Syntheses of amides via iodine-catalyzed multiple sp3 C-H bonds oxidation of methylarenes and sequential coupling with N,N-dialkylformamides

Article abstract of DOI:10.1007/s11426-014-5098-7

The oxidative coupling of methylarenes and N,N-dialkylformamides was developed, and the appropriate reaction conditions were established. By using I₂ as the catalyst, and tert-butyl hydroperoxide (TBHP) as the oxidant, the reaction provided N,N

Full text of DOI:10.1007/s11426-014-5098-7

SCIENCE CHINA
Chemistry
August 2014 Vol.57 No.8: 1176–1182
doi: 10.1007/s11426-014-5098-7
• COMMUNICATIONS •
Syntheses of amides via iodine-catalyzed multiple sp3 C–H bonds
oxidation of methylarenes and sequential coupling with
N,N-dialkylformamides
DU BingNan1 & SUN PeiPei1,2*
1Jiangsu Key Laboratory of Biofunctional Materials, College of Chemistry and Materials Science, Nanjing Normal University,
Nanjing 210097, China
2Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Nanjing 210023, China
Received January 20, 2014; accepted February 10, 2014; published online June 17, 2014
The oxidative coupling of methylarenes and N,N-dialkylformamides was developed, and the appropriate reaction conditions
were established. By using I2 as the catalyst, and tert-butyl hydroperoxide (TBHP) as the oxidant, the reaction provided
N,N-dialkylamides or N-alkylamides with moderate yields via multiple sp3 C−H bonds activation of methylarenes in aqueous
and metal-free conditions.
oxidative coupling, iodine-catalyzed, methylarenes, amides
toxic solvents, harsh oxidants, expensive reagents, difficulty
1 Introduction
in preparing transition metal catalysts etc. Thus, to develop
synthetic routes, not only atom-economical but also low
cost and more environmentally friendly, becomes a big
challenge for the chemists.
Amide moiety widely exists in biomolecules, since it is es-
sential to sustain life, making up peptide bonds in proteins
[1]. It is also one of the most important functional groups in
a variety of drug molecules [2] and materials [3]. The most
common method for the synthesis of amides is the union of
carboxylic acids or their derivatives with amines [4]. In re-
cent years, increasing attention has been devoted to devel-
oping efficient methods for amide formation, among which
employing metal catalysis in amide syntheses creates the
possibility of applying substrates other than carboxylic ac-
ids [5]. For example, the oxidative coupling of aldehydes,
alcohols and related compounds with nitrogenous com-
pounds by the catalysis of transition-metals such as Rh [6],
Ru [7], Cu [8], Fe [9] and Mn [10]. Ru-catalyzed reaction of
nitriles with alcohols [11], as well as Ir or Ru-catalyzed
rearrangement of oximes [12] were also developed for am-
ide formation. Nevertheless, many of these methods involve
Recently, a series of metal-free approaches for the for-
mation of amides were developed. For example, the
nBu4NI-catalyzed oxidative coupling of aldehydes with
formamides [13], nBu4NI [14] or I2 [15] -catalyzed oxidative
n
coupling of alcohols with formamides. A Bu4NI-catalyzed
oxidative coupling of aryl methyl ketones with formamides
[16], as well as a I2-catalyzed oxidative coupling of aryl
methyl ketones with secondary amines [17] were also re-
ported for the synthesis of α-ketoamides. We have been
continuously interested in the functionalization of inert C−H
bond. In our previous work, by using methylarenes as the
acylation reagents, the palladium catalyzed chelation-
assisted acylation of sp2 C−H bond was developed [18].
These results promoted us to employ the unprefunctional-
ized methylarene as the acyl source to form C−N bond.
Herein, we present the iodine-catalyzed sequential C−O and
Dedicated to Professor Qian Changtao on the occasion of his 80th birthday.
*Corresponding author (email: sunpeipei@njnu.edu.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2014
chem.scichina.com link.springer.com

