Nickel-catalyzed product-controllable amidation and imidation of sp3 C-H bonds in substituted toluenes with sulfonamides

Article abstract of DOI:10.1039/c7ob00022g

A nickel-catalyzed product-controllable imidation and amidation of sp³ C-H bonds in substituted toluenes with sulfonamides were developed. Based on the change of the reaction time and atmosphere from N₂ to O₂, this reaction proceeded in high yields and excellent selectivity under different conditions. Mechanistic details were also described.

Full text of DOI:10.1039/c7ob00022g

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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Nickel-Catalyzed Product-Controllable Amidation and Imidation of
sp3 C-H Bond in Substituted Toluenes with Sulfonamides
Ze-lin Lia, Li-kun Jina,and Chun Cai*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
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A nickel-catalyzed product-controllable imidation and amidation of ligand assisted amidation of primary benzylic C-H bonds by
sp3 C-H bond in substituted toluenes with sulfonamides were using toluene as the partner6b. Recently, a ligand-free copper-
developed. Based on the change of reaction time and atmosphere catalyzed amidation of benzylic hydrocarbons and inactive
from N2 to O2, this reaction proceeded in high yields and excellent aliphatic alkanes with simple amides was developed by Huang’s
selectivity under different conditions. Mechanistic details were also group6c, this process was efficient in the formation of C−N bond
described.
and the scope was wide which tolerated a range of amides.
However, the selectivity of amidation and imidation process has
The effective method for the formation of C-N bonds in aryl not been investigated. Previously, some metal catalysts such as
imines and amines plays an important role in the organic ruthenium, palladium, and copper were used in the amidation
synthetic chemistry because of the high prevalence of nitrogen- of sp3 C-H bond. Nickel is one of the most abundant, inexpensive,
containing molecules in natural and pharmaceuticals1. and environmentally friendly metals. To the best of our
Meanwhile, drugs containing the sulfonamide functional group2 knowledge, no example concerning nickel-catalyzed selective
(Scheme 1,
antagonists and showed good performance in the treatment of respect to imidation, several catalytic systems have been
congestive heart failure.
reported7. However, the high cost of metal catalyst and poor
1 and 2) have long been identified as a potential ETA amidation and imidaition of C-H bonds was reported. With
In the past few years, direct transformation from C-H bonds to selectivity inhibit its wide application in synthetic chemistry. In
C-N bonds had attracted much attention and great progress3-5 20127d, a new method for oxidative imidation of toluene deriv-
had been made. For example, ligand assisted copper-catalyzed
amination of indane with benzenesulfonamide was reported
in20066a, it provided a new route for the amidation of allylic and
benzylic C−H bonds. Then, David and his co-workers reported a.
Scheme 1. Drugs containing the sulfonamide functional group.
Scheme 2. Representative examples of amidation of sp3 C-H
bond in substituted toluenes.
aChemical Engineering College, Nanjing University of Science and Technology, 200
Xiao Ling Wei Street, Nanjing, Jiangsu, People’s Republic of China
* Corresponding Author E-mail: c.cai@ njust.edu.cn
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atives with sulfonamides was raised, but the catalyst consist of temperature on yield. Unfortunately, increasing the
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DOI: 10.1039/C7OB00022G
Pd-Au complexes was so expensive from the point of economy. temperature and decreasing the temperature all decrease the
Our group has developed a nickel-catalyzed regioselective yields (entries 17−18). After the optimization process of catalyst,
cross-dehydrogenative coupling of inactive C(sp3)−H bonds with oxidant, and reaction temperature, the following amidation was
indole derivatives to form C-C bonds8. So we next consider performed under our standard conditions: 10 mol% of Ni(OAc)2
whether this system can be used in forming C-N bonds. Inspired as the catalyst, 2 equiv. of DTBP as the oxidant. The reaction
by these, we herein demonstrated a new method for the temperature was maintained at 120 °C under N2. Furthermore,
selective amidation and imidation of sp3 C-H bond in substituted the condition of imidation was also investigated. The imidation
toluenes with sulfonamides under solvent-free conditions.
product yield was improved under O2 (entries 7, 19 and 20).The
yields of imination product was improved with the increase of
reaction time (entry 20-23).
