Highly regioselective dipolar cycloadditions of nitrile oxides with α,β-acetylenic aldehydes

Article abstract of DOI:10.1016/j.tetlet.2016.01.019

1,2-Oxazol derivatives 3 were prepared by a highly regioselective 1,3-dipolar cycloaddition of nitrile oxides and α,β-acetylenicaldehydes 1 in good yields. Reactive nitrile oxides were generated in situ from stable chloro-oxime reagents 2 and triethyl ami

Full text of DOI:10.1016/j.tetlet.2016.01.019

Accepted Manuscript
Highly regioselective dipolar cycloadditions of nitrile oxides with α,β -acety-
lenic aldehydes
Longqiang Jiang, Tao Gao, Zhi Li, Shaofa Sun, Claudia Kim, Changfeng Huang,
Haibing Guo, Jian Wang, Yalan Xing
PII:
S0040-4039(16)30018-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.01.019
TETL 47183
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
30 November 2015
26 December 2015
6 January 2016
Please cite this article as: Jiang, L., Gao, T., Li, Z., Sun, S., Kim, C., Huang, C., Guo, H., Wang, J., Xing, Y., Highly
regioselective dipolar cycloadditions of nitrile oxides with α,β -acetylenic aldehydes, Tetrahedron Letters (2016),
doi: http://dx.doi.org/10.1016/j.tetlet.2016.01.019
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Highly regioselective dipolar cycloadditions of nitrile oxides with
-acetylenic aldehydes
a
Longqiang Jiang,a Tao Gao,a Zhi Li,a Shaofa Sun,*,a Claudia Kim,b Changfeng Huang,c Haibing Guo,*, Jian Wanga and
Yalan Xing*,b
aNon-power Nuclear Technology Collaborative Innovation Center, School of Nuclear Technology and Chemistry & Life
Science, Hubei University of Science and Technology, Xianning 437100, China.
bDepartment of Chemistry, William Paterson University, 300 Pompton Rd, Wayne, NJ 07470, US
cBennett Department of Chemistry, West Virginia University, Morgantown, WV 26506, United States
*E-mail: sunshaofa@mail.hbust.com.cn, haibingguojj@yahoo.com, xingy@wpunj.edu
Graphic abstract
Keywords:
1,3-dipolar cycloaddition, nitrile oxide, -acetylenic aldehydes, regioselectivity
Abstract
1,2-oxazol derivatives 3 were prepared by a highly regioselective 1,3-dipolar cycloaddition of nitrile oxides and
-acetylenicaldehydes 1 in good yields. Reactive nitrile oxides were generated in situ from stable chloro-oxime reagents 2 and
triethyl amine. The cycloaddition reaction showed broad substrate scopes and good functional groups compatibility.
Introduction
Nitrile oxides have been extensively utilized in 1,3-dipolar cycloaddition reactions as dipoles to generate synthetically useful
heterocyclic structures.1 But to achieve the regioselective 1,3-dipolar cycloaddition of nitrile oxides has always been a challenge in
organic synthesis.2 Over the years, ketones and aldehydes have been thoroughly studied as dipolarphiles in the regioselective
cycloadditions to nitrile oxides.2 However, regioselective 1,3-dipolar cycloaddition of nitrile oxides with -acetylenic aldehydes to
afford isoxazole derivatives 3 have not been systematically investigated.
Isoxazole derivatives 3 are versatile structure motifs in organic synthesis.3 Both Sarlo4 and Caramella5 reported a synthesis of

3,5-diphenylisoxazole-4-carbaldehyde from 1,3-dipolar cycloaddition of phenyl nitrile oxide and trans-cinnamaldehyde followed by
dehydration. Unfortunately, the reaction yields of both cases were low, and thus their protocols were not synthetically applicable.
Suzuki et al. described a regioselective preparation of 3,5-diphenylisoxazole-4-carbaldehyde, the precursor of a fluorescent
1,2-oxazole compound, from 1,3-dipolar cycloaddition of phenyl nitrile oxide and 3-phenylpropiolaldehyde.6 However, the reaction
conditions were not optimized and the substrate scopes and the limitations were not explored. Moreover, the nitrile oxide was
generated from the unstable and explosive benzaldoxime under strong oxidative conditions.
Scheme 1. Synthesis of 1,2-oxazole compounds from Sarlo, Caramella and Suzuki.
As part of our ongoing effort to develop efficient and regioselective methods in preparation of heterocyclic compounds, we have
found a simple, efficient and regioselective synthesis of 1,2-oxazol derivatives from 1,3-dipolar cycloaddition of nitrile oxides with α,
β-acetylenic aldehydes.
Results and Discussion
Since nitrile oxides are very reactive and unstable, we decided to use relatively stable reagents chloro-oximes to generate
nitrile oxides in situ upon treatment with base. The reagents chloro-oximes could be easily prepared based on a known procedure.7,8
We chose phenylpropiolaldehyde,9 an α, β-acetylenic aldehyde, and -chlorobenzaldoxime as model substrates to investigate the
regioselectvity and determine the optimal reaction conditions. First different bases that were used to facilitate the oxime formation
were tested. In terms of reaction yield and regioselectivity, the 1,3-dipolar cycloaddition proceeded well with many types of bases
(Table 1). Generally, amine-type bases participated in the 1,3-dipolar cycloaddition with a better yield than inorganic bases.
Trimethylamine (TEA) was found to afford the product 3a as the single regioisomer in best yield (80%) at room temperature in 0.5 h

