Alanine triazole iridium-catalyzed C–N bond formation through borrowing hydrogen strategy

Article abstract of DOI:10.1016/j.tetlet.2016.08.093

An efficient synthesis of secondary amines has been described through alanine triazole iridium-catalyzed C–N bond formation of an aromatic amine and an alkyl amine using the borrowing hydrogen strategy. In addition, it was observed that alanine triazole iridium is also an efficient catalyst to promote C–N bond formation of an aromatic amine and alcohols with good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2016.08.093

Accepted Manuscript
Alanine triazole iridium-catalyzed C-N bond formation through borrowing hy-
drogen strategy
Xiaoli Yu, Ranran Zhao, Huida Wan, Yongchun Yang, Dawei Wang
PII:
S0040-4039(16)31130-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.08.093
TETL 48064
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
24 July 2016
29 August 2016
30 August 2016
Please cite this article as: Yu, X., Zhao, R., Wan, H., Yang, Y., Wang, D., Alanine triazole iridium-catalyzed C-N
bond formation through borrowing hydrogen strategy, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/
j.tetlet.2016.08.093
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Alanine triazole iridium-catalyzed C-
N bond formation through borrowing
hydrogen strategy
Xiaoli Yu, Ranran Zhao, Huida Wan*, Yongchun Yang and Dawei Wang*
The Key Laboratory of Food Colloids and Biotechnology, Ministry of Education, School of Chemical and Material Engineering,
Jiangnan University, Wuxi 214122, Jiangsu Province, China.
An efficient synthesis of secondary amines has been described through alanine triazole iridium-catalyzed C-N bond
formation of an aromatic amine and an alkyl amine by using the borrowing hydrogen strategy. In addition, it was observed
that alanine triazole iridium is also an efficient catalyst to promote C-N bond formation of an aromatic amine and alcohols
with good to excellent yields.

1
Contents lists available at ScienceDirect
Tetrahedron Letters
Alanine triazole iridium-catalyzed C-N bond formation through borrowing
hydrogen strategy
Xiaoli Yu, Ranran Zhao, Huida Wan*, Yongchun Yang and Dawei Wang*
The Key Laboratory of Food Colloids and Biotechnology, Ministry of Education, School of Chemical and Material Engineering, Jiangnan
University, Wuxi 214122, Jiangsu Province, China.
Email：wangdw@jiangnan.edu.cn, Tel./fax: +86 510 85917763
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient synthesis of secondary amines has been described through alanine
triazole iridium-catalyzed C-N bond formation of an aromatic amine and an
alkyl amine by using the borrowing hydrogen strategy. In addition, it was
observed that alanine triazole iridium is also an efficient catalyst to promote C-
N bond formation of an aromatic amine and alcohols with good to excellent
yields.
Available online
Keywords:
alanine,
triazole,
2
016 Elsevier Ltd. All rights reserved.
iridium,
C-N bond formation,
borrowing hydrogen,
Later, Porcheddu et al. reported palladium-catalyzed
dehydrogenative generation of imines from amines to
synthesis of indoles via cross-couplings of amines with
1
. Introduction
Hydrogen auto-transfer methodology, also called
1
0
arylhydrazines.
borrowing hydrogen, has recently received considerable
attention for providing an economically, environmentally1
sensible alternative to the conventional alkylation of amines.
Under the conditions of the “borrowing hydrogen”
methodology, alcohols are easily converted in situ into
aldehydes or ketones, which are more reactive than alcohols
Scheme 1. The borrowing hydrogen reaction of an amine with
another amine.
2
and easily react with amines (Scheme 1). However, the
borrowing hydrogen reaction of amines with amines are much
3
difficult. Based on the early amine exchange reactions, Beller
et al. demonstrated the first ruthenium-catalyzed synthesis of
aromatic amines through arylation of aliphatic amines with
anilines that proceeds under transfer hydrogenation conditions
4
in 2007. In 2009, Williams group developed iridium-
Traditionally, the catalyst plays a crucial role in borrowing
hydrogen reactions. Among this, iridium complexe is one of
catalyzed coupling of two amines with excellent selectivity in
a high temperature, even when both amine components are
capable of undergoing oxidation to an imine. Largeron et al.
the most effective and promising catalyst for this
5
11,12
transformation.
Zhang group developed
a
novel
reported a facile one-pot oxidation-imine formation-reduction
iridium/acid co-catalyzed transfer hydrogenative coupling
route to secondary amines can be achieved electrolytically
strategy to alkyl chain lengthened N-heteroaromatics from
six-membered 2-alkyl cyclic amines and aldehydes. Li et al.
6
13
from primary amines. Shimizu and Shimura showed Al
2
O
3
-
supported Pd nanoclusters are also effective catalysts for the
cross-coupling of amines. In 2012, Shimizu group developed
reported the synthesis of quinazolinones via acceptorless
coupling of o-aminobenzamides with methanol catalyzed by
7
alumina-supported Pt nanoclusters act as an effective
metal−ligand
bifunctional
catalyst
[Cp*Ir(2,2’-
1
4
heterogeneous catalyst for N-alkylation of amines with other
bpyO)(H O)]. Xu and co-workers described autocatalyzed
2
8
amines. In 2013, Wang et al. synthesized iodo-bridged
dehydrative a-alkylation reactions of ketones with alcohols to
selectively afford ketone or alcohol products by C-C bond
polymeric iridium complexes, which could serve as efficient
9
catalysts in the selective amine cross-coupling reaction.

