Application of hantzsch dihydropyridine in copper-catalyzed [3 + 2] cycloaddition of terminal alkynes with azides

Article abstract of DOI:10.1080/00397911.2013.789113

2,6-Dimethyl-3,5-bis(ethoxycarbonyl)-1,4-dihydropyridine (dihydropyridine Hantzsch ester, DHPHE) and CuSO4 · 5H2O efficiently accelerated azide-alkyne cycloaddition reactions of both aliphatic and aromatic substrates and gave 1,4-disubstituted 1,2,3-triazoles as the only isomer in good to excellent yields at room temperature with 1 mol% of CuSO4 · 5H2O/DHPHE (1:1 in molar ratio). The reaction could be carried out smoothly in methanol in air with high efficiency. DHPHE may play multiple important roles in the reaction: a reducing reagent to generate the catalytic center copper(I) from CuSO4, a base to help form the intermediate acetylide, and a ligand to stabilize the catalytic copper(I) species via coordination after being transformed to pyridine derivative. Taylor and Francis Group, LLC.

Full text of DOI:10.1080/00397911.2013.789113

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Application of Hantzsch Dihydropyridine in Copper-
Catalyzed [3 + 2] Cycloaddition of Terminal Alkynes
with Azides
Zuxi Jin a , Peng Xue a & Enqin Fu a
a College of Chemistry and Molecular Sciences, Wuhan University , Wuhan , P. R. China
Accepted author version posted online: 15 Aug 2013.
To cite this article: Synthetic Communications (2013): Application of Hantzsch Dihydropyridine in Copper-Catalyzed [3 + 2]
Cycloaddition of Terminal Alkynes with Azides, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2013.789113
To link to this article: http://dx.doi.org/10.1080/00397911.2013.789113
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Application of Hantzsch Dihydropyridine in Copper-Catalyzed [3+2] Cycloaddition
of Terminal Alkynes with Azides
Zuxi Jin1, Peng Xue1,, Enqin Fu1
1College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, P. R. China
Address correspondence to Peng Xue, College of Chemistry and Molecular Sciences,
Wuhan University, Wuhan, P. R. China. Email: chxuepeng@whu.edu.cn
Abstract
2,6-Dimethyl-3,5-bis(ethoxycarbonyl)-1,4-dihydropyridine (dihydropyridine Hantzsch
ester, DHPHE) and CuSO4·5H2O efficiently accelerated azide-alkyne cycloaddition
reactions of both aliphatic and aromatic substrates and gave 1,4-disubstituted
1,2,3-triazoles as the only isomer in good to excellent yields at room temperature with 1
mol% of CuSO4·5H2O/DHPHE (1:1 in molar ratio). The reaction could be carried out
smoothly in methanol in air with high efficiency. DHPHE may play multiple important
roles in the reaction: a reducing reagent to generate the catalytic center copper(I) from
CuSO4, a base to help form the intermediate acetylide and a ligand to stabilize the
catalytic copper (I) species via coordination after being transformed to pyridine
derivative.
[Supplementary materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications® for the following free supplemental resource(s): Full
experimental and spectral details.]
KEYWORDS: Hantzsch ester; dihydropyridine; click chemistry; cycloaddition; copper
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INTRODUCTION
Since Cu(I)-catalyzed azide-alkyne cycloaddition (AAC) for regioselective synthesis of
1,4-disubstituted 1,2,3-triazoles was reported,[1] a number of papers have appeared to
develop this simple “click” methodology[2,3] and disclose its applications in such fields as
materials science[4] and medicinal chemistry[5] due to their unique chemical and structural
properties.[6] Typically, such a cycloaddition reaction involves an intermediate of Cu(I)
acetylide, which then participates in an annulation with an azide upon coordination.
Mostly the copper sources came from direct addition of Cu(II) species, from which
catalytic Cu(I) could be generated in situ in the presence of a reducing agent such as
sodium ascorbate (NaAsc).[7] Cu(I) salts have rarely been used directly because of
instability[8] and the formation of coupling byproducts.[9] To keep the catalyst effective
and reactive, Cu(I)-catalyzed AAC usually required the presence of a nitrogen-containing
base (for CuI salts), exclusion of oxygen from the reaction system,[10] and sometimes high
loading of catalyst that might be a severe obstacle when it was applied in large scales.[11]
Recently, some AAC catalytic systems have been developed, for example, Cu(I)
species immobilized on solid supports,[12] copper-containing nanoparticles,[13] and amine,
phosphane or carbene-based complexes,[14] to enhance catalytic activity and/or recycle
the catalysts. With reducing agent free, chelation-assisted Cu(II)-accelerated AAC was
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reported on picolyl substrates,[15] it was proposed that the alcoholic solvents and/or
terminal alkynes helped form Cu(I) species.
