)/NaOH alcohol with N-substituted formamides (Scheme 1c), initially, we
focused on the I2/TBHP/base catalyzed amidation of benzylamine
(1a) with DMF.11c A series of bases including inorganic bases such as
Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory
of Soft Matter Chemistry & Collaborative Innovation Center of Suzhou Nano
NaOH, KOH, LiOHÁH2O, K2CO3 and organic bases such as pyridine
Science and Technology, University of Science and Technology of China, Hefei,
and Et3N were examined in the reaction. However, all of the
230026, P. R. China. E-mail: zwang3@ustc.edu.cn; Fax: +86 551-6360-3185
attempts only produced a trace amount of benzamide (3aa)
(Table S1, ESI,† entries 1–6). In the absence of any base,
† Electronic supplementary information (ESI) available: Experimental details,
characterization of catalysts and products. See DOI: 10.1039/c4cc00621f
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Table 1 Synthesis of amides from various benzylamines and DMFa
unexpectedly, the corresponding amide 3aa was obtained in 38%
yield when benzylamine was treated with DMF. This indicated that
the base played a negative role in this transformation. Therefore a
variety of acids instead of base were added to the reaction mixture.
For instance, HCl, HNO3 and H2SO4 were added to the reaction
respectively (Table S1, ESI,† entries 8, 12, 13). As we expected, the
reaction yield was increased up to 54% when 0.5 mL of HCl (36 wt%
aqueous solution) were added into the reaction mixture. (Table S1,
ESI,† entry 8). Afterwards, different acids, such as HNO3 and H2SO4,
were screened in this reaction. However, the addition of other acids
did not give a higher yield. This indicated that HCl was the best acid
for this transformation. The optimization of the HCl addition
showed that the 0.1 mL of HCl is the best addition amount in our
reaction scale. Subsequently, the ratio of I2/TBHP/HCl was investi-
gated, as shown in Table S2 (ESI†). The reaction gave the highest
yield when 0.1 mL HCl was added to the reaction mixture in the
presence of 25 mol% iodine and 4 equiv. of TBHP (Table S1, ESI,†
entry 12). Addition of more HCl resulted in the decrease of the yield,
perhaps due to the partial decomposition of amide. It should be
noted that other oxidants, such as K2S2O8, H2O2, DTBP (ditertbutyl
peroxide), m-CPBA and DDQ, were also employed in the reaction.
No any improvement of this reaction was observed regardless of
the addition of inorganic or organic oxidants. The experimental
results indicated that only TBHP gave the highest reaction yield
(Table S1, ESI,† entries 15–19). Finally, the reaction temperature
was also optimized. Enhancing the reaction temperature can
promote the reaction while a reaction temperature beyond
80 1C would incur a lower yield due to the partial formation
of benzoic acid from benzaldehyde. Therefore the optimal
reaction temperature was 80 1C.
After the optimization, the best reaction conditions were
established as follows: I2 (25 mol%) as the catalyst, TBHP
(4 equivalents, 70% cyclohexane solution) as the oxidant,
DMF (1 mL) as both the nitrogen source and the solvent,
concentrated HCl (0.1 mL) as the additive and the reaction was
carried out at 80 1C for 18 h (Table 1). With the optimal reaction
conditions in hand, the generality of this direct amidation of aryl-
methylamine was investigated as shown in Table 1. The reaction
proceeded smoothly with different substrates to transform a wide
range of N,N-dimethyl-substituted amides in moderate to good yields.