2
Tetrahedron Letters
15
formation with good yields and excellent chemselectivity.
3
IrCl /ATA showed much better catalytic activity. For a better
Yu et al. reported the synthesis of secondary and tertiary
amines from direct N-alkylation of primary and secondary
amines with alcohols using a heterogeneous bimetallic Pt-
yield, a series of screening of reaction conditions were
explored. The best result was achieved with xylene as the
solvent and sodium hydroxide as the base. It should be noted
1
6
Sn/γ-Al
2
O
3
catalyst. Zhao et al. reported a nice dynamic
3
that RuCl /ATA almost could not catalyze this transformation
kinetic asymmetric amination of α-branched alcohols using
borrowing hydrogen methodology through cooperative
catalysis of an iridium complex with a chiral phosphoric
(Table 1, entries 15-16).
a
Table 1. Screening of reaction conditions
1
7
acid. In 2014, we developed several bisbenzoxazolyl and
benzothienyl iridium(III) complexes, which exhibit good
catalytic activity in borrowing hydrogen for C-C or C-N bond
18
formation under mild conditions. Recently, we synthesized a
new type of ligand alanine triazole (ATA)(Scheme 2), which
exhibited the improved stability and high catalytic activities in
b
Entry
Catalyst
IrCl
[Ir(COD)Cl]2
IrCl /ATA
Base
Na CO
Na CO
Solvent
Toluene
Toluene
Toluene
Yield[%]
1
2
3
3
2
3
3
3
<5
<5
18
1
9
2
allene synthesis and hydration reaction.
In addition,
3
Na
2
CO
preliminary studies showed alanine triazole ruthenium could
be used borrowing hydrogen reactions. The concept of this
research is the reactivity and stability of metal complexes
largely depends on ligands coordinating with metal cations,
where the reactivity and stability of metal were tuning through
the ligands. When the triazole was introduced into amino acid
derivatives, the designed new ligands maybe improve the
reactivity and stability of metal catalyst through three kinds of
functional groups or coordination sites: ester group, amino
group and triazole part. Herein, we reported that alanine
triazole iridium-catalyzed C-N bond formation reactions
through borrowing hydrogen strategy, especially, for the
selective transformations of aromatic amines and alkyl
amines.
[
Ir(COD)Cl]
2
/A
4
Na
2
CO
3
3
Toluene
11
TA
5
6
7
8
9
IrCl
3
/ATA
-
Toluene
Toluene
Toluene
Toluene
Toluene
THF
<5
<5
26
17
47
32
<5
<5
65
83
<5
-
Na
2
CO
CO
CO
IrCl
IrCl
IrCl
IrCl
IrCl
IrCl
IrCl
IrCl
3
3
3
3
3
/ATA
/ATA
/ATA
/ATA
/ATA
/ATA
/ATA
/ATA
Cs
2
3
K
2
3
NaOH
NaOH
NaOH
NaOH
1
1
1
1
1
1
0
1
2
3
4
5
DCM
3
MeOH
Xylene
Xylene
Xylene
3
3
NaOH
NaOH
NaOH
c
3
RuCl /ATA
[RuCp*Cl
2 n
]
16
NaOH
Xylene
28
Scheme 2. Alanine triazole ligands (ATA) prompted reactions.
/ATA
a
Reagents and conditions: 1a (1 mmol), 2a (1 mL), [Ir] loading (2
mol%, 0.02 mmol), L (2.4 mol%). Base (1.2 mmol), solvent (3 mL),
reflux, 20 h. Isolated yield. IrCl (10 mol%), L (12 mol%), 72 h.
3 1
1
b
c
Having identified suitable reaction conditions, we explored
the above methods to other aromatic amines and triethylamine.
As shown in Table 2, a wide range of substrates and
functional groups are tolerated including methoxy, methyl,
chloro, and tert-butyl substituents at the different positions of
aromatic amines. Notably, 4-(tert-butyl)aniline was also a
suitable substrate for this transformation, and the
corresponding products was achieved in good yield under
optimized conditions.
a,b
Table 2. Substrate expansion
b
Entry
R
Yield[%]
In our previous work, we found the new alanine triazole
ligand (ATA) could great adjust reaction activity of gold and
ruthenium, but the corresponding crystals are difficult to
cultivate. Based on this, we have conducted the survey about
the coordination of ATA ligand with iridium. Even we have
paid our great efforts to these crystals but still failed. Since
many catalysts are often prepared in situ and also get great
1
2
3
4
5
6
7
8
9
p-Me
H
p-tBu
p-MeO
p-Cl
65 (3a)
66 (3b)
79 (3c)
74 (3d)
58 (3e)
53 (3f)
65 (3g)
57 (3h)
54 (3i)
69 (3j)
m-Cl
p-F
3
success, we select the simple IrCl as a catalyst and alanine
triazole as the ligand to test reaction activity. Next, p-toluidine
was chosen as a substrate to test the reaction. So, the
borrowing hydrogen reaction of p-toluidine and triethylamine
was carried on (Table 1). The experiment showed that
o-Br
(2-)Py
(1-)Np
10
a
3
Reagents and conditions: 1 (1.0 mmol), 2 (1 mL), IrCl (2

