Copper-catalyzed efficient multicomponent reaction: synthesis of benzoxazoline-amidine derivatives

Article abstract of DOI:10.1002/adsc.200900525

We have developed an efficient copper-catalyzed method for the synthesis of the benzoxazoline-amidine derivatives. The protocol uses inexpensive copper(I) iodide as the catalyst, and furnished the expected product in good to excellent yields by a three-co

Full text of DOI:10.1002/adsc.200900525

FULL PAPERS
DOI: 10.1002/adsc.200900525
Copper-Catalyzed Efficient Multicomponent Reaction: Synthesis
of Benzoxazoline-Amidine Derivatives
Yongjia Shang,a,* Xinwei He,a Jinsong Hu,a Jianwei Wu,a Min Zhang,a Shuyan Yu,a
and Qianqian Zhanga
a
Key Laboratory of Functional Molecular Solids, Ministry of Eudcation, Anhui Key Laboratory of Molecule-Based
Materials, College of Chemistry and Materials Science, Anhui Normal University, Wuhu 241000, Peopleꢀs Republic of
China
Fax : (+86)-553-386-9303; phone: (+86)-553-393-7138; e-mail: shyj@mail.ahnu.edu.cn
Received: July 28, 2009; Published online: October 28, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900525.
Abstract: We have developed an efficient copper-cat- of triethylamine. This novel synthetic protocol is se-
alyzed method for the synthesis of the benzoxazo- lective, efficient and general. A plausible mechanism
line-amidine derivatives. The protocol uses inexpen- for this process is proposed.
sive copper(I) iodide as the catalyst, and furnished
the expected product in good to excellent yields by a
three-component reaction of sulfonyl azides, termi- Keywords: alkynes; azides; benzoxazoline-amidine
nal alkynes and Schiffsꢀ bases in terahydrofuran derivatives; copper catalysis; multicomponent reac-
(THF) at room temperature for 8 h in the presence tion; phenolic Schiffsꢀ bases
Introduction
amounts of reagents such as PPTS/PPA, p-TsOH,
SOCl2/HF, PPh3-DEAD, metal catalyst/oxidizing
Arylbenzoxazoline derivatives are an important class agents, etc, and harsh reaction conditions such as
of compounds and provide a common heterocyclic strong acid, high temperature. As a result, a general,
scaffold. They exhibit a wide range of biological and practical and efficient protocol for the synthesis of
medicinal activities including anticancer, Gram-posi- benzoxazoline derivatives is of interest and remains a
tive antibacterial,[1] anti-HIV,[2] antibiotic,[3] antipara- challenging project.
sitic,[4] anti-inflamatory,[5] H2-antagonist, and elastase
Many MCRs (multicomponent reactions) show ad-
inhibitor[6] properties. They are also fluorescent vantages in atomic economy, environmental friend-
whitening agents,[7] constituents of cyanine dyes,[8] ness, simplified steps, and efficient use of resources.[24]
heat resistant fibers,[9] fluorescent materials,[10] optical The synthetic utility of the generated molecules from
brighteners,[11] metal-coordinated ligands,[12] and me- copper-catalyzed three-component reactions has been
dicinally significant compounds.[13]
extensively investigated in various areas. Recently,
It was previously demonstrated that arylbenzoxazo- CuI-catalyzed[25] MCRs concerning sulfonyl azides
line derivatives can be obtained from 2-aminophenols and alkynes have drawn special interest. Chang
via heterocyclization reactions catalyzed by strong et al.[26] and Wangꢀs group[27] have reported the effi-
acid.[14] Another method for the synthesis of arylben- cient copper-catalyzed multicomponent reactions of
zoxazoline derivatives is the oxidative cyclization of sulfonyl azides, terminal alkynes and amines, water,
Schiffsꢀ bases.[15] The oxidants could be PhI
NiO2,[17] Ba(MnO4)2,[18] DDQ,[15b] Mn
Pb
(OAc)2,[20] and ThClO4.[21] Other methods for syn- din-2-imines, iminocoumarins, and 5-arylidene-2-
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
thesis of arylbenzoxazoline derivatives involving Ru- imino-3-pyrrolines efficiently.
catalyzed hydroamination of diynes[22] and CuI-cata-
Amidines are prominent structural motifs in numer-
lyzed[23] cyclization of ortho-haloanilides have been ous bioactive natural products.[28] We accordingly en-
reported. However, most of these methodologies visioned that amidines containing benzoxazoline moi-
suffer from lengthy procedures that require excess eties may afford unique biological activities, which
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Yongjia Shang et al.
