CuI-catalyzed, one-pot, three-component huisgen cycloaddition reaction of conjugated enynes and in situ-generated azides

Article abstract of DOI:10.1080/00397911.2012.688229

A novel and efficient copper(I)-catalyzed three-component Huisgen cycloaddition reaction of conjugated enynes, alkyl halides, and sodium azide has been developed. These reactions were performed in the absence of amide ligands at room temperature, and the corresponding mono-and bis-1,2,3-triazoles were obtained in good to excellent yields in a one-pot procedure. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.

Full text of DOI:10.1080/00397911.2012.688229

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Cui-catalyzed One-Pot Three-Component Huisgen
Cycloaddition Reaction of Conjugated Enynes and in
Situ Generated Azides
Yan-Feng Zhang a , Xiao-Dan Han a , Chuan-Qing Ren a & Yu-Long Zhao a
a Department of Chemistry, Northeast Normal University, Changchun, P. R. China
Accepted author version posted online: 05 Mar 2013.
To cite this article: Yan-Feng Zhang , Xiao-Dan Han , Chuan-Qing Ren & Yu-Long Zhao (2013): Cui-catalyzed One-Pot Three-
Component Huisgen Cycloaddition Reaction of Conjugated Enynes and in Situ Generated Azides, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI:10.1080/00397911.2012.688229
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ACCEPTED MANUSCRIPT
CuI-Catalyzed One-Pot Three-component Huisgen Cycloaddition Reaction of
Conjugated Enynes and In Situ Generated Azides
Yan-Feng Zhang1, Xiao-Dan Han1, Chuan-Qing Ren1, Yu-Long Zhao1,
1Department of Chemistry, Northeast Normal University, Changchun, P. R. China
E-mail: zhaoyl351@nenu.edu.cn
Abstract
A novel and efficient copper(I)-catalyzed three-component Huisgen cycloaddition
reaction of conjugated enynes, alkyl halides and sodium azide has been developed. These
reactions were performed in the absence of amide ligands at room temperature and the
corresponding mono- and bis-1,2,3-triazoles were obtained in high to excellent yields in a
one-pot procedure.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications® to view the free supplemental file.
KEYWORDS: Click chemistry, conjugated enynes, Cu(I) catalysis, triazoles,
bis-triazoles
INTRODUCTION
Since the paramount discovery of the Cu(I)-catalyzed 1,3-dipolar azide-alkyne
cycloaddition (CuAAC) by the groups of Sharpless and Meldal independently,[1] the
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CuAAC reaction has found a myriad of applications in chemical synthesis, biology and
material science.[2] Recent efforts to further develop CuAAC have focused on one-pot
multicomponent reactions in which azides are obtained in situ prior to the cycloaddition.
The attraction of such an approach is that it avoids the isolation and handling of
hazardous azides and minimized time-consuming workup and purification protocols.
However, in contrast to many examples of one-pot multicomponent alkyne-azide
cycloaddition,[3] the Cu(I)-catalyzed three-component cycloaddition of conjugated enynes
and in situ generated azides is scarcely reported. To the best of our knowledge, only three
examples of three-component cycloaddition of conjugated enynes with in situ generated
azides have been reported by the groups of Fokin, Nielsen and Liang, but these reactions
need to be operated by heating, microwave heating or the use of mixture ionic liquids and
water as reaction media.[4] Herein, we report a copper(I)-catalyzed one-pot
three-component Huisgen cycloaddition of conjugated enynes, alkyl halides and sodium
azide at room temperature in DMSO-H2O solvent system.
Over the past decades, the potential of α-oxo ketene-S,S-acetals as versatile intermediates
in organic synthesis has been recognized.[5] During the course of our studies on the
chemistry of functionalized ketene dithioacetals,[6] a series of α-mono-, and di-ethynyl
ketene S,S-acetals 1 (Tables 1 -3) were prepared in high yields starting from easily
available -oxoketene dithioacetals under mild conditions.[7] As synthetic applications of
these electron-rich conjugated enynes, we have described the self-coupling reactions of
these conjugated enynes [8] and the addition reactions of these conjugated enynes with
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o-phenylenediamines[9a] and carboxylic acids,[9b] respectively. Recently, the [4+2]