It was found that the electronic properties of benzylamines had little
influence on the reaction (Table 1). For instance, either electron-
donating substituted (Table 1, entries 2, 3, 5) or electron-withdrawing
substituted benzylamines (Table 1, entries 6–8) afforded amides with
good to excellent yields. In contrast, the steric effects of substituents
had a great influence on the reaction. The reaction proceeded
efficiently when meta- and para-substituted benzylamines were
employed (Table 1, entries 2, 3, 5–8). However, ortho-substituents
had a negative effect on the transformation, which resulted in the
lower yields (Table 1, entries 4 and 9). It is worth noting that halo-
substituted benzylamines were well tolerated and the halo-
substituents survive the reaction (Table 1, entries 7–9). This provided
the chance for further transformations to various molecules. On the
other hand, the phenyl group in the benzylamine can be replaced by
other aryl group. For example, when the phenyl group was replaced by
Entry
R1
Product
Yieldb/%
1
2
3
4
5
6
7
8
C6H5
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
82
72
85
65
77
73
82
75
66
71
62
65
58
3-CH3C6H5
4-CH3C6H5
2-CH3OC6H5
4-CH3OC6H5
4-CF3C6H5
4-FC6H5
4-ClC6H5
2-BrC6H5
1-Naphthaly
2-Furyl
9
10
11
12
13
3ja
3ka
3la
2-Pyridyl
2-Thineyl
3ma
Reaction conditions. a Benzylamine (107.1 mg, 1 mmol), DMF (1 mL), I2
(63.5 mg, 0.25 mmol), TBHP (360 mg, 4 equiv., 70% cyclohexane
b
solution), at 80 1C for 18 h. Isolated yield.
yield (Table 1, entry 10). Similarly, heteroaryl methylamines can act as
the reaction substrate in this reaction to afford the corresponding
product with good yields (Table 1, entries 11–13).
To further establish the general utility of this transformation, we
examined the scope of N-substituted formamides. As shown in
Table 2, when other N-substituted formamides were employed, the
corresponding amides were also obtained in moderate to good
yields. For example, N,N-diethyl-formamides with 1a could give
corresponding N,N-diethyl-benzamide 3an in 75% yield. More
importantly, the challenging substrate N-methylformamide and
N-phenyl formamide worked well in the reaction to give the product
3ao and 3ap in a yield of 63% and 72% respectively (Table 2,
entries 2 and 3). Also, the piperidine benzylamide and morpholine
benzylamide can be easily obtained by this preparation with good
yields (Table 2, entries 4 and 5). Normally they are very important
intermediates in drug synthesis.
Next, we investigated the mechanism of the reaction. Firstly,
we wanted to figure out the function of the additive HCl. When
benzylamine was treated with DMF in the absence of HCl, only
38% amide 3aa was obtained. Nevertheless, the amide 3aa was
obtained in a yield of 85% when benzaldehyde was treated with
DMF in the absence of HCl (Scheme 2). Under the standard
Table 2 Reactions of benzylamine with N-substituted formamidesa
Entry
R1
R2
Product
Yieldb/%
1
2
3
4
5
Et
CH3
Ph
Piperidine
Morpholine
Et
H
H
—
—
3an
3ao
3ap
3aq
3ar
75
63
72
65
58
a
Benzylamine (107.1 mg, 1 mmol), N-substituted formamides (1 mL), I2
(63.5 mg, 0.25 mmol), TBHP (360 mg, 4 equiv., 70% cyclohexane
b
a naphthyl group, the corresponding amide 3ja was obtained in 71% solution), at 80 1C for 18 h. Isolated yield.
4086 | Chem. Commun., 2014, 50, 4085--4088
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Meanwhile, the aminyl radical 8a is generated from DMF with
the assistance of the generated tert-butoxyl radical,16 subsequent
cross-coupling of the benzoyl radical 7a with the aminyl radical
8a leads to formation of the corresponding amide 3aa.
In conclusion, the first oxidative coupling of aryl-methylamines
and N-substituted formamides has been developed. The reaction
was catalyzed by I2/TBHP via the two cleavages of the sp3 C–N bond
of aryl-methylamines and the sp2 C–N bond of N-substituted
formamides. This transition-metal-free protocol provides a novel
synthetic tool for the construction of N-substituted amides,
especially N,N-dimethyl-substituted amides. Further studies to
clearly understand the mechanism are ongoing in our laboratory.
We are grateful to the National Nature Science Foundation
of China (2127222, 91213303, 21172205, J1030412).
Scheme 2 Control experiments for the reaction mechanism.
Scheme 3 Control experiments for the reaction mechanism.
Notes and references
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Scheme 4 A proposed mechanism accounting for the formation of 3aa.
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