3
mol), L
C, 20 h. Isolated yield.
1
b(2.4 mol%), NaOH (1.2 mmol), xylene (3 mL), 150
to promote Ir-catalyzed C-N bond formation reactions of an
o
aromatic amine and alcohols with good to excellent yields.
This provides an alternative methodology to synthesis of
substituted amine derivatives.
Encouraged by the promising results, we further employed
the above methods to other phenyl amines and various
alcohols. The obtained results were summarized in Table 3.
The results showed different N-alkylated anilines were
obtained with good to excellent yields by using this catalyst.
The effect of substituents on the aromatic ring of amine has
also been explored. It was observed that anilines with
electron-donating or electron-withdrawing substituents could
react under the optimal reaction conditions with the overall
yield in 69% to 90%. Subsequently, the reactions of different
alcohols were explored. Clearly, aromatic alcohols, including
p-methylbenzyl alcohol, p-methoxylbenzyl alcohol, p-
chlorobenzyl alcohol and furfuryl alcohol could react
smoothly and give yields ranging from 72% to 93%.
Supporting Information
Supplementary data related to this paper is available free of
charge via the Internet.
Acknowledgements
We gratefully acknowledge financial support of this work
by the National Natural Science Foundation of China
(
21401080), the Natural Science Foundation of Jiangsu
Province of China (BK20130125), Jiangsu Talents Project
2013-JNHB-027), China Postdoctoral Science Foundation
(2014M550262, 2015T80495) and MOE & SAFEA for the
11 Project (B13025).
(
a, b
Table 3. Alkylation of amines with alcohols
1
References and Notes
b
1. (a) Watson, A. J. A.; Williams, J. M. J. Science 2010, 329, 635.
Entry
R
1
R
2
Yield[%]
(
b) Gunanathan, C.; Milstein, D. Science 2013, 341, 1229712.
2
.
Recent reviews: (a) Huang, F.; Liu, Z.; Yu, Z. Angew. Chem.
Int. Ed. 2016, 55, 862. (b) Yang, Q.; Wang, Q.; Yu, Z. Chem.
Soc. Rev. 2015, 44, 2305. (c) Nandakumar, A.; Midya, S. P.;
Landge, V. G.; Balaraman, E. Angew. Chem. Int. Ed. 2015, 54,
1
2
3
4
5
6
H
H
nPr
4-Me-Ph
Ph
74 (5a)
87 (5b)
11022. (d) Chen, B.; Wang, L.; Gao, S. ACS Catal. 2015, 5,
c
H
90 (5c), 85
76 (5d)
5851. (e) Shimizu, K.-I. Catal. Sci. Technol. 2015, 5, 1412. (f)
Obora, Y. ACS Catal. 2014, 4, 3972. (g) Hollmann, D.
ChemSusChem 2014, 7, 2411.
H
4-Cl-Ph
Ph
3
4
5
.
.
.
Murahashi, S.; Hirano, T.; Yano, T. J. Am. Chem. Soc. 1978,
4-Cl
H
73 (5e)
100, 348.
Hollmann, D.; Bähn,S.; Tillack, A.; Beller, M. Angew. Chem.