cycloaddition reaction of these enynes with N-arylimines was also performed
successively in the presence of trifluoromethanesulfonic acid.[10] Encouraged by these
results, together with the consideration of importance of the click chemistry,[1-4] we paid
our attention to the [3+2] cycloaddition reaction of these electron-rich conjugated enynes
1 with organic azides. Herein, we wish to report the results in this area.
RESULTS AND DISCUSSION
In the present study, initially, the model reaction of enyne 1a (1.0 equiv), ethyl
2-bromoacetate (1.0 equiv) and NaN3 (1.2 equiv) was examined to optimized the
reaction conditions (Table 1). It was found that, the three-component cycloaddition
reaction could easily proceed to give the 1,2,3-triazoles 3a1 in 52% yield in the
presence of 3 mol% of CuI in DMSO at room temperature for 8 h under N2
atmosphere (Table 1, entry 1). To our delight, the yield of 3a1 was raised to 93% with
shorter reaction time (1h) when the reaction was performed in a 1:1 mixture of DMSO
and H2O (Table 1, entry 2). However, further decreasing a catalytic amount of CuI led
to relatively lower yield of 3a1 (Table 1, entry 3). Among other solvent systems tested,
such as DMSO/H2O (v/v, 1:2) and C2H5OH/H2O (v/v, 1:1), gave lower product yields
(Table 1, entries 4 and 5). No reaction was observed when the reaction was carried out
in C2H5OH or H2O (Table 1, entries 6 and 7). Meanwhile, when other simple copper
salts, such as CuBr and CuCl, were chosen as catalyst for this process, a relatively
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lower yield of 3a1 was obtained under otherwise identical reaction conditions (Table
1, entries 8 and 9).
Under the optimal conditions, the scope of the reaction was then investigated and the
results are summarized in Table 2. It was obvious that this three-component reaction
shows wide applicability for various alkyl halides 2. As a result, various alkyl bromides
such as ethyl 2-bromoacetate, 2-bromoacetonitrile, 2-bromoacetophenones with either
electron-neutral, electron-deficient, or electron-rich groups,
2-bromo-1-(naphthalen-2-yl)ethanone, 1-(biphenyl-4-yl)-2-bromoethanone, benzyl
bromide bearing either electron-neutral, electron-deficient, or electron-rich groups,
reacted quickly with 1a and NaN3 to give the corresponding 1,2,3-triazoles 3a1-10 in
excellent yields (Table 2, entries 1-10). Notably, in the case of benzyl chloride, the
three-component reaction also worked well, yielding the desired product 3a8 in 90%
yield (Table 2, entry 11). Similarly, the desired 1,2,3-triazole 3b1 could be prepared in
90% yield from the substrate 1b (Table 2, entry 12). However, 1-bromobutane remained
inert to the three-component cycloaddition reaction under otherwise identical reaction
conditions (Table 2, entry 13).
With azide-[3+2] cycloaddition reactions of conjugated enynes firmly established, we
further examined a potential approach for achieving double cycloadditions to construct
novel bis-triazoles. As expected, the bis-1,2,3-triazoles 3c1-5 could be assembled in high
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yields in a one-pot procedure by reacting conjugated enyne 1c with various alkyl
bromides 2 and NaN3 at room temperature for 24 h under otherwise identical reaction
conditions as above (Table 3, entries 1-5).
On the basis of the above experimental results together with the related reports,[1-4,9] the
reaction mechanism for the formation 3 is proposed in Scheme 1. Owing to the strong
electron-donating effect of the alkylthio (S-C sp2-conjugation), the terminal carbon atom
of 1 is believed to be more electron-rich, which favors the formation of copper (I)
acetylide A even in the absence of amines.[11] Then the azide, generated by the SN2
reaction of NaN3 with alkyl halides, coordinates to intermediate A, leading to the
formation of intermediate B, wich undergoes an intramolecular cyclization reaction to
give the intermediate D. Finally, metalated heterocycle D undergoes protonolysis,
delivering the desired product 3a and 3b and regenerating the catalyst (Scheme 1). In the
case of diyne 1c, the monotriazole generated reacts sequentially with another in situ
generated azides to give the bis-1,2,3-triazoles 3c (Scheme 1).[12]
In conclusion, we have demonstrated a novel and efficient copper(I)-catalyzed
three-component Huisgen cycloaddition reaction of conjugated enynes, alkyl halides, and
