Direct oxidative amidation between methylarenes and amines in water

Article abstract of DOI:10.1039/c5gc00299k

An environmentally friendly direct oxidative amidation between methylarenes and free amines was developed. The aromatic amide could be prepared efficiently from raw chemicals by employing TBHP as a "green" oxidant with co-catalysis of TBAI and FeCl₃ in water.

Full text of DOI:10.1039/c5gc00299k

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Direct Oxidative Amidation between Methylarenes
and Amines in Water
Cite this: DOI: 10.1039/x0xx00000x
Tao Wang,a,b Lin Yuan,b Zhenguang Zhao,b Ailong Shao,b Meng Gao,a,b Yangfei
Huang,b Fei Xiong,a,b Huali Zhang,b and Junfeng Zhao*, a,b
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
issues. Benefited from the studies on benzylic sp3 C-H activation,8
An environmental friendly direct oxidative amidation
between methylarenes and free amines was developed. The
aromatic amide could be prepared efficiently from raw
chemicals by employing TBHP as the “green” oxidant with
toluene and other methylarenes have also been used as acyl donors
for oxidative amidations.9 Mizuno et al. reported an oxidative
amidation of methylarenes for the synthesis of aromatic primary
amides by using aqueous ammonia or its surrogates as the nitrogen
source (Scheme 1 a).9a Very recently, this concept had been
extended to the synthesis of secondary and tertiary amides by
employing activated amine surrogates such as N-chloroamine
(Scheme 1 b)9b and N,N-dimethylformamide (Scheme 1 c)9c,9d as the
nitrogen source. Regarding the cheap raw chemicals such as toluene
used as starting materials in these pioneer work, they would be more
attractive for chemical industry. However, the reaction conditions for
oxidative amidation of methyarenes are always rigorous and the
substrate scope and functional group tolerance are limited.
Moreover, prior activated amine surrogates10 are necessary to attain
satisfied results and thus resulting more synthetic steps and chemical
waste. Concerning atom-, step-economical and environmental issues,
non-modified amine would be ideal starting material for amide bond
formation. We herein reported a highly efficient direct oxidative
amidation between methylarenes and free amines which was
accomplished in water by employing tert-butyl hydroperoxide
(TBHP) as the environmental benign oxidant with the co-catalysis of
tetrabutyl-ammonium iodide (TBAI) and FeCl3 (Scheme 1 d).
the co-catalysis of TBAI and FeCl3 in water
.
Amide is an important functional group in nature due to its
ubiquitous in proteins, pharmaceutical compounds, functional
materials and other synthetic chemicals.1 Chemical reactions for
amide formation are among the most executed transformations in
organic chemistry.2 However, traditional chemical synthesis of
amide always employs prior activated carboxyl component or
coupling reagents and excess of reactants which resulted high cost
and large amount of chemical waste.3 ‘Amide formation avoiding
poor atom economy reagents’ was recognized as one of the top
challenge for organic chemistry and green chemistry.4 Consequently,
amide bond formation beyond traditional
We initiated this project by screening oxidants in CH3CN in the
presence of 30 mol% of TBAI at 100 ℃ . Unfortunately, no
significant amount of amide was detected when 30% H2O2 solution,
di-t-butyl peroxide (DTBP) and m-chloroperbenzoic acid (m-CPBA)
were used as oxidant (See supporting information). Interestingly,
amide bond formation was detected albeit with low yield when
TBHP (6 equiv)11 was employed as oxidant (Table 1, entry 1).