Int. Ed. 2007, 46, 8291.
4-OMe-Ph
87 (5f)
Saidi, O.; Blacker, A. J.; Farah, M. M.; Marsden, S. P.;
Williams, J. M. Angew. Chem. Int. Ed. 2009, 48, 7375.
Largeron, M.; Fleury, M.-B. Org. Lett. 2009, 11, 883.
Shimizu, K.-I.; Shimura, K.; Ohshima, K.; Tamura, M.;
Satsuma, A. Green Chem., 2011, 13, 3096.
Shimizu, K.-I.; Ohshima, K.; Tai, Y.; Tamura, M.; Satsuma, A.
Catal. Sci. Technol., 2012, 2, 730.
Tan, X.; Li, B.; Xu, S.; Song, H.; Wang, B. Organometallics
7
4-OMe
Ph
82 (5g)
6
7
.
.
8
9
4-F
3-Cl
Ph
4-Cl-Ph
4-OMe-Ph
Ph
76 (5h)
74 (5i)
86 (5j)
69 (5k)
85 (5l)
78 (5m)
84 (5n)
8
9
1
1
.
.
1
1
1
1
1
0
1
2
3
4
4-Cl
2013, 32, 3253.
0. Taddei, M.; Mura, M. G.; Rajamäki, S.; Luca, L. D.; Porcheddu,
A. Adv. Synth. Catal. 2013, 355, 3002.
2-Cl
1. (a) Hamid, M. H. S. A.; Slatford, P. A.; Williams, J. M. J. Adv.
Synth. Catal. 2007, 349, 1555. (b) Guillena, G.; Ramon, D. J.;
Yus, M. Angew. Chem. Int. Ed. 2007, 46, 2358. (c) Nixon, T.
D.; Whittlesey, M. K.; Williams, J. M. Dalton Trans. 2009, 753
(d) Mata, J. A.; Hahn, F. E.; Peris, E. Chem. Sci. 2014, 5, 1723.
2. (a) Song, C.; Qu, S.; Tao, Y.; Dang, Y.; Wang, Z.-X. ACS
Catal. 2014, 4, 2854. (b) Li, H.; Wang, X.; Huang, F.; Lu, G.;
Jiang, J.; Wang, Z.-X. Organometallics 2011, 30, 5233. (c) Cui,
X.; Dai, X.; Deng, Y.; Shi, F. Chem. Eur. J. 2013, 19, 3665. (d)
Cui, X.; Zhang, C.; Shi, F.; Deng, Y. Chem. Commun. 2012, 48,
(2-)Py
Ph
Ph
(2-)furyl
Ph
(1-)Naph
1
a
Reagents and conditions: 1 (1.0 mmol), 2 (1.1 mmol), IrCl
3
(2
o
mol%), L
1
(2.4 mol%). NaOH (1.2 mmol), toluene (3 mL), 120 C,
b
c
2
2 n
0 h. Isolated yield. [RuCp*Cl ] /ATA (2 mol%), ref 19.
9391. (e) Cui, X.; Zhang, Y.; Shi, F.; Deng, Y. Chem. Eur. J.
2011, 17, 1021 (f) Liu, X.; Ding, R.-S.; He, L.; Liu, Y.-M.; Cao,
Y.; He, H.-Y.; Fan, K.-N. ChemSusChem 2013, 6, 604. (g)
Tang, C.-H.; He, L.; Liu, Y.-M.; Cao, Y.; He, H.-Y.; Fan, K.-N.
Chem. Eur. J. 2011, 17, 7172. (h) He, L.; Lou, X.-B.; Ni, J.;
Liu, Y.-M.; Cao, Y.; He, H.-Y.; Fan, K.-N. Chem. Eur. J. 2010,
16, 13965.
Conclusions
In summary, an efficient method for secondary amines
synthesis has been developed through alanine triazole iridium-
catalyzed cross-coupling of an aromatic amine and an alkyl
amine by using the borrowing hydrogen strategy. In addition,
it was observed that alanine triazole is also an effective ligand
13. (a) Xiong, B.; Li, Y.; Lv, W.; Tan, Z.; Jiang, H.; Zhang, M.;
Org. Lett. 2015, 17, 4054. (b) Xie, F.; Zhang, M.; Chen, M.; Lv,
W.; Jiang, H. ChemCatChem 2015, 7, 349. (c) Xie, F.; Zhang,