Du BN, et al. Sci China Chem August (2014) Vol.57 No.8
1177
C−N bond formation via multiple sp3 C−H bond activation
of easily available and inexpensive methylarenes, providing
an efficient approach to arylamides.
168.4, 136.4, 130.3, 130.1, 129.5, 127.7, 127.2, 38.0, 34.6.
1
3-Chloro-N,N-dimethylbenzamide (3ea) [15]: H NMR
(400 MHz, CDCl3) δ 7.41–7.29 (m, 4H), 3.11 (s, 3H), 2.98
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.0, 138.0,
134.42, 129.8, 129.6, 127.2, 125.1, 39.5, 35.4.
1
2 Experimental
4-Chloro-N,N-dimethylbenzamide (3fa) [15]: H NMR
(400 MHz, CDCl3) δ 7.40–7.35 (m, 4H), 3.10 (s, 3H), 2.97
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.5, 135.6, 134.7,
130.9, 128.6, 39.5, 35.4.
2.1 General information
1
All reactions were run in a sealed tube with a Teflon lined
cap under air atmosphere. All chemical reagents and sol-
vents were purchased from Aldrich, Alfa Aesar and Si-
nopharm chemical reagent Co. Ltd., and were used without
4-Cyano-N,N-dimethylbenzamide (3ga) [15]: H NMR
(400 MHz, CDCl3) δ 7.90 (d, J = 6.8 Hz, 2H), 7.49 (d, J =
6.8 Hz, 2H), 3.12 (s, 3H), 2.96 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 190.3, 166.5, 141.3, 131.5, 131.0, 129.4, 37.0,
34.1.
1
further purification. H NMR (400 MHz) and 13C NMR
1
(100 MHz) spectra were recorded on a Bruker Avance 400
Methyl 4-(dimethylcarbamoyl)benzoate (3ha) [13]: H
1
spectrometers in CDCl3 (using (CH3)4Si (for H, δ = 0.00;
NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.0 Hz, 2H), 7.50 (d,
J = 8.0 Hz, 2H), 3.96 (s, 3H) 3.15 (s, 3H), 2.98 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 170.6, 166.4, 140.7, 131.0,
129.7, 127.0, 52.3, 39.4, 35.3.
for 13C, δ = 77.00) as internal standard). The following ab-
breviations were used to explain the multiplicities: s = sin-
glet, d = doublet, t = triplet, q = quartet, m = multiplet.
1
3-Methoxy-N,N-dimethylbenzamide (3ia) [14]: H NMR
2.2 General experimental procedures and characteri-
zations
(400 MHz, CDCl3) δ 7.33–7.29(m, 1H), 6.98–6.93 (m, 3H),
3.83 (s, 3H), 3.11 (s, 3H), 2.98 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 171.4, 159.5, 137.7, 129.4, 119.1, 115.4, 112.4,
55.3, 39.5, 35.3.
Toluene derivatives 1 (1.0 mmol), I2 (0.2 mmol), TBHP (3.0
mmol), NaOH (0.4 mmol) and H2O (1 mL) were added in a
25 mL sealed tube with a Teflon lined cap. Then
N,N-dialkylformamides 2 (6.0 mmol) and TBHP (5.0 mmol)
were added in batches. The mixture was stirred in an oil
bath at 80 oC. After 20 h, the reaction mixture was cooled to
room temperature, and diluted with water, then extracted
with ethyl acetate (15 mL × 3). The combined organic layer
was washed with water and dried with anhydrous Na2SO4,
the solvent was then removed under vacuum. The residue
was purified by flash column chromatography on silica gel
using hexane/ethyl acetate as eluent to give the correspond-
ing product.
3,4-Dichloro-N,N-dimethylbenzamide (3ja) [19]: 1H
NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.49 (d, J = 8.4 Hz,
1H), 7.26 (d, J = 8.4 Hz, 1H), 3.10 (s, 3H), 2.99 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 169.1, 136.1, 133.9, 132.8,
130.5, 129.3, 126.4, 39.5, 35.4.
N,N,3-trimethylbenzamide (3ka) [15]: 1H NMR (400
MHz, CDCl3) δ 7.26–7.17 (m, 4H), 3.09 (s, 3H), 2.96 (s,
3H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.8,
138.2, 136.3, 130.2, 128.1, 127.6, 123.9, 39.6, 35.3, 21.3.
N,N,4-trimethylbenzamide (3la) [15]: 1H NMR (400
MHz, CDCl3) δ 7.32 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz,
2H), 3.05 (s, 6H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 171.8, 139.6, 133.3, 128.9, 127.2, 39.7, 35.4, 21.4.
N,N,3,5-tetramethylbenzamide (3ma) [20]: 1H NMR
(400 MHz, CDCl3) δ 7.03 (s, 1H), 7.01 (s, 2H), 3.10 (s, 3H),
2.97 (s, 3H), 2.33 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
172.0, 137.9, 136.3, 131.0, 124.6, 39.6, 35.2, 21.2.
1
All products are known compounds. The H NMR and
13C NMR spectra can be seen in the Supporting Information
online. The 1H NMR and 13C NMR data are shown below:
N,N-dimethylbenzamide (3aa) [15]: 1H NMR (400 MHz,
CDCl3) δ 7.41–7.28 (m, 5H), 3.08 (s, 3H), 2.91 (s, 3H); 13
C
1
NMR (100 MHz, CDCl3) δ 171.6, 136.4, 129.5, 128.3,
N,N-diethylbenzamide (3ab) [15]: H NMR (400 MHz,
127.0, 39.6, 35.3.
CDCl3) δ 7.40–7.34 (m, 5H), 3.55 (s, 2H), 3.26 (s, 2H),
1.27–1.24 (m, 3H), 1.21–1.11 (m,3H); 13C NMR (100 MHz,
CDCl3) δ 171.3, 137.3, 129.1, 128.4, 126.3, 43.3, 39.2, 14.2,
12.9.
1
4-Fluoro-N,N-dimethylbenzamide (3ba) [15]: H NMR
(400 MHz, CDCl3) δ 7.45–7.41 (m, 2H), 7.11–7.06 (m, 2H),
3.10 (s, 3H), 2.99 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
170.7, 164.5, 162.0, 132.3, 132.2, 129.4, 129.3, 115.5,
115.3, 58.3, 39.6, 35.9.
1
Phenyl(piperidin-1-yl)methanone (3ac) [15]: H NMR
(400 MHz, CDCl3) δ 7.40 (m, 5H), 3.72 (s, 2H), 3.34 (s,
2H), 1.68 (s, 4H), 1.53 (s, 2H); 13C NMR (100 MHz, CDCl3)
δ 170.3, 136.5, 129.3, 128.4, 126.8, 48.7, 43.1, 26.4, 25.6,
24.6.
1
4-Bromo-N,N-dimethylbenzamide (3ca) [15]: H NMR
(400 MHz, CDCl3) δ 7.53 (d, J = 8.8 Hz, 2H), 7.29 (d, J =
8.8 Hz, 2H), 3.08 (s, 3H), 2.96 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 170.5, 135.1, 131. 6, 128.8, 123.8, 39.5, 35.4.
1
4-Benzoylmorpholine (3ad) [15]: H NMR (400 MHz,
1
2-Chloro-N,N-dimethylbenzamide (3da) [14]: H NMR
CDCl3) δ 7.45–7.40 (m, 5H), 3.76–3.66 (m, 6H), 3.53–3.47
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 170.5, 135.3, 129.9,
128.6, 127.1, 66.9, 48.2, 42.6.
(400 MHz, CDCl3) δ 7.39–7.36 (m, 1H), 7.31–7.27 (m, 3H),
3.12 (s, 3H), 2.84 (s, 3H); 13C NMR (100 MHz, CDCl3) δ