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(Scheme 1). At the outset of our studies, we tried to
optimize the reaction conditions and studied the
effect of the substituents of the substrates, and then
we also proposed a plausible mechanism for this
three-component reaction.
Scheme 1. Synthesis of benzoxazoline-amidine derivatives
(4). Conditions: 1) CuI (0.1 equiv.), 2) TEA (2 equiv., slow
addition), 3) THF (solvent), 0–58C, 8 h.
Results and Discussion
We began our investigation by performing the three-
component reaction of p-tolylsulfonyl azide, phenyl-
provided the impetus to synthesize these novel com-
pounds.
ACHTUNGTRENNUNG
Meanwhile the application of the copper-catalyzed (Table 1, entry 2), the major isolated product was not
three-component reactions as a tool for the synthesis the expected azetidinimine (11%) product 5h,[25d] but
of high utility compounds continues to expand. And instead benzoxazoline-amidine 4h (62%) was isolated.
copper-catalyzed azide-alkyne three-component reac- The structure of product 4h was unambiguously con-
tions are an efficient way to produce the N-sulfonyl- firmed by X-ray diffraction analysis, which was in ac-
1
G
synthesis of benzoxazoline-amidine derivatives via HR-MS results (Figure 1).[29]
CuI-catalyzed multicomponent reactions of sulfonyl
In order to study the effect of various reaction con-
azides, alkynes and phenolic Schiffsꢀ bases ditions, we tested a wide range of reaction parame-
ters, including catalyst, bases, temperatures and sol-
vents. While no reaction took place in the absence of
a copper catalyst, when the reaction of p-tolylsulfonyl
Table 1. The optimal reaction conditions of CuI-catalyzed
three-component reactions of sulfonyl azides, alkynes and
azide (1a) with phenylacetylene (2a) and the phenolic
Schiffsꢀ base (3b) was tried with CuI in the absence of
an external base, also no conversion was observed.
We found that the use of alternative bases, such as
phenolic Schiffsꢀ bases.
Entry
Base
Solvent
Temp. [oC]
Yield [%][a]
4h
5h
1
2
3
4
5
6
7
8
TEA
TEA
TEA
TEA
Pyridine
K3PO4
K3PO4
K3PO4
K2CO3
TEA
THF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0–5
0–5
0–5
0–5
50
70
62
67
63
47
69
65
71[b]
65
53
72
54
5
DMF
CH3CN
CH2Cl2
THF
THF
CH2Cl2
THF
THF
DMSO
THF
11
10
9
7
6
11
trace
8
9
10
11
12
9
TEA
TEA
trace
15
THF
[a]
Reaction conditions: 1a (1.1 mmol), 2a (1.0 mmol), 3a
(1.1 mmol), CuI (0.1 mmol), and TEA (2.0 mmol), 8 h,
N2, 0 ~58C.
[b]
Reaction time: 12 h.
Figure 1. X-ray crystal structure of product 4h.
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Copper-Catalyzed Efficient Multicomponent Reaction
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Table 2. Cu-catalyzed tri-component coupling for the formation of arylbenzoxazolines.[a]
Entry
R1
R2
R3
Product
Yield [%]
1
2
3
4
5
6
7
8
C6H5 (1a)
4-MeC6H4 (1b)
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1b
1a
1b
1b
C6H5 (2a)
2a
CH2CH2OTBS (2b)
2b
n-C5H11 (2c)
2c
2a
2a
2b
2b
2c
2c
2a
2b
2b
2c
H (3a)
3a
3a
3a
3a
3a
4-CH3 (3b)
3b
3b
3b
3b
3b
4-Cl (3c)
3c
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
70
73
81
83
92
90
75
72
79
83
92
91
85
80
84
91
65
86
83
90
91
83
9
10
11
12
13
14
15
16
17
18
19
20
21
22
3c
3c
1a
1b
1a
1b
2a
2b
2b
2c
4-NO2 (3d)
3d
3d
4-OCH3 (3e)
3e
3a
4s
4t
4u
4v
1a
2c
4-ClC6H4 (1c)
4-CH3C6H4 (2d)
[a]
Reaction conditions: sulfonyl azide (1.1 mmol), alkyne (1.0 mmol), phenolic Schiffsꢀ bases (1.1 mmol), CuI (0.1 mmol),
THF (5 mL), TEA (2.0 mmol), N2, 0–58C, 8 h
Et3N, and solvents, such as tetrahydrofuran (THF), in of products were also obtained from substrates incor-
the reaction gave good chemoselectivity. Solvents porating additional substituents on the phenolic
other than terahydrofuran afforded low yields Schiffsꢀ bases. Electron-donating groups (Table 2, en-
(Table 1, entries 2–4 and 10). As shown in Table 1, the tries 7 and 20) on the phenolic Schiffsꢀ bases gave
optimal reaction conditions are those with THF as higher yields compared to electron-withdrawing
solvent, K3PO4 or TEA as base, at the temperature of groups (Table 2, entry 17). Phenyl- and p-tolylsulfonyl
0–58C (Table 1, entries 8 and 11), which led to the azides appeared to have similar reactivity and equally
formation of benzoxazoline-amidines in 71% or 72% high yields were obtained with these azides.