4
Tetrahedron Letters
M.; Jiang, H.; Chen, M.; Lv, W.; Zheng, A.; Jian. X. Green
Chem. 2015, 17, 279. (d) Chen, M.; Zhang, M.; Xiong, B.; Tan,
Z.; Lv, W.; Jiang, H. Org. Lett. 2014, 16, 6028. (e) Tan, Z.;
Jiang, H.; Zhang, M. Chem. Commun. 2016, 52, 9359. (f) Tan,
Z.; Jiang, H.; Zhang, M. Org. Lett. 2016, 18, 3174. (g) Xiong,
B.; Zhang, S.; Jiang, H.; Zhang, M. Org. Lett. 2016, 18, 724.
1
4. (a) Lu, L.; Ma, J.; Qu, P.; Li, F. Org. Lett. 2015, 17, 2350. (b)
Wang, R.; Ma, J.; Li, F. J. Org. Chem. 2015, 80, 10769. (c) Qu,
P.; Sun, C.; Ma, J.; Li, F., Adv. Synth. Catal. 2014, 356, 447-
4
2
59. (d) Li, F.; Qu, P.; Ma, J.; Zou, X.; Sun, C., ChemCatChem
013, 5, 2178-2182. (e) Li, F.; Sun, C.; Shan, H.; Zou, X.; Xie,
J. ChemCatChem 2013, 5, 1543-1552. (f) Sun, C.; Zou, X.; Li,
F. Chem. Eur. J. 2013, 19, 14030. (g) Li, F.; Shan, H.; Chen, L.;
Kang, Q.; Zou, P., Chem. Commun. 2012, 48, 603-605. (h) Li,
F.; Lu, L.; Liu, P. Org. Lett. 2016, 18, 2580.
1
5. (a) Li, S.; Li, X.; Li, Q.; Yuan, Q.; Shi,X.; Xu, Q. Green Chem.
2
015, 17, 3260. (b) Shi, X.; Guo, J.; Liu, J.; Ye, M.; Xu, Q.
Chem. Eur. J. 2015, 21, 9988. (c) Xu, Q.; Chen, J.; Tian, H.;
Yuan, X.; Li, S.; Zhou, C.; Liu, J. Angew. Chem. Int. Ed. 2014,
5
3
3
3, 225. (d) Xu, Q.; Chen, J.; Liu, Q. Adv. Synth. Catal. 2013,
55, 697. (e) Xu, Q.; Zhu, X.; Chen, J.; Adv. Synth. Catal. 2013,
55, 73. (f) Zhang, E.; Tian, H.; Xu, S.; Yu, X.; Xu, Q. Org.
Lett. 2013, 15, 2704.
1
1
6. (a) He, W.; Wang, L.; Sun, C.; Wu, K.; He, S.; Chen, J.; Wu, P.
Yu, Z. Chem. Eur. J. 2011, 17, 13308. (b) Wang, L.; He, W.;
Wu, K.; He, S.; Sun, C.; Yu, Z. Tetrahedron Lett. 2011, 52,
7
103.
7. (a) Rong, Z.-Q.; Zhang, Y.; Chua, R. H. B.; Pan, H.-J.; Zhao, Y.
J. Am. Chem. Soc. 2015, 137, 4944. (b) Pan, H.-J.; Ng, T. W.;
Zhao, Y. Chem. Commun. 2015, 51, 11907. (c) Zhang, Y.; Lim,
C.-S.; Sim, D. S. B.; Pan, H.-J.; Zhao, Y. Angew. Chem. Int. Ed.
2
014, 53, 1399.
8. (a) Wang, D.; Zhao, K.; Xu, C.; Miao, H.; Ding, Y. ACS Catal.
014, 4, 3910. (b) Wang, D.; Zhao, K.; Yu, X.; Miao, H.; Ding,
Y. RSC Adv. 2014, 4, 42924.
9. Yang, Y.; Qin, A.; Zhao, K.; Wang, D.; Shi, X. Adv. Synth.
Catal. 2016, 358, 1433.
1
1
2

5
Highlights



Borrowing hydrogen reaction of an aromatic amine and an alkyl amine
C-N bond formation of an aromatic amine and alcohols
Alanine triazole iridium-catalyzed secondary amines synthesis