Copper-catalyzed regioselective 2-amination of o-haloanilides with aqueous ammonia

Article abstract of DOI:10.1016/j.tetlet.2021.153001

An efficient Cu(II)-vasicine catalytic system has been developed for intramolecular C[sbnd]N bond formation. In this way, regioselective 2-amination of o-haloanilides with aqueous ammonia in EtOH has been achieved. This strategy provides several advantages, such as good regioselectivity, high yields and functional group tolerance.

Full text of DOI:10.1016/j.tetlet.2021.153001

Tetrahedron Letters 69 (2021) 153001
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper-catalyzed regioselective 2-amination of o-haloanilides with
aqueous ammonia
1
1
⇑
⇑
Yan-Ling Tang , Mei-Ling Li , Jin-Chun Gao, Yun Sun , Lu Qu, Feng Huang, Ze-Wei Mao
School of Chinese Materia Medica, Yunnan University of Chinese Medicine, Kunming 650500, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient Cu(II)-vasicine catalytic system has been developed for intramolecular CAN bond formation.
In this way, regioselective 2-amination of o-haloanilides with aqueous ammonia in EtOH has been
achieved. This strategy provides several advantages, such as good regioselectivity, high yields and func-
tional group tolerance.
Received 13 January 2021
Revised 6 March 2021
Accepted 9 March 2021
Available online 16 March 2021
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Cu-catalyzed
Regioselective
2
-Amination
o-Haloanilides
Nitrogen containing compounds are of great importance in nat-
catalyzed
direct
amination
of
ortho-functionalized
2-
ural products, pharmaceutical agents, materials as well as syn-
thetic intermediates [1]. Therefore, the formation of the CAN
bond has attracted more and more attention [2]. In the past dec-
ades, many significant methods have been developed in CAN cou-
pling reactions [3], especially the transition metal-catalyzed
synthetic strategy has been considered as one of the most efficient
manners, such as copper [4], palladium [5], cobalt [6], nickel [7]
and silver [8]. Among them, Cu is the most commonly used metal
for CAN bond forming cross-coupling reactions, which was first
reported by Ullmann and Goldberg [9]. In recent years, various
copper salts were introduced in CAN bond formation in the pres-
ence of ligands and bases [4,10].
o-Phenylenediamines are important intermediates in synthesis
of medicines or natural products [11]. In general, there are two
commonly used methods for preparation of o-phenylenediamines.
The classical method is the reduction of nitrobenzene [12], and the
other is the metal-catalyzed amination of functionalized aryl
halides [13], especially the amination of o-haloanilides is the more
green and efficient strategy. However, there are very few reports
about CAN cross-couplings of o-haloanilides to give 2-aminoani-
halobenzamide with NaN
3
as the amino source [14b]. From
reported methods, we could see that there were still some
limitations including limited substrate scope, low yields and
toxic solvents. In addition, it was very difficult to achieve direct
2-amination of multihaloanilides. Therefore, it is worthwhile to
explore a more efficient protocol for regioselective synthesis of
2-aminoanilides from o-haloanilides with aqueous ammonia via
CAN cross-coupling reactions in green condition. Vasicine is a
bioactive natural product of alkaloid isolated from leaves and
stems of A. vasica, which could be used as small organic molecule
catalyst in methodology in recent years [15]. In present work, we
have explored an efficient Cu(II)-vasicine catalytic system, and
achieved regioselective 2-amination of o-haloanilides with aque-
ous ammonia via intramolecular CAN bond coupling using envi-
ronmentally friendly EtOH as the solvent.
Initially, N-(2-bromophenyl) benzamide (1aa) was chosen as a
model substrate to identify and check the optimal Ullmann cou-
pling conditions including Cu sources, ligands, bases and tempera-
ture, the results were shown in Table 1. First of all, 1aa was carried
out using different Cu sources (CuI, CuBr
2 2
, CuSO , Cu(OAc) and Cu
4
lides so far [14]. In 2009, Ma et al. have reported CuI/
L
-proline cat-
(OTf) ) and ligands (L1-L4) in presence of K
2
2
CO in EtOH at 90 °C
3
alyzed cross-coupling of aqueous ammonia with 2-iodoanilides to
form 2-aminoanilides [14a]. In 2010, Fu et al. have developed CuI-
(Table 1, Entry 1–20). The results showed that benzoxazole 2a
was easy to form from 1aa via Cu-catalyzed intramolecular O-ary-
lation, but regioselective 2-amination and chemoselective Ullmann
condensation of 1aa were hard to perform on the whole. When CuI
was introduced, 3a was obtained in 65% and 32% yield using CuI/L2
or CuI/L4 catalysts (Table 1, Entry 1–4). In addition, there was no
⇑
Corresponding authors.