2,6-Dimethyl-3,5-bis(ethoxycarbonyl)-1,4-dihydropyridine (dihydropyridine Hantzsch
ester, DHPHE), readily available by simple preparation[16] or commercial sources, stable
in air, soluble in most organic solvents, and always used as a model compound for
Coenzyme I, NADH, can reduce Cu(II) to Cu(I) to give pyridine Hantzsch ester (PHE),[17]
which may serve as both a ligand[18] and a base. Bearing this in mind, DHPHE should
take multiple roles such as a reducing reagent to form copper(I), a base to help form Cu(I)
acetylide and a ligand for Cu(I) species after oxidized by copper(II), thus may find
application in AAC as an alternative to NaAsc when it is carried out in organic media.
Herein we report the results of this efficient catalytic system, CuSO4/DHPHE, for AAC
in air at room temperature.
DISCUSSION
Simple substrates such as benzyl azide and phenylacetylene were chosen for the model
reaction, the catalytic activity of copper(I) depended on the counterions: with 1 mol%
.
loading of Cu2+ and DHPHE, CuSO4 5H2O gave the highest yield and exhibited high
catalytic activity in MeOH: 98% yield in 10 h, whereas other Cu(II) salts such as
.
.
.
.
CuCl2 2H2O (20%), Cu(NO3)2 3H2O (40%), Cu(AcO)2 H2O (48%), Cu(ClO4)2 6H2O
(12%) gave poor to moderate yields; in the absence of DHPHE and PHE, CuBr (10%)
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and CuI (6%) gave poor yields. Increasing the catalyst loading enhanced the efficiency of
the reaction, for example, with the loadings changed to 10 mol%, both
.
CuSO4 5H2O/DHPHE (96% in 4 h) and CuBr/PHE (90% in 10 h) gave excellent yields.
.
Lowering the loading of CuSO4 5H2O even to 0.25 mol% had a little effect on the yield
(93% in 24 h). Addition of 5 mol% CaCO3 as acid scavenger had little improvement on
the yield (98%), though protons, which may prevent the formation of Cu (I) acetylide,
might be produced during the aromatization of DHPHE. [17]
DHPHE is necessary for the reaction with the ability of reducing to generate copper(I)
.
species. With 1 mol% CuSO4 5H2O, 19% yield of the above model reaction was achieved
in the absence of DHPHE even though the reaction was extended to 24 h, which was in
sharp contrast with that in the presence of DHPHE ( 98% yield). On the other hand, the
presence of PHE (1 mol%), the product of DHPHE upon oxidation, improved the yields
.
of the reactions with copper(I) halides and CuSO4 5H2O (the yields were 25%, 15% and
.
36% for 1 mol% CuBr, CuI and CuSO4 5H2O, respectively, whereas the yields were 10% ,
6% and 19% without PHE as mentioned above) , which indicates that PHE may play dual
roles of ligand and base in the reaction and improve the catalytic activity.
Besides in MeOH, in DMF it also gave excellent yield (98%), solvents such as EtOH
(70%), DMSO (60%), H2O (60%) were moderate, while t-BuOH, i-PrOH, THF, CH3CN
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were poor (less than 10%). However, in DMF, the reaction was required to be carried out
in an inert atmosphere.
.
We performed AAC under the optimized conditions as follows: 1 mol% CuSO4 5H2O as
the catalyst, 1 mol% DHPHE as the additive, and methanol as the reaction medium, at
room temperature without the air excluded out.
As shown in Table 1, for all the examined substrates, reactions were run smoothly to
reach completion in about 10 h, and the corresponding triazoles were obtained in high
yields and quality after simple filtration and washings. Several single crystals suitable for
X-ray diffraction were obtained by slow diffusion of petroleum ether into each CH2Cl2
solution of the products 3, 4, 18. The configurations confirmed the structure as the
1,4-isomer. Figure 1 shows the structure of 18.
Electronic properties of the substituents seem to take little effect: both electron-rich and
electron-poor substrates reacted well even with steric hindrance as shown in Entries 4, 11,
12, 16, 18. Double "clicks" also worked well with diynes and diazides as shown in
Entries 19-23. This is probably due to the unique nature of the catalytic system
.