1178
Du BN, et al. Sci China Chem August (2014) Vol.57 No.8
1
1-(4-Cyanobenzoyl)piperidine (3gc) [8b]: H NMR (400
reaction gave a yield of 58% in a reaction time of 20 h (Ta-
ble 1, entry 7), while others were inefficient (entries 9 and
10). Catalyst was also important for the reaction. Without a
catalyst, the reaction could not proceed. Iodine and some
MHz, CDCl3) δ 7.91 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz,
2H), 3.73–3.70 (m, 2H), 3.31–3.28 (m, 2H), 1.72–1.70 (m,
4H), 1.58–1.55 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
190.6, 164.9, 141.3, 131.7, 130.9, 129.4, 47.1, 42.3, 26.3,
25.5, 24.4.
n
iodides such as Bu4NI, KI, NaI, CuI and PhI(OAc)2 were
tested for this reaction (entries 1–7), in which iodine
showed the highest catalytic activity. Further studies indi-
cated that 20 mol% of I2 was optimal for the reaction, as
there was no significant increase with the yield when 40
mol% of I2 was used (entry 16). The presence of base also
seemed to be essential. Adding 0.4 equiv. NaOH to the reac-
tion mixture could promote this transformation, while other
bases such as KOH, NaOAc and Na2CO3 turned out to be
inferior (entries 12–14). The assessment of the reaction
conditions also indicated that the appropriate reaction tem-
perature was 80 °C. The yield had no significant change
when the reaction temperature was elevated to 90 °C, but
lowering the temperature to 60 °C resulted in a poor yield of
25%. It should be pointed out that the reaction was con-
ducted in water. Organic solvents, like 1,2-dichloroethane
and CHCl3, led to decrease of the yields (entries 17 and 18).
As for the scope of this I2-TBHP catalyzed oxidative
coupling reaction, we explored the reaction of various tolu-
ene derivatives (1a–m) with N,N-dialkylformamide (2a–d)
under the established conditions (Table 2). At the beginning
of our investigation, DMF was chosen as the amino source
for this reaction. For most toluene derivatives, with either
4-Chloro-N-isopropylbenzamide (3fe) [21]: 1H NMR
(400 MHz, CDCl3) δ 7.70 (d, J = 8.4 Hz, 2H), 7.38 (d, J =
8.4 Hz, 2H), 6.06 (br, 1H), 4.31–4.23 (m, 1H), 1.26 (d, J =
6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 165.7, 137.4,
133.3, 128.7, 128.3, 42.0, 22.8, 22.3.
4-Bromo-N-isopropylbenzamide (3ce) [22]: 1H NMR
(400 MHz, CDCl3) δ 7.63 (d, J = 8.8 Hz, 2H), 7.55 (d, J =
8.8 Hz, 2H), 6.02 (br, 1H), 4.32–4.23 (m, 1H), 1.27 (d, J =
6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 165.7, 133.8,
131.7, 128.5, 125.9, 42.1, 22.8, 22.3.
3 Results and discussion
We initiated our studies with the oxidative coupling of tol-
uene (1a) with N,N-dimethylfomamide (2a) in the presence
of an oxidant using iodine or iodide as the catalyst. The re-
sults are assembled in Table 1. The oxidant proved to be
very important for this reaction. Among three oxidants
TBHP, DTBP (di-tert-butylperoxide) and K2S2O8, TBHP
was effective, and in the presence of 8 equiv. TBHP, the
Table 1 Optimization of the reaction conditions a)
Entry
1
Catalyst (mol%)
nBu4NI (20)
KI (20)
NaI (20)
CuI (20)
PhI(OAc)2 (20)

