CuBr-NCS-Mediated Multicomponent Azide-Alkyne Cycloaddition: Mild and Efficient Synthesis of 5-Bromo-1,4-Disubstituted-1,2,3-Triazoles

Abstract

CuBr-NCS was found to be a mild and efficient reaction system to promote the multicomponent azide-alkyne cycloaddition reactions. Under the reaction conditions, terminal alkynes and azides can react smoothly at ambient temperature to give the target products 5-bromo-1,4-disubsituted-1,2,3-triazoles in moderate to good yields with a wide tolerance of other sensitive functional groups. The further successful application of the CuBr-NCS reaction system in sugar and cyclic adenosine 5′-diphosphoribose (cADPR) analogues illustrated the value of this method in the synthesis of designed biomolecules.

multicomponent azide-alkyne cycloaddition - 5-bromo-1,4-disubstituted-1,2,3-triazole - click chemistry - copper catalysis

References and Notes

<A NAME="RW19810ST-1">1</A> Tron GC. Pirali T. Billington RA. Canonico PL. Sorba G. Genazzani AA. Med. Res. Rev.  2008,  28:  178 

<A NAME="RW19810ST-2">2</A> Amblard F. Hyun Cho JH. Schinazi RF. Chem. Rev.  2009,  109:  4207 

<A NAME="RW19810ST-3">3</A> Meldal M. Tornøe CW. Chem. Rev.  2008,  108:  2952 

<A NAME="RW19810ST-4">4</A> Kolb HC. Sharpless KB. Drug Discov. Today  2003,  8:  1128 ; and references therein

<A NAME="RW19810ST-5">5</A> Thibault RJ. Takizawa K. Lowenheilm P. Brett Helms B. Justin L. Mynar JL. Jean MJ. Fréchet JJ. Hawker CJ. J. Am. Chem. Soc.  2006,  128:  12084 

<A NAME="RW19810ST-6">6</A> Bock VD. Hiemstra H. Maarseveen JH. Eur. J. Org. Chem.  2006,  71:  51 

<A NAME="RW19810ST-7">7</A> Nahrwold M. Bogner T. Eissler S. Verma S. Sewald N. Org. Lett.  2010,  12:  1064 

<A NAME="RW19810ST-8">8</A> Somu RV. Boshoff H. Qiao C. Bennett EM. Barry CE. Aldrich CC. J. Med. Chem.  2006,  49:  31 

<A NAME="RW19810ST-9">9</A> Pagliai F. Pirali T. Del Grosso E. Di Brisco R. Tron GC. Sorba G. Genazzani AA. J. Med. Chem.  2006,  49:  467 

<A NAME="RW19810ST-10">10</A> Alam MS. Kajiki R. Hanatani H. Kong X. Ozoe F. Matsui Y. Matsumura F. Ozoe Y. J. Agric. Food Chem.  2006,  54:  1361 

<A NAME="RW19810ST-11">11</A> Li L. Siebrands CC. Yang Z. Zhang L. Guse AH. Zhang L. Org. Biomol. Chem.  2010,  1843 

<A NAME="RW19810ST-12">12</A> Li L. Lin B. Yang Z. Zhang L. Zhang L. Tetrahedron Lett.  2008,  49:  4491 

<A NAME="RW19810ST-13">13</A> Spiteri C. Moses JE. Angew. Chem. Int. Ed.  2010,  49:  31 

<A NAME="RW19810ST-14">14</A> Hein JE. Tripp JC. Krasnova L. Sharpless KB. Fokin VV. Angew. Chem.  2009,  121:  8162 

<A NAME="RW19810ST-15">15</A> Li L. Zhang G. Zhu A. Zhang L. J. Org. Chem.  2008,  130:  3630 

<A NAME="RW19810ST-16">16</A> Wu YM. Deng J. Li Y. Chen QY. Synthesis  2005,  1314 

<A NAME="RW19810ST-17">17</A> Malnuit V. Duca M. Manout A. Bougrin K. Benhida R. Synlett  2009,  2123 

<A NAME="RW19810ST-18">18</A> Zhang X. Hsung RP. Li H. Chem. Commun.  2007,  2420 

<A NAME="RW19810ST-19">19</A> Gerard B. Ryan J. Beeler AB. Porco JA. Tetrahedron  2006,  62:  6405 

<A NAME="RW19810ST-20">20</A> Gu XF. Yang ZJ. Zhang LR. Kunerth S. Fliegert R. Weber K. Guse AH. Zhang LH. J. Med. Chem.  2004,  47:  5674 

<A NAME="RW19810ST-21">21</A> Zhang B. Wagner GK. Weber K. Garnham C. Morgan AJ. Galione A. Guse AH. Potter BVL.
J. Med. Chem.  2008,  51:  1623 

<A NAME="RW19810ST-22">22</A> Huang J. Macdonald SJF. Harrity JPA. Chem. Commun.  2009,  436 

<A NAME="RW19810ST-23">23</A> Kuijpers BHM. Dijkmans GCT. Groothuys S. Quaedflieg PJLM. Blaauw RH. van Delft FL. Rutjes FPJT. Synlett  2005,  3059 

<A NAME="RW19810ST-24">24</A>

NCS (0.072 mmol) and TBAB (0.072 mmol) were dissolved in THF (1.5 mL), and a light yellow solution was obtained immediately. The UV spectrum showed ε_max = 382 nm, which agreed with the UV spectrum of active bromine reagent BrCl.

<A NAME="RW19810ST-25">25</A>

Representative Procedure A mixture of 1 (0.048 mmol), 2 (0.072 mmol), CuBr (10 mg, 0.072 mmol), DIPEA (9 mg, 0.072 mmol), and NCS (9.5 mg, 0.072 mmol) in THF (3 mL) was stirred at r.t. The reaction procedure was monitored by TLC. When the reaction was completed, the mixture was evaporated, and the residue was partitioned between EtOAc and H₂O. The organic layer was washed with brine, dried over anhyd Na₂SO₄, and evaporated. The residue was purified by silica gel column chromatography to give compound 3.