2-Amino homopropargyl alcohols from the highly regioselective Ag2CO3-catalyzed nucleophilic openings of alkynyl epoxides by amines

Article abstract of DOI:10.1016/j.cclet.2017.09.001

The nucleophilic ring opening reaction of propargyl epoxides by amines based on a silver catalyst is presented. The reaction takes place under mild conditions and features a high regioselectivity to provide an effective method for the synthesis of 2-amino homopropargyl alcohols in moderate to high yields.

Full text of DOI:10.1016/j.cclet.2017.09.001

Accepted Manuscript
Title: 2-Amino homopropargyl alcohols from the highly
regioselective Ag2CO3-catalyzed nucleophilic openings of
alkynyl epoxides by amines
Authors: Jianlin Yang, Ming Zhang, Peng Wang, Wenjuan
Liu, Ruwei Shen
PII:
S1001-8417(17)30342-X
DOI:
Reference:
http://dx.doi.org/10.1016/j.cclet.2017.09.001
CCLET 4207
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Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
4-7-2017
26-8-2017
1-9-2017
Please cite this article as: Jianlin Yang, Ming Zhang, Peng Wang, Wenjuan Liu,
RuweiShen, 2-AminohomopropargylalcoholsfromthehighlyregioselectiveAg2CO3-
catalyzed nucleophilic openings of alkynyl epoxides by amines, Chinese Chemical
Lettershttp://dx.doi.org/10.1016/j.cclet.2017.09.001
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Communication
2-Amino homopropargyl alcohols from the highly regioselective Ag2CO3-catalyzed
nucleophilic openings of alkynyl epoxides by amines
Jianlin Yang a, Ming Zhang a, Peng Wang a, Wenjuan Liub , Ruwei Shena,

a State Key Laboratory of Materials-Oriented Chemical Engineering, College of Chemical Engineering, Nanjing Tech University, Nanjing 210009, China
b College of materials science and engineering, Nanjing Tech University, Nanjing 210009, China
 Corresponding author.
E-mail address: shenrw@njtech.edu.cn
ARTICLE INFO
Article history:
Received 4 July 2017
Received in revised form 26 August 2017
Accepted 30 August 2017
Available online
Graphical Abstract
2-Amino homopropargyl alcohols from the highly regioselective Ag2CO3-catalyzed nucleophilic openings of alkynyl epoxides
by amines
Jianlin Yanga, Ming Zhanga, Peng Wanga, Wenjuan Liub, Ruwei Shena, *
a
State Key Laboratory of Materials-Oriented Chemical Engineering, College of Chemical Engineering, Nanjing Tech
University, Nanjing 210009, China
b College of materials science and engineering, Nanjing Tech University, Nanjing 210009, China
The nucleophilic ring opening of propargyl epoxides by amines based on a silver catalyst is presented. The reaction takes place
under mild conditions and features a high regioselectivity to provide an effective method for the synthesis of 2-amino
homopropargyl alcohols in moderate to high yields.
ABSTRACT
The nucleophilic ring opening reaction of propargyl epoxides by amines based on a silver catalyst is presented. The reaction takes
place under mild conditions and features a high regioselectivity to provide an effective method for the synthesis of 2-amino
homopropargyl alcohols in moderate to high yields.
———