Among the screened catalysts, TBAI was identified to be the best
one (For details, see supporting information). TBHP in water
provide higher yield than that of pure TBHP (Table 1, entry 2). This
result hinted that water may has some effects on this reaction. To our
delight, the yield improved significantly when the reaction was
performed in water (Table 1, entry 7). Next, other factors such as
additive and temperature were also evaluated. The yield can be
further improved with the presence of 15 mol% FeCl3·6H2O (Table
1, entry 8). The 4 Å molecular sieves is
Scheme 1 Oxidative amidation of methylarenes.
coupling strategy emerged as attractive alternatives for preparation
of amide in recent years.5 Especially the direct oxidative amidation
between aldehydes6 or alcohols7 and amine has attracted much
attention because of the atom economic and environmental benign
Table 1. Optimization of reaction conditionsa
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benzene were used as the starting materials (3b-3e). Notably, the
reaction of heterocyclic methylarene, such as methyl thiophene also
went smoothly to provide the amide in moderate yields (3m, 3n).
entry
1c
2d
3
solvent
CH3CN
CH3CN
DMSO
DMF
additive
Yieldb
29
36
2
-
-
-
4
-
3
5
DCE
-
27
25
47
64
6
PhMe
H2O
-
7
-
8
H2O
FeCl3·6H2O (15 mol%)
9
10e
H2O
67
FeCl3·6H2O (15 mol%), 4 Å MS
FeCl3·6H2O (15 mol%), 4 Å MS
H2O
73
a 1a (5 mmol), 2a (0.24 mmol), solvent (1.5 mL), 24 h. b Isolated yield. c Pure
TBHP (6 equiv). d TBHP 70 wt % in water (6 equiv). e This reaction was
carried out at 60 ℃. MS = molecular sieves.
also helpful for this reaction (Table 1, entry 9). Interestingly, the
yield was furhter increased a little when the reaction was carried out
at 60 ℃. Finally, the highest yield up to 73% was obtained when the
reaction was carried out at 60 ℃ in water with the presence of 6
equivalent of TBHP, 30 mol% of TBAI, 15 mol% of FeCl3·6H2O
and 4 Å molecular sieves (Table 1, entry 10).
Scheme 3 Scope of the reaction with amines 2. Reaction conditions: 1f (5 mmol),
amines 2 (0.24 mmol), water (1.5 mL), TBHP 70 wt % in water (6 equiv), TBAI
a
(30 mol%), FeCl3•6H2O (15 mol%), 4 Å MS (100 mg), 60 ℃, 24 h. Without
FeCl3•6H2O. b Replaced FeCl3•6H2O (15 mol%) with CaCO3 (15 mol%).
Next, the generality of the amine part also had been tested and the
result was listed in scheme 3. Most of the tested amines work well
for this reaction. In terms of linear aliphatic amines, the reaction
efficiency is slightly influenced by the length of the chain. Not only
the linear amines but also amines with branch chains are good
substrates for this transformation. For example, the α-tertiary carbon
can be tolerated and good yields were obtained (4i-4k).
Significantly, even the amine containing a quaternary carbon went
smoothly to provide amide in satisfied yield (4l). Notably, the
reaction scope can be expanded to the salt of N-terminal free peptide
as well as amino ester (4m-4o). Importantly, no racemization was
detected in the oxidative amidation of chiral α-amino ester. 15 mol%
of CaCO3 instead of FeCl3·6H2O was used for the amidation of
amine salt.
Scheme 2 Scope of the reaction with methylarenes 1. Reaction conditions:
methylarene (5 mmol), 2a (0.24 mmol), water (1.5 mL), TBHP 70 wt % in water
(6 equiv), TBAI (30 mol%), FeCl3•6H2O (15 mol%), 4 Å MS (100 mg), 60 ℃, 24
h.
With this optimized reaction conditions in hand, we next studied
the substrate scope of this reaction. A variety of methylarenes were
examined and the result was shown in Scheme 2. Both electron-
donating and weak electron-withdrawing groups are compatible for
this reaction. Generally, methylarenes containing electron-donating
groups offer better yields than those containing electon-withdrawing
ones. While slightly decreased yield was observed, the sterically
demanding ortho-xylene works well for this transformation (3c).
Excellent chemo-selectivity was obtained and no bi or tri amide was
detected when ortho-, para-, meta-xylene and 1, 3, 5-tri-methyl
Scheme 4 Reaction conditions: methylarene (5 mmol), 5 (0.24 mmol), water (1.5
mL), TBHP 70 wt % in water (6 equiv), TBAI (30 mol%), FeCl3•6H2O (15
mol%), 4 Å MS (100 mg), 60 ℃, 24 h.