E-mail addresses: 41546147@qq.com (Y. Sun), maozw@ynutcm.edu.cn
(
Z.-W. Mao).
These authors contributed equally to this work.
1
2 4 2
difference between CuBr , CuSO and Cu(OAc) in presence of
https://doi.org/10.1016/j.tetlet.2021.153001
040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
0

Yan-Ling Tang, Mei-Ling Li, Jin-Chun Gao et al.
Tetrahedron Letters 69 (2021) 153001
Table 1
a,b
Optimization of reaction conditions for Ullmann coupling of 1aa with aqueous ammonia.
Entry
[Cu]
L
Base
Solvent
T (°C)
Yield (%)
2a
3a
4a
1
2
3
4
5
6
7
8
9
CuI
CuI
CuI
CuI
L1
L2
L3
L4
L1
L2
L3
L4
L1
L2
L3
L4
L1
L2
L3
L4
L1
L2
L3
L4
L4
L4
L4
L4
L4
L4
L4
L4
K
K
K
K
K
K
K
K
K
K
K
K
K
K
K
K
K
K
K
K
K
K
K
K
K
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
60
70
80
100
110
70
70
70
58
20
52
45
36
NR
34
22
47
trace
25
44
77
53
60
48
64
20
NRc
65
Trace
32
NR
NR
NR
Trace
NR
NR
NR
NR
NR
Trace
Trace
20
15
34
41
50
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
12
trace
NR
trace
32
NR
NR
18
CuBr
CuBr
CuBr
CuBr
CuSO
CuSO
CuSO
CuSO
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
2
2
2
2
4
4
4
4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
2
2
2
2
2
2
2
2
2
2
2
2
2
14
trace
NR
NR
trace
trace
trace
NR
trace
13
63
87
62
Trace
Trace
88
61
58
83
83
NR
NR
NR
Cu(OTf)
Cu(OTf)
Cu(OTf)
2
K
Et
DIPEA
3
PO
4
2
3
N
2
a
b
c
All reactions were performed using 1aa (1 mmol), [Cu] (0.05 mmol), L (0.1 mmol), base (2 mmol), ammonia (25% wt, 1 mL), solvent (4 mL) in a sealed tube for 12 h.
Isolated yield after chromatographic purification.
NR represented no title product.
L1-L4, benzoxazole 2a was obtained in most case except Cu(OAc)
L4 catalyst (Table 1, Entry 5–16). To our delight, when Cu(OTf)
was used, the yield of 2-aminoanilide 3a was obviously increased
and 2a was decreased in presence of four ligands (Table 1, Entry
2
-
at 70 °C, the results were shown in Table 2. Firstly, in order to
study the reactivity of different halogens, 2-chloro, 2-bromo and
2-iodo anilides were performed under optimal reaction conditions
(Table 2, Entry 1–2). To our delight, although 2-chloroanilides did
not form corresponding 2-aminoanilides, 2-bromoanilides and 2-
iodoanilides gave title products 3a and 3b in good yields (84–
90%), and the activity of 2-iodoanilides was better than that of
2
1
7–20). These results indicated that Cu(II)-vasicine complex could
promote regioselective synthesis of 2-aminoanilides from o-haloa-
nilides with aqueous ammonia. On this basis, we studied the effect
of temperature on the Ullmann coupling. With the temperature
increasing from 60 to 110 °C, the rate of 4a was increased (Table 1,
Entry 21–25). Especially, when the reaction was carried out at
2
2-bromoanilides (Table 2). This indicated that the Cu(OTf) /va-
sicine catalyst system was chemoselective to 2-Br and 2-I. In
addition, the influence of various substituted groups was exam-
ined as well, and o-haloanilides bearing electron donating groups
7
0 °C or 100 °C, the yield of 3a or 4a was the best than others
(
up to 87% and 83%, respectively). The results revealed that Cu/va-
(CH
NO
3
, C
2 5 3 3
H , CH O, X, etc) and electron withdrawing group (CF ,
sicine-catalyzed Ullmann coupling of o-haloanilides with aqueous
ammonia could be achieved. In order to investigate the effect of
different bases on Ullmann coupling of o-haloanilides, other three
2
) were carried out. From the results, we found that the devel-
oped strategy was effective to all 2-bromoanilides and 2-iodoani-
lides to form 2-aminoanilides in good to high yields. Besides, the
protocol was tolerable to both EDG and EWG, and there was no
obvious difference. For instance, N-(2-iodophenyl)benzamide
gave 3a in 90% yield, N-(2-iodophenyl)-4-chlorobenzamide
formed 3h in 85% yield, and N-(2-iodophenyl)-4-trifluoromethyl-
benzamide formed 3n in 84% yield. Moreover, the position of the
substituents had been studied, and there was obvious influence
on Ullmann coupling of o-haloanilides with aqueous ammonia
bases (K
system at 70 °C, and the results were quite different. Among them,
PO contributed to 3a in higher yields (88%) than that of other
bases. Therefore, it was quite clear that Cu(OTf) -vasicine catalyst
was beneficial to Ullmann coupling of o-haloanilides with aqueous
ammonia using K PO as base in EtOH, which could achieve regios-
3 4 3
PO , Et N and DIPEA) were tested to check the catalytic
K
3
4
2
3
4
elective preparation of 2-aminoanilides from o-haloanilides.