Table 1. Optimization of the reaction conditions[a]
With a set of reaction conditions in hand, we then investigated
the range of sulfonamide coupling partners that could be
employed. Gratifyingly, this transformation showed excellent
tolerance for sulfonamide derivatives and provided the
corresponding amidation products in good to excellent yields.
For example, benzenesulfonamides containing electron-
donating groups (Me and OMe) could produce the desired
products in 70% and 72% yields. Benzamides bearing electron-
withdrawing groups, such as Cl and Br, proceeded the reaction
in relatively lower yields (65% and 63%). Methanesulfonamide
was also tolerated in the nickel-catalyzed amidation
methodology. To our delight, xylenes and mesitylene coupled
with benzamide well. Halogen-containing toluene was also
tolerated and gave the N-alkylation products in good yields,
however, the yields of ortho and meta substituted toluene was
relatively lower than para substituted toluene because of steric
effect.
Entry
Cat.
Oxidant
Temp
Time
(h)
Atm
3a(%)[b]
4a(%)[b]
(oC）
1
2
NiCl2
NiCl2
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
TBHP[c]
TBHP[d]
TBPB
DDQ
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
100
140
120
120
120
120
120
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
18
12
6
Air
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
Air
O2
O2
O2
O2
56
69
15
Trace
3
NiBr2
35
Trace
4
NiCl2(PPh3)2
Ni(acac)2
Ni(OTf)2
Ni(OAc)2
CuCl
20
0
5
28
0
6
13
0
7
75
Trace
8
30
0
0
9
Cu(OAc)2
FeCl2
25
Furthermore, the imidation reaction of toluenes was
investigated (Table 3). For the reaction of toluene with
benzenesulfonamide, 72% isolated yield was obtained.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
0
0
CoCl2
0
0
Meanwhile,
the
reaction
of
toluenes
and
4-
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
15
0
methylbenzenesulfonamide proceeded well too.
33
0
Some experiments were investigated to get insight into the
reaction mechanism. Firstly, under standard conditions, 2.0
equivalents of 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO)
were added, no desired product was detected in the reaction
mixture (determined by GC−MS; Scheme3, 1 and 2), which
implied that the radical process proceeded in both amidation
and imination. Subsequently, a series of reactions were
conducted.
As shown in Scheme4, (1)-(3), the results indicated that
imidation progress is mainly consistent with the oxidative
dehydrogenation pathway rather than aldehyde amine
condensation. Therefore, a possible mechanism based on our
experimental results and previous reports9 for the amidation
and imidation of benzylic sp3 C-H bonds is proposed in Scheme
5. Our proposed mechanism begins with the decomposition of
DTBP to produce a tert-butoxy radical and tert-butoxide anion
assisted by Ni(OAc)2. Then, the tert-butoxy radical abstract a
hydrogen atom from toluene to form a benzyl radical. At the
same time, sulfonamides react with the tert-butoxide anion and
provides anion intermediate (C). Subsequently, the benzyl
radical reacts. with intermediate (C) to provide radical anion (D).
Next, (D) affording the amidation product (E) via SET process.
Finally, (E) undergoes an oxidative dehydrogenation progress to
Trace
0
0
0
K2S2O8
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
Trace
24
0
0
50
0
70
13
72
40
33
Trace
3
41
59
Trace
[a]Reaction condition: sulfonamide (0.5 mmol), cat.(10%mmol),
toluene (1.5 mL), oxidant (2 equiv.). [b] Isolated yield. [c]70% aq.
[d] 5N in decane.
Initially, benzenesulfonamide 1a and toluene 2a was chosen as
model substrates to identify suitable reaction conditions (Table
1). To our delight, the yield was increased to 69% when we
change atmosphere from air to N2 (entry 2). Next, the choice of
catalyst and oxidant were made, Ni(OAc)2 (entries 3−11) and
DTBP (entries 12−16) proved to be critical to the reaction
efficiency. In addition, we explored the influence of reaction
produce the imidation product (F) assited by Ni(OAc)2
。
2 | J. Name., 2012, 00, 1-3
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Table 2. Nickel-catalyzed amidation of sp3 C-H bond in Table
COMMUNICATION
3
.