With the success on primary amines, we go further to test the
oxidative amidation of secondary amines. However, the target
tertiary amide was obtained in poor yield accompanied by some
secondary amide which resulted from a C-N bond cleavage.
Interestingly, unlike common secondary amines, morpholine do
2 | J. Name., 2012, 00, 1-3
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indeed offer good yield of the target products efficiently. A series of
methylarenes were tested and most of them worked well for this
reaction (Scheme 4). Electronic effect of substituent has little
influence on the reaction efficiency. No matter electron-withdrawing,
neutral or –donating groups present on the phenyl ring, the
corresponding tertiary amides were obtained in good yields. Steric
effect of ortho methyl group resulted slight decrease of the yield
(6b). The amidation of methyl thiophene also proceeded smoothly to
give the corresponding amides in high yields (6h, 6i).
pathways had ever been proposed to rationalize oxidative amidation
of benzaldehyde (Scheme 6). Li et al. proposed that the oxidative
amidation of aldehyde might go through the hemiaminal
intermediate, which can be further oxidized to amide (Path A).6a On
the other hand, very recently, acyl radical was proposed as the key
intermediate for the oxidative amidation of aldehyde6c,6d and its
analogues.5h Lei and Lan’s DFT calculation illustrated that
nucleophilic attack of primary amine toward acyl radical followed
by a single electron transfer oxidation and release of proton will also
afford the amide (Path B).5h According to our experimental results,
pathway A is more reasonable while pathway B is unlikely involved.
In summary, we have developed an environmental friendly direct
oxidative amidation of methylarenes and free amines in water.
Unlike the traditional amide formation strategies, which involving
expensive coupling reagents, pre-activated carboxylate derivatives or
activated amine surrogates, this protocol employed cheap raw
chemicals such as methylarenes and free amines as the starting
material to produce high value amides. In addition, water was used
as the solvent avoiding using of other organic solvent. With TBHP
as the “green” oxidant and cheap, low toxic TBAI and FeCl3·6H2O
as the catalysts, this protocol would be more attractive for
pharmaceuticals and other fine chemical synthesis.
Scheme 5 Mechanistic studies and control experiments
To understand the reaction mechanism, some control experiments
were carried out (Scheme 5). Benzyl alcohol and benzaldehyde
would be intermediates (both of them had been detected as side
products in the reaction) for this transformation because quantitative
yield of N-butylbenzamide 3a was obtained when either of them was
employed as acyl donor under the optimized reaction conditions
(Scheme 5 a, b).
This work is supported by the National Natural Science
Foundation of China (21462023, 21262018) and the Natural Science
Foundation
of
Jiangxi
Province
(20143ACB20007,
20133ACB20008).
Notes and references
a National Research Center for Carbohydrate Synthesis and Key Laboratory
of Chemical Biology, Jiangxi Province, Nanchang 330022, Jiangxi, P. R.
China
b
College of Chemistry and Chemical Engineering, Jiangxi Normal
University, Nanchang, 330022, Jiangxi, P. R. China
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/c000000x/
1
(a) R. Larock, VCH Publishers, New York, Weinheim, 1999; (b) J. M.
Humphrey and A. R. Chamberlin, Chem. Rev., 1997, 97, 2243; (c) A.
Greenberg, C. M. Breneman and J. F. Liebman, The Amide Linkage:
Structural Significance in Chemistry, Biochemistry, and Materials
Science, John Wiley & Sons, 2000; (d) J. Zabicky, Chemistry of Amides,
Wiley-Interscience, New York, 1970.
2
(a) V. R. Pattabiraman and J. W. Bode, Nature, 2011, 480, 471; (b) C. P.
R. Hackenberger and D. Schwarzer, Angew. Chem. Int. Ed., 2008, 47,
10030; (c) E. Valeur and M. Bradley, Chem. Soc. Rev., 2009, 38, 606.