Keywords:
Alkynyl epoxide
Ring opening
Silver catalysis
Regioselectivity
Amino alcohol
Alkynyl epoxides are molecules with rich chemistry due to the presence of a strained oxirane in proximity with a carbon−carbon
triple bond, attracting many researchers to investigate their reactivity and applications in organic synthesis [1-3]. One of the most
important transformations is the nucleophilic ring-opening reaction with various nucleophiles [4]. Generally, the reactions could take
place via 1,4-manner to produce allenol products (Scheme 1A, path a), or alternatively a direct epoxide opening to give functional
propargyl or homopropargyl alcohols (Scheme 1A, path b). The selectivity of the reaction is often complicated, depending on the
nature of the nucleophiles, the substituted patterns of the alkynyl oxiranes as well as the use of the catalysts. The nucleophilic opening
of epoxides by amines is a useful and widely studied reaction to produce amino alcohols [5]. However, a literature survey shows that
similar reaction with alkynyl epoxides has not been well studied. The early examples involve a long-time heating of the alkynyl
oxiranes with excess amines in a protic solvent, yielding amino propargyl alcohols selectively but often in unsatisfactory yields [6]. A
well-established system is the aminolysis of 1-alkynyl-7-oxabicyclo[4.1.0]heptane promoted by excess LiClO4 (Scheme 1B, eq. a) [7].
The reaction also selectively gives amino propargyl alcohols as the major products, which have been utilized for the synthesis of
4,5,6,7-tetrahydro-1H-indoles via further cyclization [7b, 7c]. A reversal regioselectivity to produce 2-amino homopropargyl alcohols
was scarcely reported until recently the Nishibayashi group described a very nice copper-catalyzed enantioselective ring opening of
ethynyl epoxides by amines (Scheme 1B, eq. b) [8]. The reaction is believed to proceed via copper-allenylidene complex as the key
intermediate, thus only ethynyl epoxides are suitable substrates.
Scheme 1. Nucleophilic ring opening of alkynyl epoxides.
In this paper, we report a Ag2CO3-catalyzed ring-opening reaction of alkynyl epoxides with various amines. Very recently we
identified a Ag2CO3-catalyzed hydrophosphorylation of propargyl epoxides by the use of the nucleophilic P(O)H compounds [9].
Different from the softer phosphorus nucleophiles, which reacted with alkynyl epoxides to afford phosphoryl allenols in a 1,4-manner,
the reactions of amines in the presence of the silver catalyst took place in a 1,2-manner. The reaction is highly regioselective, and
particularly both terminal and internal alkynyl oxiranes are applicable, thereby providing a mild and atom-economic way to access a
variety of 2-amino homopropargyl alcohols (Scheme 1C) [10].
Our study began with the reaction of 2-ethynyl-2-phenyloxirane (1a) and N-methylaniline (2a). When a catalytic amount of Ag2CO3
(5 mol%) was added to a solution of 1a (0.24 mmol) and 2a (0.2 mmol) in toluene (2 mL) followed by stirring at room temperature for
2 h, the ring-opened product, i.e., 2-(methyl(phenyl)amino)-2-phenylbut-3-yn-1-ol (3a), was obtained in 89% yield (Table 1, entry 1).
The reaction is highly regioselective, and is not air or moisture sensitive. The possible byproducts from hydroamination of the C-C
triple bond or further cyclized products were not detected. Several other silver salts also show reactivity towards the transformation
albeit giving the products in lower yields. For example, AgOAc and AgNO3 catalyzed the reaction to give 3a in 63% and 76% yield,
respectively (Table 1, entries 2 and 3). AgCl is also competent to catalyze the reaction to give 3a in 84% yield (Table 1, entry 4).
Nevertheless, the more cationic AgSbF6 gave a poor yield (Table 1, entry 5) [11]. With Ag2CO3 as the catalyst, a brief examination on
the solvent effect was undertaken. The reactions in DCM and THF gave 3a in moderate yields (Table 1, entries 6 and 7). The use of
MeOH and MeCN gave 3a in 64% and 60% yield, respectively (Table 1, entries 8 and 9). However, the use of DMSO as a solvent did
not result in the formation of the product (Table 1, entry 10). Finally, we also examined the reaction with a low catalyst loading (1
mol%), in which a low product yield was obtained (Table 1, entry 11).