yield with a trace amount of the corresponding azeti-
We propose a plausible mechanism for this three-
dinimines. Other bases and solvents gave lower yields component domino-like process (Scheme 2). First, in
and chemoselectivities. We also found that increasing the presence of CuI, sulfonyl azide 1 reacts with the
the reaction temperature to 508C (Table 1, entry 12), alkyne 2 to form the ketenimine species B proposed
also led to lower yields and lower chemoselectivities. by Chang[26] and Wang.[27] Protonation of A gives
Utilizing the optimal reaction conditions, we inves- rise to the highly reactive ketenimine B, and the
tigated the scope of the multicomponent reaction of imine nitrogen of 3 attacks the intermediate B to
various sulfonyl azides, phenolic Schiffsꢀ bases, and generate a [2+2] cycloaddition product 5. And then
terminal alkynes to produce arylbenzoxazoline deriv- the base (TEA) removes a proton of the hydroxy
atives.[28] The results of these reactions are given in group of 5 to give a phenoxide ion C, which quickly
Table 2.
attacks the carbon of the azetidinimine ring to gen-
We found that both alkyl- and arylalkynes gave the erate the anionic benzoxazoline D, which receives a
desired products, but the arylalkynes gave relatively proton to generate the benzoxazoline-amidines de-
lower yields of the products. Good to excellent yields rivatives 4.
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Yongjia Shang et al.
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Scheme 2. Possible mechanistic pathways leading to the benzoxazoline-amidines derivatives 4.
Conclusions
mesh), purchased from Qingdao Haiyang Chemical Plang,
China.
In conclusion, a novel, selective and efficient general
method for the synthesis of benzoxazoline-amidines
via a three-component reaction of readily available
sulfonyl azides, terminal alkynes and phenolic Schiffsꢀ
bases is presented. The resulting heterocycle products
should have an important potential applications in the
synthesis of the medicines, dyes, and pesticides etc.
Further studies on related MCRs and their applica-
tions are in progress.
General Procedure for the Synthesis of
Benzoxazoline-Amidine Derivatives
To a stirred mixture of CuI (0.1 mmol), p-toluenesulfonyl
azide (1.2 mmol), phenylacetylene (1 mmol), and phenolic
Schiffsꢀ base (1.2 mmol) in anhydrous tetrahydrofuran
(5 mL) was slowly added triethylamine (2 mL) via syringe
under an N2 atmosphere at 0–58C. After stirring the reac-
tion mixture for 8 h, it was evaporated, washed by water,
and then extracted with CH2Cl2. The combined organic
layers were dried over anhydrous Na2SO4, filtered, and con-
centrated under vacuum. The residue was purified by flash
column chromatography on silica gel (200–300 mesh) with
ethyl acetate and petroleum ether (1:15) as eluting solvent
to give the desired product 4.
Experimental Section
General Comments
All reagents involved in the experiments were commercially
available and used without further purification. Melting
points were determined on XT4A (uncorrected tempera-
tures are given). IR spectra were obtained on a Perkin–
Elmer FT-IR spectrometer spectrum-2000 using potassium
bromide pellets or as liquid films between two sodium chlo-
ride pellets. Mass spectra were recorded in a TOF-mass
spectrometer model no. Agilent 6460. 1H NMR and
13C NMR spectra (300 MHz) were recorded on a Bruker
Acknowledgements
The authors thank National Natural Science Foundation of
China (Grant No. 20872001) and the Anhui Education De-
partment (Grant No. TD200707).
spectrospin 300 MHz. All NMR samples were run in CDCl3 References
and chemical shifts are expressed as ppm relative to internal
Me4Si and the metallic nature of the particles was confirmed
with a UV spectrophotometer (Shimadzu). Column chroma-
tography was carried out with the use of silica gel (200–300
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