sodium azide. These reactions were performed in the absence of amide ligands at room
temperature and the corresponding mono- and bis-1,2,3-triazoles were obtained in high to
excellent yields in a one-pot procedure. The procedure avoids isolation and handling of
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organic azide, making this already powerful click process even more user-friendly and
safe. Further studies are in progress.
EXPERIMENTAL SECTION
All reagents were commercial and were used without further purification.
Chromatography was carried on flash silica gel (300-400 mesh). All reactions were
monitored using TLC on silica gel plates. The 1H NMR spectra were recorded at 500
MHz in CDCl3 and the 13C NMR spectra were recorded at 125 MHz in CDCl3 or
DMSO-d6. All coupling constants (J values) were reported in Hertz (Hz). IR (KBr)
spectra were recorded on in the range of 400~4000 cm-1. High-resolution mass spectra
(HRMS) were obtained using a Bruker microTOF II focus spectrometer (ESI).
General Procedure For The Preparation Of 3 (3a1 As Example)
Under a nitrogen atmosphere, CuI (0.03 mmol, 5.7 mg) was added in one portion to a
stirred solution of 1a (1.0 mmol, 214 mg), ethyl 2-bromoacetate (1.0 mmol, 0.11 mL),
NaN3 (1.2 mmol, 78 mg) in DMSO and H2O (8.0 mL, 1:1). The reaction mixture was
stirred for 1.0 h at room temperature. After 1a was consumed (monitored by TLC), the
reaction mixture was poured into water (40 mL) under stirring. The precipitated solid was
collected by filtration, and dried in vacuo to afford the crude product, which was purified
by a short chromatography column (silica gel, petroleum ether/acetone/dichloromethane
= 6/1/1) to give 3a1 (319 mg, 93 %) as a white solid. mp 122–124 °C; 1H NMR (CDCl3,
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500 MHz) δ 1.30 (t, J = 7.0 Hz, 3H), 2.18 (q, J = 7.0 Hz, 2H), 2.89 (t, J = 7.0 Hz, 2H),
3.01 (t, J = 7.0 Hz, 2H), 3.72 (s, 3H), 4.27 (q, J = 7.0 Hz, 2H), 5.19 (s, 2H), 7.66 (s, 1H);
13C NMR (CDCl3, 125 MHz) δ 14.3, 23.8, 29.6, 29.9, 51.2, 52.0, 62.6, 111.5, 125.3,
143.3, 163.6, 165.3, 166.4; IR (KBr, cm-1): 3143, 2928, 1759, 1691, 1480, 1375, 1361,
+
1219, 1075; HRMS (ESI-TOF) calcd for C13H18N3O4S2 ([M + H]+): 344.0733, found:
344.0734.
Complete experimental details can be found online in the Supporting Information.
ACKNOWLEDGMENT
Financial support from the National Natural Sciences Foundation of China (21172032
and 20972026) is gratefully acknowledged.
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Table 1. Optimization of reactin conditions
Entry
Catalyst
(mol%)
Solvent
Time
(h)
3a1
Yielda
(%)
52
1
2
CuI (3)
CuI (3)
DMSO
8
1
DMSO-H2O (v/v,
1/1)
93
3
4
5
CuI (2)
CuI (3)
CuI (3)
DMSO-H2O (v/v,
1/1)
3
81
61
40
DMSO-H2O (v/v,
1/2)
8
C2H5OH-H2O
(v/v, 1/1)
C2H5OH
24
6
7
8
9
CuI (3)
24
24
0
CuI (3)
H2O
0
CuBr (3)
CuCl (3)
DMSO-H2O (1/1) 1
DMSO-H2O (1/1) 1
76
82
aIsolated yields.
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Table 2. One-pot synthesis of 1,2,3-triazoles 3a and 3b from alkyl halides, NaN3, and
enynes 1a and 1ba
Entry
R
n
R1
X
Time Product
(h)
Yieldb
(%)
93
1
1
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CONHPh
CO2Me
2
2
2
2
2
2
2
2
2
2
2
1
2
C2H5OCO
CN
Br 1.0
Br 1.0
Br 1.5
Br 1.5
Br 1.5
Br 1.5
Br 1.5
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1a
3a1
3a2
3a3
3a4
3a5
3a6
3a7
3a8
3a9
3a10
3a8
3b1
3a11
2
92
3
C6H5CO
90
4
4-ClC6H4CO
4-CH3OC6H4CO
89
5
86
6
92
7
90
8
C6H5
Br
Br
Br
Cl
2
1
2
5
95
9
4-NO2C6H4
4-CH3C6H4
C6H5
97
10
11
12
13
93
90
4-ClC6H4CO
CH3CH2CH2
Br 1.5
Br
90
8
0
aReaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), NaN3 (1.2 mmol), 3% CuI in
DMSO/H2O (8.0 mL; v/v, 1:1) at room temperature.
bIsolated yields.
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Table 3. One-pot synthesis of bis-1,2,3-triazoles 3c from alkyl bromides, NaN3, and
enyne 1ca
Entry
R1
Time
(h)
24
Product
Yielda
(%)
85
1
2
3
4
5
C2H5OCO
CN
3c1
3c2
3c3
3c4
3c5
24
88
C6H5
24
83
4-NO2C6H4
4-CH3C6H4
24
85
24
80
aReaction conditions: 1c (1.0 mmol), 2 (2.0 mmol), NaN3 (2.2 mmol), 3% CuI in
DMSO/H2O (10.0 mL; v/v, 1:1) at room temperature.
bIsolated yields.
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16

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Scheme 1. Proposed mechanism for the formation of 3
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17