Metal-free synthesis of 1,2-amino alcohols by one-pot olefin aziridination and acid ring-opening

Article abstract of DOI:10.1016/j.tetlet.2018.06.002

A one-pot, two-step reaction comprising olefin aziridination and ring-opening of an aziridine intermediate to synthesize 1,2-amino alcohols has been developed. This reaction is suitable for several types of olefin. This methodology allows an efficient and

Full text of DOI:10.1016/j.tetlet.2018.06.002

Accepted Manuscript
Metal-free synthesis of 1,2-amino alcohols by one-pot olefin aziridination and
acid ring-opening
Yong-Gang Hua, Qian-Qian Yang, Yi Yang, Mei-Jing Wang, Wen-Chao Chu,
Peng-Yan Bai, De-Yun Cui, En Zhang, Hong-Min Liu
PII:
S0040-4039(18)30732-9
https://doi.org/10.1016/j.tetlet.2018.06.002
TETL 50040
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
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1 March 2018
28 May 2018
1 June 2018
Please cite this article as: Hua, Y-G., Yang, Q-Q., Yang, Y., Wang, M-J., Chu, W-C., Bai, P-Y., Cui, D-Y., Zhang,
E., Liu, H-M., Metal-free synthesis of 1,2-amino alcohols by one-pot olefin aziridination and acid ring-opening,
Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.06.002
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Tetrahedron Letters
Metal-free synthesis of 1,2-amino alcohols by one-pot olefin aziridination and acid
ring-opening
Yong-Gang Hua,a Qian-Qian Yang,a Yi Yang,a Mei-Jing Wang,a Wen-Chao Chu,a Peng-Yan Bai,a De-Yun
Cui,a En Zhang,a,b* and Hong-Min Liua,b*
a School of Pharmaceutical Sciences; Institute of Drug Discovery and Development; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of
Education of China; Zhengzhou University, Zhengzhou 450001, PR China; b Collaborative Innovation Center of New Drug Research and Safety Evaluation,
Henan Province, Zhengzhou 450001, PR China
* Corresponding author. Tel: +86 371 67781739; Email: zhangen@zzu.edu.cn; liuhm@zzu.edu.cn
ABSTRACT
ARTICLE INFO
Article history:
Received
Received in revised form
Accepted
A one-pot, two-step reaction comprising olefin aziridination and ring-opening of an aziridine
intermediate to synthesize 1,2-amino alcohols has been developed. This reaction is suitable for
several types of olefin. This methodology allows an efficient and highly stereoselective
approach to various 1,2-amino alcohols, readily providing an alternative route to conventional
vicinal amino alcohols.
Available online
2018 Elsevier Ltd. All rights reserved.
Keywords:
one-pot reaction
olefin aziridination
ring-opening of aziridines
1,2-amino alcohols
Aziridines20 are present in a wide range of biologically active
molecules and natural products,21,22 and represent one of the most
1. Introduction
1,2-Amino alcohols are important structural features1 and are
ubiquitous in natural products and therapeutic agents possessing
a wide variety of biological activities, as well as in chiral ligands
and auxiliaries for asymmetric synthesis.2-4 The hormones
epinephrine and norepinephrine5 are well known amino alcohols
(Fig. 1). The α-glucosidase inhibitor miglitol is an approved oral
anti-diabetic drug.6 Metoprolol is a β1 receptor blocker used for
the treatment of a number of cardiovascular conditions.7 Jaspine
B, also known as pachastrissamine, is a naturally-occurring novel
anhydrosphin-
gosine derivative that was isolated from a marine sponge, and is
cytotoxic against P388, A549, HT29, and Mell 28 cell lines at an
IC50 level of 0.01 μg/mL.8,9 For this reason, much effort has been
devoted to the development of new effective methods for the
enantioselective synthesis of β-amino alcohols.1 A variety of
powerful procedures has been reported,10-14 including the ring
opening of aziridines.15-19
valuable three-membered ring systems in modern synthetic
chemistry. Aziridines are widely recognized as important
versatile building blocks for chemical bond elaborations and
functional group transformations.23-28 Numerous olefin
aziridination methods involve the use of metal salts or complexes
as catalysts.29-34 From both environmental and economical
viewpoints, electrochemical aziridination has been reported, and
N-aminophthalimide has been used for synthesis of aziridine.35-37
Moreover, PhI(OAc)2- and aryl iodide-mediated aziridination of
alkenes has been described for metal-free catalyzed C–N bond
forming reactions.38-40 Nitrene equivalent-mediated reactions of
alkenyl bromides, alkylidenecy-
clopropanes, and allylic alcohols are shown in Scheme 1.41-43 To
the best of our knowledge, there has been no reports on the
ring-opening reaction of N-phthalimide aziridines with acid as a
one-pot reaction (Scheme 1).
Scheme 1. Nitrene equivalent-mediated reactions of alkenes
Figure 1. Molecules with 1,2-amino alcohol substructures