in toluene (entry 1). This high regioselectivity was consistent with Suzuki’s report.6 We then screened different solvents of this
cycloaddition reaction. Toluene delivered higher regioselectivity (80% yield) than benzene, THF, CH3CN, or C2H5OH (entries 1-8),
whereas poor yields were observed in chlorinated solvents such as CH2Cl2 and CHCl3 (~ 40%) even with longer reaction time and no
reaction at all in H2O. The single product 3a was obtained in all the above conditions with no other isomers detected. Therefore, TEA
and Toluene as the base and solvent respectively at room temperature were identified as the optimal reaction conditions.
Entrya
Solvent
T (h)
0.5
0.5
0.5
0.5
2
Yield (%)b
Base
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
1
2
3
4
5
6
7
8
80
75
73
65
62
45
43
n.r
Toluene
Benzene
THF
CH3CN
C2H5OH
CH2Cl2
CHCl3
H2O
3
3
4
9
DCHA
Toluene
0.5
73
10
11
12
13
14
15
0.5
2
75
70
40
65
55
72
n-butylamine
pyridine
NaOH
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
2
NaOAc
2
NaHCO3
2
K2HPO4
2
a Reaction conditions: a mixture of 1a (1.0 mmol), 2a (1.1 mmol), Base (1.2
mmol), in solvent (2 mL) were stirred at room temperature for a certain period of
time. b Yield of isolated product.
Table 1. Optimization of reaction conditions

With the optimal conditions in hand, we next extended our attention to explore the substrate scopes and limitations of one reaction
partner α, β-acetylenic aldehydes (Table 2). A wide scope of α, β-acetylenic aldehydes including aromatic, aliphatic and heterocyclic
aromatic derivatives could participate well in the cycloadditon reaction regioselectively. Aryl α, β-acetylenic aldehydes all
regioselectively provided the cycloaddition products in good to moderate yields (products 3a-3h). Electron withdrawing groups such
as fluorine and bromine and electron donating groups such as methoxyl, methyl, and t-butyl groups on the aromatic ring did not affect
the reaction yields. Heterocyclic aromatic ring such as thiophene also gave good yield (3g, 75%) of the corresponding product.
Relatively lower yields (3i-3j) were observed when alkyl α, β-acetylenic aldehydes were used in this cycloaddition reaction.
R1
Product
3f
R1
Yield（%）
Yield（%）
Product
3a
80
70
3b
3c
3d
3e
78
81
73
76
3g
3h
3i
75
70
65
67
3j
Table 2: Scope of propioaldehydes
We lastly investigated the substrate scopes and limitations of another reaction partner chloro-oximes (Table 3). Aryl chloro-oximes
underwent the 1,3-dipolar cycloaddition with phenylpropiolaldehyde in good yields and showed excellent regioselectivity. The
substitution of aryl chloro-oximes with electron-donating or withdrawing groups on different positions of the aromatic rings was all
accommodated, furnishing the 1,2-oxazol derivatives regioselectively in good yields (3k-n, 3q, 3r, 3t). Similar as that of alkyl

aldehydes partner, alkyl or alkene substituted chloro-oximes gave relatively lower yields than that of aromatic counterparts.
product
3k
R2
Yield (%) product
R2
Yield (%)
65
76
3p
3l
3m
3n
78
78
69
3q
3r
3s
82
83
65
3o
68
3t
76
Table 3 Scope of chloro-oximes
This reaction is a typical 1,3-dipolar cycloaddition reaction. First, treatment of chloro-oximes with TEA generates the reactive
1,3-dipolar nitrile oxide in situ. Then the typical 1,3-dipolar cycloaddition of nitrile oxide with alkynes delivers the isoxazole
derivatives. The excellent regioselectivity of this cycloaddition can be explained by the electronic effect of the , -acetylenic
aldehyde, as shown in scheme 2, the nucleophilic oxygen of nitrile oxide would regioselectively add to the electron-deficient -carbon
of the aldehyde.
Scheme 2. Reaction mechanism
Conclusion
In summary, a highly regioselective 1,3-dipolar cycloaddition of nitrile oxides and -acetylenic aldehydes was developed using
nitrile oxides generated in situ from stable chloro-oximes reagents by base. The cycloaddition reaction afforded the 1,2-oxazol
derivatives at room temperature in good yields under mild reaction conditions and in short time. Both chloro-oximes and
-acetylenic aldehydes reaction partners showed broad substrate scopes. To the best of our knowledge, this is the first systematic
investigation of a regioselective 1,3-dipolar cycloaddition of nitrile oxides and -acetylenic aldehydes to prepare 1,2-oxazol

derivatives. Further extension of this efficient synthetic strategy to the scope of -acetylenic ketones and esters and continuing
exploration of its application is under way in our laboratory and will be presented in due course.
Acknowledgement
The authors are grateful to the National Natural Science Foundation of China (NSFC-21202136). This research was supported (in part)
by a grant from the Center for Research, College of Science and Health, William Paterson University of New Jersey.
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