Lewis acid-catalyzed redox-neutral amination of 2-(3-pyrroline-1-yl)benzaldehydes via intramolecular [1,5]-hydride shift/isomerization reaction

Article abstract of DOI:10.3762/bjoc.10.306

Lewis acid-catalyzed redox-neutral amination of 2-(3-pyrroline-1-yl)benzaldehydes via intramolcular [1,5]-hydride shift/isomerization reaction has been realized, using the inherent reducing power of 3-pyrrolines. A series of N- arylpyrrole containing amines are obtained in high yields.

Full text of DOI:10.3762/bjoc.10.306

Lewis acid-catalyzed redox-neutral amination of 2-(3-
pyrroline-1-yl)benzaldehydes via intramolecular
[1,5]-hydride shift/isomerization reaction
Chun-Huan Jiang, Xiantao Lei, Le Zhen, Hong-Jin Du, Xiaoan Wen, Qing-Long Xu*
and Hongbin Sun*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 2892–2896.
State Key Laboratory of Natural Medicines and Jiangsu Key
Laboratory of Drug Discovery for Metabolic Disease, China
Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China
doi:10.3762/bjoc.10.306
Received: 20 October 2014
Accepted: 26 November 2014
Published: 05 December 2014
Email:
Qing-Long Xu* - xuqing307@126.com; Hongbin Sun* -
hbsun2000@yahoo.com
Associate Editor: D. Y.-K. Chen
* Corresponding author
© 2014 Jiang et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
catalysis; C–H activation; hydride-shift; Lewis acid; redox reaction
Abstract
Lewis acid-catalyzed redox-neutral amination of 2-(3-pyrroline-1-yl)benzaldehydes via intramolcular [1,5]-hydride shift/isomeriza-
tion reaction has been realized, using the inherent reducing power of 3-pyrrolines. A series of N-arylpyrrole containing amines are
obtained in high yields.
Introduction
The direct and selective functionalization of the inactive complex molecules and exhibit a larger number of biological
C(sp3)–H bond constitute an economically attractive strategy effects [31-33].
for organic syntheses [1-10]. Until now, a number of transition
metals can be used for the activation of C–H bonds [11-18]. In 2009, Tunge's group disclosed that N-alkylpyrroles could be
Among the reported transformations, intramolecular redox formed via a redox isomerization reaction (Scheme 1, reaction
processes based on direct functionalization of C(sp3)–H bonds 1) [34-36]. Moreover, we recently realized a Lewis acid-
linking with α heteroatoms are useful for the synthesis of struc- catalyzed intramolecular redox reaction using an aldehyde
turally diverse amines and ether derivatives [19-30]. On the group as the H-shift acceptor to afford (2-(1H-pyrrol-1-yl)phen-
other hand, compounds containing the N-arylpyrrole moiety yl)methanol (Scheme 1, reaction 2) [37]. As part of our interest
serve as important building blocks for the synthesis of various in expanding the inherent reducing power of 3-pyrrolines, we
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Beilstein J. Org. Chem. 2014, 10, 2892–2896.
report herein the Lewis acid-catalyzed redox-neutral amination Finally, we established the optimized reaction conditions using
of 2-(3-pyrroline-1-yl)benzaldehydes using the iminium group ZnCl2 (5 mol %) as the catalyst and CH2Cl2 as the solvent, and
as the H-shift acceptor (Scheme 1, reaction 3). Notably, this running the reaction at room temperature or under reflux.
reaction should meet the requirement that the iminium
formation reaction should be faster than the aldehyde redox Under the optimized conditions, the results of the amination
reaction.
reaction of 2a with various 2-(3-pyrroline-1-yl)benzaldehydes 1
are shown in Scheme 2. The reactions proceeded smoothly to
give the corresponding N-arylpyrrole amines 3 in good to excel-
Results and Discussion
In our initial investigation, aldehyde 1a and dibenzylamine (2a) lent yields (71–97% yields). Notably, the substitution of the
were chosen as the model reaction substrates. In the presence of benzene ring had little effect on the reaction since both electron-
10 mol % PhCOOH, the reaction of 1a with 2a in DCE at rt for donating (3b, 3c) and electron-withdrawing groups (3d–i) were
24 h gave the trisubstituted amine 3a in 50% yield (entry 1, tolerated in the reaction.
Table 1). Encouraged by this result, we screened readily avail-
able Brønsted and Lewis acids (Table 1). Except the Lewis acid Next, the scope of amines 2 was explored. The results are
AlCl3, other strong Brønsted acids and common Lewis acids summarized in Scheme 3. Reaction of secondary amines
could be used as the catalyst in this reaction, affording the possessing aryl–aryl, alkyl–alkyl and aryl–alkyl moieties yield