Multicomponent reactions (MCRs) are an effective strategy to
improve the efficiency of a chemical reaction by avoiding
A series of terminal and internal alkenes were then examined
to explore the generality of the present procedure (Table 2).
Styrenes with electron-donating substituents at different positions
of the phenyl ring afforded the desired products in good yields
(Table 2, products 3b–3d). In contrast, styrenes with halogen
substituents gave inferior yields (3e–3i). This reaction also gave
good yields of 1,1-disubstituted styrenes (3j). The reaction gave
moderate yields with 1-vinylnaphthalene and its conjugate alkene
(3k and 3l). Reactions of 1-octodecene and 1-tetradecene under
these conditions afforded the corresponding 1,2-amino esters in
lower yield (3m–3n). In a cycloalkene reaction, the product was
obtained in a moderate yield (3o). To our delight, chalcones were
also good substrates for this one-pot reaction. All expected
products were produced from differently-substituted chalcones in
moderate to good yield in this reaction.
lengthy
separation
processes
and
purification
of
intermediates.44,45 Many powerful MCRs have been developed
and applied to the synthesis of active pharmaceutical
ingredients.46
We wish to highlight our results on an MCR involving olefin
aziridination and ring-opening of N-phthalimide aziridines with
various carboxylic acids from our continued efforts to establish
novel 1,2-amino alcohol derivatives with good biological
activity47-49 and tandem reaction with olefins.43 This work is an
extension of Che's work (Scheme 1). Different types of olefins
and carboxylic acids gave the desired products using this method.
2. Results and discussion
Table 2. Investigation of the scope of olefins 1a
Our investigations began with a one-pot olefin aziridination,
followed by ring-opening with H2O.16 In the process, the
expected 1,2 amino alcohol 5 and a small amount of unexpected
product 3a were isolated (Scheme 2). Different reaction
conditions were screened to improve the yield of 3a.
Scheme 2. One-pot reaction of olefin aziridination followed by
ring-opening with H2O
Styrene was used as the model substrate, and initial studies
revealed that without any base, the reaction yield increased with
increasing amounts of N-aminophthalimide (PhthNH2) and
PhI(OAc)2 (Table 1, entries 1–4). When using a larger dosage of
PhthNH2 and PhI(OAc)2, a base was used to improve the reaction
yield. K2CO3 was selected as the base giving a decrease of both
PhthNH2 and PhI(OAc)2 (Table 1, entries 5–7). Treatment of
styrene (1 equiv) with 1.4 equiv of PhthNH2, 1.5 equiv of
PhI(OAc)2, and 2.8 equiv of K2CO3 produced the β-amino ester
3a in 65% yield (Table 1, entry 8). When the reaction was
conducted at −20 °C, a lower yield was obtained (Table 1, entry
9). Compared with toluene, dichloromethane was a better solvent
for this reaction (Table 1, entry 10).
Table 1. Optimization of the reaction conditions
Entry
Solvent
Base
Equiv.a
Yield (%)b
1
2
3
4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
—
—
—
—
1/1.4/1.5
1/2/1.5
50
50
59
67
1/2/2.2
a Similar conditions as for Table 1, entry 8. All reactions
were performed for 12 h for the first step, then CH3CO2H
was added. 1 (10 mmol) at room temperature for 12 h.
1/2.5/2.5
5
6
7
CH2Cl2
CH2Cl2
CH2Cl2
K2CO3
K2CO3
K2CO3
1/2/1.5/2.8
1/2/2/4
54
55
65
b
c
First step as entry 8 of Table 1, second step at 40 °C for 8 h.
1/2.5/2.5/5
In general, this reaction was suitable for several types of olefin
and gave expected products in moderate to good yields. For the
purpose of examining the synthetic potential of the present
approach, a gram-scale synthesis of ring-opened product was
performed for this system. The final product (3.3 g, 13.5mmol,
Table 2, product 3d) was obtained in a total yield of 87% under
the same reaction conditions.
8
CH2Cl2
CH2Cl2
K2CO3
K2CO3
1/1.4/1.5/2.8
1/1.4/1.5/2.8
65
57
9c
10
Toluene
K2CO3
1/1.4/1.5/2.8
60
a All reactions were performed at room temperature for 12 h with
styrene (1 mmol)/PhI(OAc)2/N-aminophthalimide/base molar
To probe the regioselectivity and diastereoselectivity of the
present MCR reaction, X-ray diffraction analysis of 3a and 3v
was carried out (Figure 2).50 The regioselectivity and
diastereoselectivity of this one-pot reaction was confirmed. These
ratio.
b Isolated yield;
c Reaction was performed at -20°C