Oxidant (equiv.)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (6)
K2S2O8 (8)
DTBP (8)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
Base (equiv.)
NaOH (0.4)
NaOH (0.4)
NaOH (0.4)
NaOH (0.4)
NaOH (0.4)
NaOH (0.4)
NaOH (0.4)
NaOH (0.4)
NaOH (0.4)
NaOH (0.4)
NaOH (0.2)
KOH (0.4)
Yield (%)
38
2
32
3
35
4
< 10
< 10
trace
58
5
6
7
I2 (20)
8
I2 (20)
48
9
I2 (20)
trace
trace
48
10
11
12
13
14
15
16
17 b)
18 c)
I2 (20)
I2 (20)
I2 (20)
52
I2 (20)
NaOAc (0.4)
Na2CO3 (0.4)
NaOH (0.4)
NaOH (0.4)
NaOH (0.4)
NaOH (0.4)
38
I2 (20)
43
I2 (10)
35
I2 (40)
56
I2 (20)
42
I2 (20)
< 10
a) Unless otherwise specified, all the reactions were carried out in a sealed tube in the presence of toluene (1a, 1 mmol), N,N-dimethylfomamide (2a, 6
mmol), catalyst, oxidant and base in H2O (1 mL) under air atmosphere at 80 °C for 20 h. The yield is isolated one based on 1a. b) In 1,2-dichloroethane; c) In
CHCl3.

Du BN, et al. Sci China Chem August (2014) Vol.57 No.8
Table 2 I2-TBHP catalyzed synthesis of amides a)
1179
Entry
1
Substrate 1
Substrate 2
Product
O
Yield (%)
58
N
O
1a
3aa
N
2
3
4
5
6
57
62
56
60
63
F
1b
F
3ba
O
N
Br
1c
Br
3ca
Cl
Cl
O
N
3da
1d
O
O
Cl
Cl
N
1e
1f
3ea
3fa
3ga
N
Cl
O
N
7
8
9
55
43
NC
O
1g
NC
O
O
N
O
1h
O
3ha
O
O
O
N
37
61
1i
3ia
O
Cl
Cl
Cl
N
10
11
12
1j
Cl
3ja
O
N
55
52
1k
3ka
3la
O
N
1l
O
N
13
40
1m
3ma
(To be continued on the next page)