Table 1
Ag-catalyzed aminolysis ring-opening reaction of 1a with 2a.a
Entry [Ag]
Solvent
Toluene
Toluene
Toluene
Toluene
Toluene
DCM
Yield of 3a (%)b
1
2
3
Ag2CO3
89
63
76
84
51
72
76
64
60
nd
71
AgOAc
AgNO3
AgCl
4
5
6
7
8
AgSbF6
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
THF
MeOH
MeCN
DMSO
Toluene
9
10
11c
a Reaction conditions: 1a (0.24 mmol), 2a (0.2 mmol), [Ag] (10 mol%, referring to the molar content of silver atom in the silver salts), solvent
(2 mL);
b Isolated yields;
c 1 mol% Ag2CO3.
Fig. 1 shows the scope of the ring opening of alkynyl epoxides with a variety of amines. In addition to 1a, terminal alkynyl epoxides
1b-1e bearing substituted phenyls all reacted with N-methylaniline (2a) in the presence of 5 mol% of Ag2CO3 affording the expected
products in good to high yields (72%-89%). The substrate 1f with a naphthalenyl group was also applicable to produce the expected
product 3f in 68% yield. However, ethynyl epoxides bearing alkyl group at the propargyl position are not applicable. With respect to
the nucleophiles, a broad range of amines were proved as good substrates for the transformation. As shown in Fig. 1, a variety of
primary aromatic amines reacted smoothly with 1a to afford the coresponding ring-opened products. The yields of the products (3g-3k)
were usually high when para-substituted anilines were employed, whereas anilines bearing substituents at the ortho-position of the
phenyl groups gave moderate yields (3l-3n) due to the steric effect. This effect becomes more apparent in the reaction of a more
sterically hindering substrate, i.e., 2,6-diisopropylaniline, which only led to the formation of 3o in a trace amount after stirring for 24 h.
In contrast to primary aromatic amines, primary aliphatic amines are not suitable substrates as nucleophiles for the present
transformation. For example, when 1-butanamine was employed to react with 1a in the presence of Ag2CO3, the expected ring-opened
product was not obtained. Changing Ag2CO3 to the more cationic AgOTf led to the formation of the product only in a very low yield,
and a significant amount of byproducts were accompanied. As for secondary amines, N-methylanilines having Me, MeO and Cl
substituents at the para- or meta- position of the phenyl groups all reacted smoothly with 1a, affording the products 3p-3s in 75%-93%
yields. Probably due to the steric effect, N-(n-butyl)aniline gave the product 3t in a moderate yield. In case of a more sterically
demanding substrate, i.e., N-isopropylaniline, the reaction took place less efficiently and the product 3u was formed only in 23% yield.
Notably, a cyano group is tolerated as examplified by the reaction of 3-(methyl(phenyl)amino) propanenitrile with 1a to produce 3v in
72% yield. In addition, cyclic secondary amines such as 1,2,3,4-tetrahydroquinoline, pyrrolidine and morpholine are also applicable to
afford the desired prodcuts 3w-3y in moderate yields. Moreover, different from the copper catalyzed ring-opening reaction [8], the
present reaction also enables internal alkynyl epoxides to be selectively converted to 2-amino homopropargyl alcohols, as examplified
by the successul preparation of 3z, 3aa and 3ab in 52%-88% yields. The regioselectivity of the ring-opening reaction was
unambiguously confirmed by the analysis of two typical crystalline products 3k and 3y through the X-ray crystallography technique
(Fig. 2). The corresponding crystallographic data of 3k and 3y (CCDC 1519643 and 1555636) can be obtained from the Cambridge
Crystallographic Data Centre.

Fig. 1. The reaction scope and structures of products.
Fig. 2. Molecular structures of compounds 3k and 3y.
Finally, a possible mechanism is proposed in Scheme 2. Initially, the mild Ag(I) species generated from Ag2CO3 coordinate to 1 to
activate the epoxide ring and the carbon-carbon triple bonds as a Lewis acid. The selective cleavage of one C-O bond releases the
strain energy of epoxide ring and may lead to the formation of the propargyl cation B, which is partially stabilized by the aryl
substituent. Different from a softer phosphorus nucleophile, the nucleophilic attack of amine 2 to the propargyl carbon of B may form
the intermediate C, protodemetalation of which finally gives the product and regenerate the catalyst [9a]. In addition, the direct attack
of the amine 2 to the intermediate A may also lead to the formation of the intermediate C. Mechanistically, this route is not fully
excluded and may also be considered.
Scheme 2. A proposed mechanism.
In summary, we have reported a Ag-catalyzed atom-economic ring-opening of propargyl epoxides with various amines. The reaction
takes place efficiently under mild conditions with high regioselectivity to provide an efficient and practical method for the synthesis of
a variety of 2-amino homopropargyl alcohols. Applications of the products for the synthesis of heterocyclic compounds are underway
and will be reported in due course.
Acknowledgments

We are grateful to the National Natural Science Foundation of China (No. 21302095), Research Fund for the Doctoral Program of
Higher Education of China (No. 20133221120003) and Jiangsu Provincial NSFC (Nos. BK20130945, BK20130924), Top-notch
Academic Programs Project of Jiangsu Higher Education Institutions (TAPP) and Nanjing Tech University for financial support. We
thank Mr. Yuanhua Wu and Prof. Dunru Zhu of Nanjing Tech University for the help of X-ray single crystal analysis.
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