a
results were in accordance with a previously reported olefin
aziridination and acid ring-opening.51
Similar conditions as Table 1, entry 8. All reactions were
performed for 12 h for the first step, then the different carboxylic
acids were added.
3. Conclusions
In conclusion, we have discovered a new one-pot olefin
aziridination and ring-opening reaction with carboxylic acids
under metal-free conditions. Furthermore, various functionalized
1,2-amino alcohols were obtained with high regioselectivity and
diastereoselectivity from olefins without purification of the
aziridine intermediates using this efficient method. Given the
advantages of this effective protocol, we expect this method to
become widely applicable in organic synthesis and drug
development.
3a
3v
Figure 2. X-ray structures of 3a and 3v
To confirm the reaction mechanism of the one-pot reaction,
we obtained intermediate 2a from the first step of the one-pot
reaction and proved its structure by NMR. After acetic acid was
used for the nucleophile attack on intermediate 2a, compound 3a
was obtained successfully in 90% yield.
Acknowledgments
To verify whether a nitrenium ion52 or a nitrene was the
reactive species, another experiment was carried out (Scheme 3).
In this experiment, hydrochloric acid, phosphoric acid or acetic
acid (2 mmol) was added instead of base to afford only aziridine
2a after 24 h. This proved that a nitrenium ion is probably not the
reactive species in this reaction. The amount of acid (35 mmol) is
crucial for the ring-opening reaction.
Project supported by the National Natural Science Foundation of
China (No. U1204206, 21702190), Science and Technology
Department of Henan Province (No. 172102310227) and the
education department of Henan province (No. 17A350004). We
thank Christina M. Jones, Ph.D, from Liwen Bianji, Edanz
Editing China (www.liwenbianji.cn/ac), for editing the English
text of a draft of this manuscript.
Scheme 3. Mechanism verification experiment
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3
Highlights
1) A new method for ring opening of aziridines by acid has been developed.
2) This method completes an one-pot conversion of olefins to 1,2-aminoalcohols.
3) This new reaction is applicable to a wide range of olefins and acid.

4
Graphical Abstract
Metal-free synthesis of 1,2-amino alcohols by one-pot olefin aziridination and acid ring-opening
Yong-Gang Hua, Qian-Qian Yang, Yi Yang, Mei-Jing Wang, Wen-Chao Chu, Peng-Yan Bai, De-Yun Cui, En
Zhang, and Hong-Min Liu.