1180
Du BN, et al. Sci China Chem August (2014) Vol.57 No.8
(Continued)
Entry
Substrate 1
Substrate 2
Product
O
Yield (%)
53
N
14
15
1a
3ab
O
N
60
56
61
1a
1a
3ac
O
N
16
17
O
3ad
O
N
NC
1g
NC
3gc
a) All the reactions were carried out in a sealed tube in the presence of toluene derivatives (1, 1 mmol), N,N-dialkylfomamide (2, 6 mmol), I2 (0.2 mmol),
TBHP (8 equiv.) and NaOH (0.4 equiv.) in H2O (1 mL) under air atmosphere at 80 °C for 20 h. The yield is isolated one based on 1.
electron-withdrawing or electron-donating substitution, the
reaction gave the corresponding products in moderate yields
within a reaction time of 20 h. The tolerance to the chemi-
cally active functional groups was also studied. Halogen (F,
Cl, Br), ester and cyano group on benzene ring of toluene
were well tolerated for this reaction (entries 2–8, Table 2),
and the substituent pattern on the benzene ring had no sig-
nificant influence on the reaction. Interestingly, toluene
derivatives with more than one methyl group such as
m-xylene, p-xylene, and 1,3,5-trimethylbenzene, the reac-
tion took place on one methyl group and the others re-
mained to be untouched (entries 11–13). However, when
excessive amounts of TBHP (12 equiv.), and DMF (10 equiv.)
were applied, the reaction mixture turned to be quite com-
plicated. Next we employed a series of N,N-dialkylforma-
mides, including cyclic and acyclic formamides (2b–d), as
the coupling partner, the results were quite similar to the
reaction with DMF (entries 14–17).
To our surprise, when N,N-diisopropylformamide was
used as the amino source, instead of the general product
N,N-diisopropylarylamide, a N-isopropylarylamide was
generated (Scheme 1). Though the exact mechanism is un-
clear, we presume that it may be related to the steric hin-
drance of isopropyl. Meantime, it also indicated that the
cleavage of alkyl C–N bond was possible in this I2-TBHP
catalytic system.
To study the mechanism of this reaction, 1 mmol
2,2,6,6-tetramethyl piperidine-N-oxyl (TEMPO, a radical
scavenger) was added to the reaction system of 1a and 2a,
and no desired product was detected. This result revealed
that the reaction might go through a radical pathway. In
addition, the replacement of DMF with dimethylamine led
to no corresponding oxidative coupling product 3aa, which
implied that dimethylamine was not the reaction intermedi-
ate (Scheme 2).
In our previous report, the partial oxidation of toluene by
TBHP to benzaldehyde was observed [18b]. In addition, the
decarbonylation of DMF has been well-documented [23]. A
13C-isotope labeling experiment by Wan further proved that
the cleavage of C–N bond of DMF was possible in the
TBHP system, giving N,N-dimethylamino radical [13].
Based on our experimental results and the related reports
[13–15, 23], a plausible catalytic mechanism is presented in
Scheme 3. Initially, TBHP decomposed to a tbutoxyl radical
and a hydroxyl anion catalyzed by I2. After toluene (1a) was
partially oxidized to benzaldehyde under the oxidative con-
t
ditions, butoxyl radical abstracted hydrogen from the
Scheme 1 Formation of N-isopropylarylamide.
Scheme 2 The control experiments.

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Scheme 3 Plausible reaction mechanism.
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In summary, we developed a convenient method for the
synthesis of amides from the low toxic, inexpensive, stable
and commercially available substrates toluene and its deriv-
atives. The reaction was conducted in aqueous media and
metal-free conditions. To the best of our knowledge, this
represents the first example to form C−O and C−N bond
sequentially via multiple inert sp3 C−H bonds activation.
This work was supported by the National Natural Science Foundation of
China (21272117, 20972068) and the Priority Academic Program Devel-
opment of Jiangsu Higher Education Institutions.
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SUN PeiPei obtained his BSc from Anhui University in 1985 and a MSc from East China Normal
University in 1994. After obtaining a PhD from Hangzhou University in 1997, he joined the faculty
of Nanjing Normal University as an associate professor of chemistry. He has ever been as a visiting
scholar and as a postdoctoral fellow at Shanghai Institute of Organic Chemistry, the Chinese Acad-
emy of Sciences, Tsing Hua University (Hsinchu, Taiwan, China) and Nanjing University, respec-
tively. He became a full professor at Nanjing Normal University in 2005. His research interests in-
clude organometallic chemistry, organic synthetic methodology and organic materials.