With the optimal reaction conditions in hand, various kinds of
o-haloanilides were chosen to examine the scope of 2-amination
using the Cu(OTf)
para substituted o-haloanilides were higher than that of meta,
2
/vasicine catalyst. On the whole, the yields of
2

Yan-Ling Tang, Mei-Ling Li, Jin-Chun Gao et al.
Tetrahedron Letters 69 (2021) 153001
Table 2
a,b
Substrates scope of 2-aminoanilides.
X=Cl,
trace
1
X=Br, 88
X=I, 90
X=Cl,
trace
X=Br, 84
X=I, 88
2
3
4
5
6
X=Br, 83
X=I, 89
X=Br, 84
X=I, 88
X=Br, 87
X=I, 90
X=Br, 77
X=I, 78
X=Br, 83
X=I, 84
7
8
X=Br, 83
X=I, 85
X=Br, 79
X=I, 82
9
X=Br, 72
X=I, 74
1
0
and the yields of ortho substituted o-haloanilides were lower than
others. For example, N-(2-bromophenyl)-2-fluorobenzamide,
amide moiety were tested to verify substrate scope. However, 5b
and 5c were not converted to amination product. Based on this,
N-(2-bromophenyl)-2,6-dichlorobenzamide
mophenyl)-2-trifluoromethylbenzamide gave 3f, 3j and 3l in
7%, 72% and 74% yield under standard conditions, respectively.
Moreover, alkyl amide and heterocyclic acylamide were tested
to check the optimal reaction conditions, and 3q and 3r were
obtained in high yields (83–90%). Finally, different electrical prop-
erty (electron donating and withdrawing groups) on the halo-
genated benzene had an obvious influence on 2-amination of o-
and
N-(2-bro-
2
the present Cu(acac) -vasicine catalyst was regioselective for 2-
amination of o-haloanilides.
7
In addition, to explore the possible amination mechanism,
many control reactions were carried out (Scheme 2). First of all,
in the absence of vasicine, 1ab was not converted to title product
(Scheme 2a). When the reaction was carried out by not using base,
only 2a (14%) was formed (Scheme 2b). As reaction temperature
rising to 100 °C, the yiled of 2-amination decreased to 62%, and
4a was obtained (Scheme 2c). Therefore, the possible catalytic ami-
nation mechanism according to the above results is as follows. o-
Halobenzanilides complex react with CuL to form intermediate II,
which gives III via oxidative addition. Subsequently, substitution
haloanilides. EWG (NO
beneficial to 2-amination than EDG (CH
2
) on the halogenated benzene was more
), and 3t was obtained
3
in up to 92% yield (Entry 19–20). Therefore, it was verified that
Cu(II)-vasicine catalytic system could be used in regioselective
2
-amination of 2-bromoanilides and 2-iodoanilides with
ammonia.
Besides, we studied the applicability of other aryl halides using
3
of III with NH provides coordinate IV. Reduction elimination of
IV leads to 2-aminoanilides with release of CuL for reuse
(Scheme 3).
the present catalytic conditions. As shown in Scheme 1, 5a was
performed by copper catalytic conditions, but only trace 6a was
obtained. In addition, substrates without bearing a neighboring
In conclusion, we have developed an efficient Cu-vasicine cat-
alytic system for CAN bond formation. This strategy is applicable
to synthesis of
a wide variety of 2-aminoanilides from
3

Yan-Ling Tang, Mei-Ling Li, Jin-Chun Gao et al.