I. Coin, M. Beyermann and M. Bienert, Nat. Protocols, 2007, 2, 3247.
D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey, J. J. L.
Leazer, R. J. Linderman, K. Lorenz, J. Manley, B. A. Pearlman, A.
Wells, A. Zaks and T. Y. Zhang, Green Chem., 2007, 9, 411.
(a) C. Gunanathan, Y. Ben-David and D. Milstein, Science, 2007, 317,
790; (b) D. I. Enache, J. K. Edwards, P. Landon, B. Solsona-Espriu, A.
F. Carley, A. A. Herzing, M. Watanabe, C. J. Kiely, D. W. Knight and G.
J. Hutchings, Science, 2006, 311, 362; (c) B. Shen, D. M. Makley and J.
Scheme 6 Proposed mechanism
TEMPO (2 equiv) was added to the reaction system with an attempt
to probe whether radical was involved in this process (Scheme 5).
However, unlike literatures,5h,6d no acyl radical was trapped in all of
our control experiments (Scheme 5 a, b and c). Interestingly, in the
presence of TEMPO, the reaction of toluene and benzyl alcohol was
completely inhibited while the reaction of benzaldehyde was kept
intact (Scheme 5). This result suggested that the oxidation of toluene
and benzyl alcohol might involve radical process. In addition,
control experiments disclosed that FeCl3 might play an important
role in the oxidation of toluene and benzyl alcohol. Recent studies
demonstrated that hypervalent iodine species such as hypoiodite (IO-
3
4
5
N. Johnston, Nature, 2010, 465, 1027; (d)
J. W. Bode, R. M.
Fox and K. D. Baucom, Angew. Chem. Int. Ed., 2006, 45, 1248; (e) A.
M. Dumas, G. A. Molander and J. W. Bode, Angew. Chem. Int. Ed.,
2012, 51, 5683; (f) C. Singh, V. Kumar, U. Sharma, N. Kumar and B.
Singh, Curr. Org. Synth., 2013, 10, 241; (g) W. Li, C. Liu, H. Zhang, K.
Ye, G. Zhang, W. Zhang, Z. Duan, S. You and A. Lei, Angew. Chem.
Int. Edit., 2014, 53, 2443; (h) J. Liu, Q. Liu, H. Yi, C. Qin, R. Bai, X.
Qi, Y. Lan and A. Lei, Angew. Chem. Int. Edit., 2014, 53, 502; (i) J.
Wang, C. Liu, J. Yuan and A. Lei, Chem. Commun., 2014, 50, 4736; (j)
R. García-Álvarez, P. Crochet and V. Cadierno, Green Chem., 2013, 15,
46; (k) R. V. Kolakowski, N. Shangguan, R. R. Sauers and L. J.
-
) or iodite (IO2 ) should be the real oxidant for TBHP/TBAI
system.11,12 Based on our experimental results and literatures, we
proposed that toluene was oxidized to benzyl alcohol by IO- or IO2
-
with the assistance of FeCl3.13 Further oxidation of benzyl alcohol
will offer the key intermediate benzaldehyde. Two different
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Williams, J. Am. Chem. Soc., 2006, 128, 5695.
6
(a) W.-J. Yoo and C.-J. Li, J. Am. Chem. Soc., 2006, 128, 13064; (b) K.
R. Reddy, C. U. Maheswari, M. Venkateshwar and M. L. Kantam, Eur.
J. Org. Chem., 2008, 2008, 3619; (c) B. Tan, N. Toda and C. F. Barbas,
Angew. Chem. Int. Ed., 2012, 51, 12538; (d) Z. Liu, J. Zhang, S. Chen,
E. Shi, Y. Xu and X. Wan, Angew. Chem. Int. Ed., 2012, 51, 3231; (e)
K. Ekoue-Kovi and C. Wolf, Org. Lett., 2007, 9, 3429; (f) J.-J. Shie and
J.-M. Fang, J. Org. Chem., 2002, 68, 1158.