Two representative nickel-catalyzeVdiew iAmrticidleaOtniloinne
DOI: 10.1039/C7OB00022G
substituted toluenes with sulfonamides
substrates were examined.
[a]Reaction condition: sulfonamide (0.5 mmol), cat. (10% mmol),
toluene derivatives (1.5 mL), oxidant (2 equiv.), 24h under O2.
Scheme 3. Control experiments.
Scheme 4. Control experiments.
(1)
(2)
(3)
[a]Reaction condition: sulfonamide (0.5 mmol), cat. (10% mmol),
toluene derivatives (1.5 mL), oxidant (2 equiv.), 24h under N2
Nickel appears to play two roles in our system. First, nickel
catalyzes the decomposition of DTBP to generate tert-butoxy
radical and tert-butoxide anion, which are the species that
cleave the C−H bond of the primary benzylic hydrocarbons and
the N-H bond of sulfonamides. Second, nickel participates in the
imidation after the amidation progress to form the imidation
product.
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Scheme 5. Possible mechanism.
(a) S.-M. Au, J.-S. Huang, C.-M. Che, W.-Y. Yu, J. Org. Chem. 2000, 65,
View Article Online
7858. (b) Y. Cui, C. He, J. Am. Chem. Soc. 2003, 125, 16202. (c) C. Liang,;
DOI: 10.1039/C7OB00022G
F. Robert-Peillard, C. Fruit, P. M€uller, R. H. Dodd, P. Dauban, Angew.
Chem., Int. Ed. 2006, 45, 4641–4644. (d) Y. Zhang, H. Fu, Y. Jiang, Y.
Zhao, Org. Lett. 2007, 9, 3813. (e) X. Liu, Y. Zhang, L. Wang, H. Fu, Y.
Jiang, Y. Zhao, J. Org. Chem. 2008, 73, 6207. (f) H. Lu, V. Subbarayan,
J. Tao, X.- P. Zhang, Organometallics 2010, 29, 389–393. (g) D. Ramesh,
U. Ramulu, K. Mukkanti, Y. Venkateswarlu, Tetrahedron Lett. 2012, 53,
2904−2908. (h) F. Teng, S. Sun, Y. Jiang, J.-T. Yu, J. Cheng, Chem.
Commun. 2015, 51, 5902−5905.
(5) For recent reviews: (a) H. M. L. Davies, M. S. Long, Angew. Chem.,
Int. Ed. 2005, 44, 3518. (b) H. M. L. Davies, Angew. Chem., Int. Ed.
2006, 45, 6422. (c) H. M. L. Davies, J. R. Manning, Nature 2008, 451,
417–424. (d) C.-M. Che, V. K.-Y. Lo, C.-Y. Zhou, J.-S. Huang, Chem. Soc.
Rev. 2011, 40, 1950−1975.
(6) (a) G. Pelletier, D. A. Powell, Org. Lett. 2006, 8, 6031-6034. (b) D.
A. Powell, H. Fan, J. Org. Chem. 2010, 75, 2726-2729. (c) H.-T. Zeng, J.
Huang, Org. Lett. 2015, 17, 4276-4279.
(7) (a) B. Gnanaprakasam, J. Zhang, D. Milstein, Angew. Chem., Int.
Ed. 2010, 49, 1468–1471. (b) X.-J. Cui, Y. Zhang, F. Shi, Y. Q. Deng,
Chem. Eur. J. 2011, 17, 1021 – 1028. (c) C.-Z. Liu, S.-H. Liao, Q. Li, S.-l.
Feng, Q. Sun, X.-C. Yu, Q. Xu, J. Org. Chem. 2011, 76, 5759-5773. (d)
X.-J. Cui, F. Shi, Y.-Q. Deng, Chem. Commun. 2012, 48, 7586−7588. (e)
R, Cano, D.- J, Ramon, M. Yus, J. Org. Chem. 2011, 76, 5547-5557.
(8) Li.-K. Jin, L. Wan, J. Feng, C. Cai, Org. Lett. 2015, 17, 4276-4279.
(9) (a) K. Yamaguchi, N. Mizuno, Angew. Chem., Int. Ed. 2003, 42,
1480–1483. (b) J.-R. Wang, Y. Fu, B.-B. Zhang, X. Cui, L. Liu, Q.-X. Guo
Tetrahedron Lett. 2006, 47, 8293−8297. (c) Y.-M. Zhang, H. Fu, Y.-Y.