Tetrahedron Letters 69 (2021) 153001
X=Br, 83
X=I, 86
1
1
X=Br, 74
X=I, 76
1
1
1
1
2
3
4
5
X=Br, 80
X=I, 81
X=Br, 82
X=I, 84
Scheme 3. Possible mechanism.
X=Br, 72
X=I, 74
o-haloanilides by regioselective Cu-catalyzed Ullmann coupling
under mild and green conditions.
Declaration of Competing Interest
X=Br, 88
X=I, 91
1
1
1
6
7
8
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
X=Br, 83
X=I, 90
Acknowledgments
X=Br, 83
X=I, 87
This work was financially supported by the National Natural
Science Foundation of China (81760775, 81960784), the Yunnan
Provincial Science and Technology Department-Applied Basic
Research Joint Special Funds of Yunnan University of Chinese Med-
icine [2017FF117(-023), 2018FF001(-050), 2019FF002(-010)].
X=Br, 54
X=I, 62
1
9
0
X=Br, 88
X=I, 92
2
Appendix A. Supplementary data
a
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153001.
All reactions were carried out using o-haloanilides (1 mmol), Cu(OTf)
PO (2 mmol), ammonia (25% wt, 1 mL), EtOH
2
(
(
0.05 mmol), vasicine (0.1 mmol), K
3
4
4 mL) in a sealed tube at 70 °C for 12 h.
b
Isolated yield.
References
[
1] (a) R. Tanifuji, A. Minami, H. Oguri, H. Oikawa, Nat. Prod. Rep. 37 (2020) 1098;
(
(
(
b) Z. Jin, G. Yao, Nat. Prod. Rep. 36 (2019) 1462;
c) A.K. Chattopadhyay, S. Hanessian, Chem. Rev. 117 (2017) 4104;
d) M. Chrzanowska, A. Grajewska, M.D. Rozwadowska, Chem. Rev. 116 (2016)
12369.
[
2] (a) M. Matsumoto, K. Wada, K. Urakawa, H. Ishikawa, Org. Lett. 22 (2020) 781;
(
(
(
(
(
b) E.M. Beccalli, G. Broggini, M. Martinelli, S. Sottocornola, Chem. Rev. 107
2007) 5318;
c) S. Roscales, A.G. Csáky, Chem. Soc. Rev. 49 (2020) 5159;
d) Y. Zhao, W. Xia, Chem. Soc. Rev. 47 (2018) 2591;
e) J. Bariwal, E.V. Eycken, Chem. Soc. Rev. 42 (2013) 9283.
[
3] (a) T. Kim, H.Y. Yang, B.G. Park, S.Y. Jung, J.H. Park, K.D. Park, S.J. Min, J. Tae, H.
Yang, S. Cho, S.J. Cho, H. Song, I. Mook-Jung, J. Lee, A.N. Pae, Eur. J. Med. Chem.
Scheme 1. Substrate scope of other Ar-X.
1
(
8
(
25 (2017) 1172;
b) F. Ke, P. Zhang, C. Lin, X. Lin, J. Xu, X. Zhou, Org. Biomol. Chem. 16 (2018)
090;
c) D. Yang, H. Fu, L. Hu, Y. Jiang, Y. Zhao, J. Org. Chem. 73 (2008) 7841.
4] (a) A.M. Kulkarni, K. Srinivas, M.V. Deshpande, C.V. Ramana, Org. Chem. Front.
(2016) 43;
b) S. Rasheed, D.N. Rao, K.R. Reddy, S. Aravinda, R.A. Vishwakarma, P. Das, RSC
[
[
3
(
Adv. 4 (2014) 4960.
5] (a) D.S. Surry, S.L. Buchwald, Chem. Sci. 2 (2011) 27;
(
(
(
(
b) D. Maiti, B.P. Fors, J.L. Henderson, Y. Nakamura, S.L. Buchwald, Chem. Sci. 2
2011) 57;
c) P. Ruiz-Castillo, S.L. Buchwald, Chem. Rev. 116 (2016) 12564;
d) L.M. Baumgartner, J.M. Dennis, N.A. White, S.L. Buchwald, K.F. Jensen, Org.
Process Res. Dev. 23 (2019) 1594.