CuSO4 5H2O/DHPHE: DHPHE may take multiple roles such as a reducing reagent to
form copper(I), a base to help form Cu(I) acetylide and a ligand for Cu(I) species after
oxidized by copper(II). It should be noted that the solubility of the substrates in methanol
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was vital for the reaction rate. For those solid substrates that were not readily soluble in
methanol, some CH2Cl2 (10% in volume) was used to facilitate dissolving, and the
reactions could complete without time prolonged and gave excellent yields.
.
In conclusion, we have developed a new catalytic system, CuSO4 5H2O/DHPHE, which
can highly efficiently promote the [3+2] cycloaddition of both aliphatic and aromatic
azides and alkynes in methanol without exclusion of air at room temperature. Electronic
properties and steric hindrance of the substituents on the substrates take little effect on the
reaction efficiency. DHPHE may take multiple roles in the reaction, such as a reducing
reagent to form copper(I), a base to help form Cu(I) acetylide and a ligand for stabilizing
Cu(I) species after oxidized by copper(II). Moreover, a single regioisomer,
1,4-disubstituted 1,2,3-triazole formed. This system may find applications especially for
those AAC reactions in which substrates are only soluble in organic solvents.
EXPERIMENTAL
General Procedure For Cycloaddition Of Alkyne-Azide
To a mixture of azide (0.79 mmol) and alkyne (0.83 mmol) was added a solution of
CuSO4⋅5H2O (10 µL, 2 mg, 1 mol% based on azide, with 2.00 g of CuSO4⋅5H2O in 10
mL H2O), followed by a solution of dihydropyridine Hantzsch ester (10 µL, 2.2 mg, 1
mol% based on azide, with 2.20 g of dihydropyridine in 10 mL CH3OH), and finally
methanol (1 mL) via syringes. The mixture was stirred for a period as indicated at room
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temperature. After checked by TLC (CHCl3/CH3OH), the reaction mixture was
concentrated to dryness under reduced pressure. A small amount of water was used to
wash the solid product followed by petroleum ether (1H NMR spectrum showed it is
pure). If needed, the reaction mixture was loaded onto a short plug of silica gel using a
fine solvent gradient (CHCl3/CH3OH) to afford the analytically pure product. For some
substrates, the scales were reduced.
2-((1-Butyl-1H-1,2,3-Triazol-4-Yl)Methyl)Isoindoline-1,3-Dione (Compound 18)
White solids. Yield: 100 mg, 76% (Table 1, Entry 18). mp: 125-127 oC 1H NMR (300
MHz, CDCl3): δ/ppm 7.86 (d, J=3.0 Hz, 2H), 7.73 (d, J=3.3 Hz, 2H), 7.59 (s, 1H), 5.00 (s,
2H), 4.31 (dd, J1=7.5 Hz, J2=7.2 Hz, 2H), 1.91-1.81 (m, 2H), 1.38-1.26 (m, 2H), 0.94 (dd,
J1=7.2 Hz, J2=7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ/ppm 168.1, 143.0, 134.5,
132.3, 123.8, 123.0, 50.4, 33.4, 32.6, 20.0, 13.8. GC-MS (EI, m/z): 284 (M+, 100). Elem.
Anal.: Calcd. for C15H16N4O2: C, 63.37; H, 5.67; N, 19.71. Found: C, 63.32; H, 5.48; N,
19.90%.
SUPPLEMENTARY DATA
Full experimental detail, characterization data (including melting points, copies of 1H and
13C NMR spectra, GC-MS and/or elemental analysis), crystallographic structure
parameters and X-ray crystallographic information files (CIFs) for compound 3, 4 and 18
(CCDC 802897-802899), and X-ray molecular structures of 3 and 4 are available online.
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ACKNOWLEDGEMENT
We thank the National Natural Science Foundation of China (21072154) for financial
support.
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Table 1. Scope of substrates.a
Entry Product
Yield (%)b
1
98
91
90
97
87
2
3
4
5
6
7
80d
92c
8
86c
75e
89
9
10
11
12
90
91d
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13
14
15
16
90
93
84
92c,d
17
18
19
20
21
22
23
85
76d
91
90
95
93
96d
aReaction conditions: azide (1.0 equiv), alkyne (1.05 equiv), CH3OH, 1 mol%
.
CuSO4 5H2O (in 8 mM), 1 mol% DHPHE, 10 h, r.t., exposed in air.
bIsolated yield.
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cCompleted in 12 h.
dSubstrate was dissolved in 0.1 mL CH2Cl2 and then the other reactants were added .
eReaction time was prolonged to 14 h.
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Figure 1. The single-crystal structure of triazole 18.
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