Conclusions
In summary, we described an efficient and excellent chemo-
selective nickel-catalyzed amidation and imination of primary
benzylic hydrocarbons and sulfonamides. The protocol uses
cheap Ni(OAc)2 as the catalyst, DTBP as the oxidant under Jiang, Y.-F. Zhao, Org. Lett. 2007, 9, 3813-3816. (d) R.-H. Fan, W.-X. Li,
D.-M. Pu, L. Zhang, Org. Lett. 2009, 11, 1425-1428. (e) S. Guin, S. K.
Rout, A. Banerjee, S. Nandi, B. K. Patel, Org. Lett. 2012, 20, 5294-5297.
(f) S. Lei, Y.-Y. Mai, C.-J. Yan, J.-W. Mao, H. Cao, Org. Lett. 2016, 18,
3282-3285. (g) Y. Aihara, N. Chatani, J. Am. Chem. Soc. 2013, 135,
5308−5311.
ligand-free and solvent-free conditions. Worth noting is that the
reactions are influenced by oxygen and reaction time. Besides,
benzenesulfonamide, methanesulfonamide and a variety of
toluene derivatives were all tolerated well in this procedure.
Further studies along mechanistic details and more mild
reaction conditions are under investigation.
Notes and references
(1) (a) G.-W. Wang, T.-T. Yuan, D.-D. Li, Angew. Chem., Int. Ed. 2011,
50, 1380−1383. (b) X.-X. Zhang, W.-T. Teo, P. W. H. J. Chan,
Organomet. Chem. 2011, 696, 331−337. (c) J. M. Chong and T.-R. Wu,
J. Am. Chem. Soc., 2006, 128, 9646. (d) T. Mita, J.-Y. Chen, M.
Sugawara and Y. Sato, Angew. Chem., Int. Ed., 2011, 50, 1393. (e) S. E.
Denmark and T. W. Wilson, Nat. Chem., 2010, 2, 937.
(2) (a) N. Murugesan, Z. Gu, P. D. Stein, S. Bisaha, S. Spergel, R. Girotra,
V. G. Lee, J. Lloyd, R. N. Misra, J. Schmidt, J. Med. Chem. 1998, 41,
5198–5218. (b) N. Murugesan, Z. Gu, S. Spergel, M. Young, P. Chen, A.
Mathur, L. Leith, M. Hermsmeier, E. C.-K. Liu, R. Zhang, J. Med. Chem.
2003, 46, 125–137.
(3) Representative intramolecular metal-nitrene based amidations:
(a) J.-L. Liang, S.-X. Yuan, J.-S. Huang, W.-Y. Yu, C.-M. Che, Angew.
Chem., Int. Ed. 2002, 41, 3465–3468. (b) J.-L. Liang, S.-X. Yuan, J.-S.
Huang, C.-M. Che, J. Org. Chem. 2004, 69, 3610–3619. (c) M. Kim, J.
V. Mulcahy, C. G. Espino, Du Bois, J. Org. Lett. 2006, 8, 1073–1076.
(d) E. Milczek, N. Boudet, S. Blakey, Angew. Chem., Int. Ed. 2008, 47,
6825–6828. (e) K. W. Fiori, C. G. Espino, B. H. Brodsky, J. DuBois,
Tetrahedron 2009, 65, 3042–3051. (f) M. Yang, X. Jiang, Z.-J. Shi, Org.
Chem. Front. 2015, 2, 51−54. (g) Q. Qin, S. Yu, Org. Lett. 2015, 17,
1894−1897. (h) A. Verma, S. Patel, Meenakshi, A. Kumar, A. Yadav, S.
Kumar, S. Jana, S. Sharma, C. D. Prasad and S. Kumar, Chem. Commun.,
2015, 51, 1371--1374
(4) Representative intermolecular metal-nitrene based amidations:
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Oxidant
H
H
O
O
S
O
S
Ni catalyst
H
Ni catalyst
H
R
N
R
S
NH2
R
N
R'
O2 24h
O
O
N2 24h
O
R'
R'
Product- controllable
Graphical abstract