desired products in excellent yields (entries 2–8, Table 1). the corresponding N-arylpyrrole amines 3j–p in high yields
Considering that ZnCl2 is cheaper and easy to handle, it was (81–94% yields). Various cyclic secondary amines were also
chosen as the catalyst for further optimization reactions. good substrates for this reaction, affording the desired products
Furthermore, various solvents such as DCE, CH2Cl2, CHCl3, (3q, 3r, 3s) in good to high yields (77–98% yields) with DCE as
toluene, CH3CN and THF were examined. All the solvents the solvent under reflux conditions. The reaction with indoline,
afforded the desired product in satisfactory yields (entries 8–13, tetrahydroquinoline, and tetrahydroisoquinoline could also be
Table 1). Subsequently, the loading of dibenzylamine (2a) and realized to give products 3t, 3u, and 3v in good yields (76–88%
the catalyst was examined. The results show that decreasing the yields), respectively. Finally, primary amines were examined.
amount of 2a to 1.2 equiv and ZnCl2 to 5 mol % did not affect The reaction with excess benzylamine (5.0 equiv) in the pres-
the yield (entry 16, Table 1).
ence of Zn(OTf)2 as the catalyst afforded the desired product
Scheme 1: Synthesis of N-substituted pyrroles via redox-neutral reaction.
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Beilstein J. Org. Chem. 2014, 10, 2892–2896.
Table 1: Optimization of the redox-neutral amination reaction.a
entry
catalyst
X
Y
solvent
yield (%)b
1
2
PhCOOH
CF3COOH
p-TsOH.H2O
Sc(OTf)3
Cu(OTf)2
Zn(OTf)2
AlCl3
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.2
1.0
1.2
1.2
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
5
DCE
DCE
50
87
90
94
94
97
76
95
97
95
94
96
71
97
93
95
91
3
DCE
4
DCE
5
DCE
6
DCE
7
DCE
8
ZnCl2
DCE
9
ZnCl2
CH2Cl2
CHCl3
toluene
CH3CN
THF
10
11
12
13
14
15
16
17
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ZnCl2
ZnCl2
ZnCl2
2
a1a (0.5 mmol), 2a (X equiv), catalyst (Y mol %), solvent (5 mL), room temperature, 24 h. bIsolated yield.
Scheme 2: Substrate scope of aryl aldehydes 1. Reagents and conditions: 1 (0.3 mmol), 2a (1.2 equiv), ZnCl2 (5 mol %), CH2Cl2 (3.0 mL). aRoom
temperature. bDCE, reflux.
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Beilstein J. Org. Chem. 2014, 10, 2892–2896.
Scheme 3: Substrate scope of amines 2. Reagents and conditions: 1a (0.5 mmol), 2 (1.2 equiv), ZnCl2 (5 mol %), CH2Cl2 (5.0 mL), rt. aReflux. bDCE,
reflux. cZn(OTf)2 (5 mol %), n-butylamine (5.0 equiv), DCE, reflux. dp-TsOH·H2O (5 mol %), PhNH2 (5.0 equiv), CH2Cl2, rt.
3w in 98% yield. However, when n-BuNH2 was used as the hydride shift/isomerization reaction has been realized. Various
substrate, the yield was reduced to 33% even under high types of amines and 2-(3-pyrroline-1-yl)benzaldehydes are well
temperature. Notably, according to the 1H NMR spectrum of tolerated in this reaction, affording the corresponding
the crude product, the reaction with phenylamine using N-arylpyrrolamines in good to high yields. Further studies on
Zn(OTf)2 as the catalyst afforded only the corresponding imine synthetic applications of [1,5]-hydride shift/isomerization reac-
product, indicating that the [1,5]-hydride shift/isomerization tions that utilize the inherent reducing power of 3-pyrrolines are
reaction did not occur. To our delight, this reaction proceeded underway in our laboratory.
smoothly at room temperature to give the desired N-arylpyrrole
amine 3y in high yield (99% yield) when p-TsOH·H2O was Experimental
used as the catalyst instead of Zn(OTf)2.
General procedure for the preparation of N-arylpyrroles 3:
A mixture of benzaldehyde 1 (0.3–0.5 mmol), amine 2
(1.2 equiv) and ZnCl2 (5 mol %) were stirred in dichloro-
Conclusion
In conclusion, Lewis acid-catalyzed redox-neutral amination of methane or DCE (5.0 mL) at room temperature or reflux and
2-(3-pyrroline-1-yl)benzaldehydes via intramolcular [1,5]- monitored by TLC. After completion of the reaction (about
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Beilstein J. Org. Chem. 2014, 10, 2892–2896.
19.Tobisu, M.; Chatani, N. Angew. Chem., Int. Ed. 2006, 45, 1683–1684.
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Supporting Information
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Experimental details, analytical data, and copies of the 1H
and 13C NMR spectra of the final products.
[http://www.beilstein-journals.org/bjoc/content/
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Financial support from the National Natural Science Founda-
tion of China (grants 81373303 and 81473080) is gratefully
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