7
8
7(a) X.-F. Wu, M. Sharif, A. Pews-Davtyan, P. Langer, K. Ayub and M.
Beller, Eur. J. Org. Chem., 2013, 2783; (b) Y. Wang, D. P. Zhu, L. Tang,
S. J. Wang and Z. Y. Wang, Angew. Chem. Int. Edit., 2011, 50, 8917; (c)
J.-F. Soulé, H. Miyamura and S. Kobayashi, J. Am. Chem. Soc., 2011,
133, 18550; (d) K. Yamaguchi, H. Kobayashi, T. Oishi and N. Mizuno,
Angew. Chem. Int. Ed., 2012, 51, 544.
(a) S. Guin, S. K. Rout, A. Banerjee, S. Nandi and B. K. Patel, Org.
Lett., 2012, 14, 5294; (b) G. Majji, S. Guin, A. Gogoi, S. K. Rout and
B. K. Patel, Chem. Commun., 2013, 49, 3031; (c) S. K. Rout, S. Guin,
A. Banerjee, N. Khatun, A. Gogoi and B. K. Patel, Org. Lett., 2013, 15,
4106; (d) D. L. Priebbenow and C. Bolm, Org. Lett., 2014, 16, 1650; (e)
S. K. Rout, S. Guin, W. Ali, A. Gogoi and B. K. Patel, Org. Lett., 2014,
16, 3086; (f) C. Liu, J. Wang, L. Meng, Y. Deng, Y. Li and A. Lei,
Angew. Chem. Int. Ed., 2011, 50, 5144.
9
(a) Y. Wang, K. Yamaguchi and N. Mizuno, Angew. Chem. Int. Ed.,
2012, 51, 7250; (b) R. Vanjari, T. Guntreddi and K. N. Singh, Org. Lett.,
2013, 15, 4908; (c) J.-B. Feng, D. Wei, J.-L. Gong, X. Qi and X.-F. Wu,
Tetrahedron Lett., 2014, 55, 5082; (d) B. Du and P. Sun, Sci. China
Chem., 2014, 57, 1176; (e) Y. R. Kim, S. Cho and P. H. Lee, Org. Lett.,
2014, 16, 3098.
10 After this manuscript was submitted, we noticed that Heydari and co-
workers reported an elegant oxidative amidation of methylarenes by
using amine salts as nitrogen source with KI/TBHP as the oxidant
system. However, only trace amout of amide was obtained when free
amine was employed in their reaction system. K. Azizi, M. Karimi and
A. Heydari, RSC Advances, 2014, 4, 31817.
11 For review of application of TBHP/TBAI oxidation system, see: (a) X.-
F. Wu, J.-L. Gong and X. Qi, Org. Biomol. Chem., 2014, 12, 5807; (b)
D.
Liu
and
A.
Lei,
Chem. Asian J., 2015, DOI: 10.1002
/asia.201403248; (c) M. Uyanik and K. Ishihara, ChemCatChem, 2012,
4, 177.
12 (a) M. Uyanik, H. Okamoto, T. Yasui and K. Ishihara, Science, 2010,
328, 1376; (b) M. Uyanik, H. Hayashi and K. Ishihara, Science, 2014,
345, 291; (c) C. Zhu and Y. Wei, ChemSusChem, 2011, 4, 1082.
13 (a) Z. Li, L. Cao, C.-J. Li, Angew. Chem. Int. Ed. 2007, 46, 6505; (b) M.
Nakanishi, C. Bolm, Adv. Synth. Catal. 2007, 349, 861.
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DOI: 10.1039/C5GC00299K
Direct Oxidative Amidation between Methylarenes and
Amines in Water
Tao Wang,a,b Lin Yuan,b Zhenguang Zhao,b Ailong Shao,b Meng Gao,a,b Yangfei Huang,b Fei
Xiong,a,b Huali Zhang,b and Junfeng Zhao*, a,b