[
6] (a) P. Saha, M.A. Ali, P. Ghosh, T. Punniyamurthy, Org. Biomol. Chem. 8 (2010)
5
(
692;
b) A.R. Hajipour, Z. Khorsandi, M. Mortazavi, H. Farrokhpour, RSC Adv. 5
(2015) 107822.
Scheme 2. Control reactions of mechanistic studies.
4

Yan-Ling Tang, Mei-Ling Li, Jin-Chun Gao et al.
Tetrahedron Letters 69 (2021) 153001
[12] (a) Z. Zhao, H. Yang, Y. Lia, X. Guo, Green Chem. 16 (2014) 1274;
[
7] (a) C.M. Lavoie, M. Stradiotto, ACS Catal. 8 (2018) 7228;
(
(
b) Z.H. Qi, J. Ma, ACS Catal. 8 (2018) 1456;
c) R.Y. Liu, J.M. Dennis, S.L. Buchwald, J. Am. Chem. Soc. 142 (2020) 4500.
(b) S. Anantharaj, M. Jayachandrana, S. Kundu, Chem. Sci. 7 (2016) 3188.
[13] H.S. Jung, T. Yun, Y. Cho, H.B. Jeon, Tetrahedron, 2016, 72, 5988; (b) H.J. Xu, Y.F.
Liang, Z.Y. Cai, H.X. Qi, C.Y. Yang. Y.S. Feng, J. Org. Chem., 2011, 76, 2296.
[14] (a) X. Diao, Y. Wang, Y. Jiang, D. Ma, J. Org. Chem. 74 (2009) 7974;
(b) H. Zhao, H. Fu, R. Qiao, J. Org. Chem. 75 (2010) 3311.
[15] (a) J.K. Malik, A. Sharma, S. Singh, S. Jain, Drug Inv. Tod. 5 (2013) 32;
(b) Y. Zhua, W. Liu, S. Qi, H. Wang, Y. Wang, G. Deng, Y. Zhang, S. Li, C. Ma, Y.
Wang, X. Cheng, C. Wang, Eur. J. Pharm. Sci. 123 (2018) 459;
(c) S. Sharma, M. Kumar, S. Sharma, O.S. Nayal, N. Kumar, B. Singh, U. Sharma,
Org. Biomol. Chem. 14 (2016) 8536;
[
8] (a) Y. Wang, C. Wei, R. Tang, H. Zhan, J. Lin, Z. Liu, W. Tao, Z. Fang, Org. Biomol.
Chem. 16 (2018) 6191;
(
Ribas, ACS Catal. 8 (2018) 10430.
9] (a) F. Ullmann, Ber. Dtsch. Chem. Ges. 36 (1903) 2382;
b) L. Capdevila, E. Andris, A. Briš, M. Tarrés, S. Roldán-Gómez, J. Roithová, X.
[
(
b) I. Goldberg, Ber. Dtsch. Chem. Ges. 39 (1906) 1691.
10] (a) R. Berrino, S. Cacchi, G. Fabrizi, A. Goggiamani, J. Org. Chem. 77 (2012)
537;
[
2
(
(
b) Y.F. Wang, X. Zhu, S. Chiba, J. Am. Chem. Soc. 134 (2012) 3679;
c) M. Li, Y. Tang, H. Gao, G. Rao, Z. Mao, Asian J. Org. Chem. 9 (2020) 1027.
(d) S. Sharma, M. Kumar, V. Bhatt, O.S. Nayal, M.S. Thakur, N. Kumar, B. Singh,
U. Sharma, Tetrahedron Lett. 57 (2016) 5003;
[
11] (a) S. Azeez, P. Sureshbabu, P. Chaudhary, S. Sabiah, J. Kandasamy,
Tetrahedron Lett. 61 (2020) 151735;
(e) S. Sharma, M. Kumar, V. Kumar, N. Kumar, Tetrahedron Lett. 54 (2013)
4868;
(
(
(
b) M. Dey, K. Deb, S.S. Dhar, Chin. Chem. Lett. 22 (2011) 296;
c) J. Gao, Z.G. Ren, J.P. Lang, Chin. Chem. Lett. 28 (2017) 1087;
d) L.T. Tran, T.H. Ho, N.T.A. Phan, T.T. Nguyen, N.T.S. Phan, Org. Biomol. Chem.
(f) M.A. Aga, B. Kumar, A. Rouf, B.A. Shah, S.C. Taneja, Tetrahedron Lett. 55
(2014) 2639.
1
8 (2018) 5652.
5