Letter pubs.acs.org/acscatalysis
Catalytic Intermolecular Cross-Couplings of Azides and LUMOActivated Unsaturated Acyl Azoliums Wenjun Li,† Manjaly J. Ajitha,§ Ming Lang,† Kuo-Wei Huang,*,§ and Jian Wang*,† †
School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China Division of Physical Sciences & Engineering and KAUST Catalysis Center, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia
§
ACS Catal. 2017.7:2139-2144. Downloaded from pubs.acs.org by TULANE UNIV on 01/21/19. For personal use only.
S Supporting Information *
ABSTRACT: An example for the catalytic synthesis of densely functionalized 1,2,3-triazoles through a LUMO activation mode has been developed. The protocol is enabled by intermolecular crosscoupling reactions of azides with in situ-generated α,β-unsaturated acyl azoliums. High yields and broad scope as well as the investigation of reaction mechanism are reported. KEYWORDS: 1,2,3-triazoles, azides, 1,3-dipolar cycloaddition, organocatalysis, unsaturated acyl azolium
T
he 1,2,3-triazole nucleus is one of the promising heterocycles found in pharmaceutical chemistry and material science.1 It has earned the “privileged structure” title in drug discovery because of its plentiful pharmaceutical properties. On the other hand, ever-increasing demands especially in small-molecule drug screening, drive the development of new synthetic tools that enable the construction of drug-like molecules with versatile substitutions.2 Within the context of triazole assembly, regioselectivity control has attracted much attention from the organic chemistry community. Classic thermal 1,3-dipolar cycloadditions of alkynes and azides required high temperatures and resulted in triazoles with low levels of regioselectivity control.3 Subsequently, the problem of regioselectivity control was resolved through the copper-catalyzed azide−alkyne cycloaddition (CuAAC),4 a paradigm of the “click reaction“, thus affording 1,4-disubstituted 1,2,3-triazoles in good yields. In addition, the urgent appearance of ruthenium-catalyzed (RuAAC)5 and iridium-catalyzed (IrAAC)6 azide−alkyne reactions enables the regioselective synthesis of 1,5-disubstituted7 or 1,4,5trisubstituted 1,2,3-triazoles8 to be practicable and feasible. Although the above methods are very important advances, the availability and the high cost of the starting materials (e.g. alkynes) prompted us to explore additional protocols. As one of the most promising alternative strategies, the organocatalytic Ramachary−Bressy−Wang [3 + 2] cycloaddition of azides with in situ-generated enamines has significantly contributed to furnishing 1,2,3-triazoles via a highly regioselective fashion (Figure 1a, I).9 Shortly after, the Ramachary group reported another impressive DBU-catalyzed [3 + 2] cycloaddition protocol of aryl azides with in situ-generated enolates,10 thus giving substituted 1,2,3-triazoles in good yields (Figure 1a, II). In 2014, Wang et al. introduced a new direction to make 1,2,3triazoles through an efficient [3 + 2] cycloaddition process of azides with in situ-generated zwitterion catalyzed by DBU © 2017 American Chemical Society
Figure 1. An overview for organocatalytic 1,2,3-triazole synthesis.
(Figure 1a, III).11 It is important to note that the Dehaen group also independently reported an elegant multi-component reaction to access diversely functionalized 1,2,3-triazoles in situ through a DBU-catalyzed Knoevenagel condensation step.12 Although the breakthrough of metal-free synthesis of Received: December 25, 2016 Revised: February 12, 2017 Published: February 15, 2017 2139
DOI: 10.1021/acscatal.6b03674 ACS Catal. 2017, 7, 2139−2144
Letter
ACS Catalysis Table 1. Optimization of the Reaction Conditionsa,g
1,2,3-triazoles is reported, the development of more sustainable variants is still highly desired as the 1,2,3-triazole core has already demonstrated numerous important applications in pharmaceutical chemistry and biological science.1 Despite recent significant progresses on the organcatalytic synthesis of 1,2,3-triazoles, a few issues have not yet been fully resolved: (i) a compatible synthetic protocol for both 1,4disubstituted and 1,4,5-trisubstituted 1,2,3-triazoles with considerable molecular diversity enabling structure−activity relationship studies (SAR) to be readily available; (ii) a practical procedure to synthesize 1,2,3-triazoles from commercially available and commonly used starting materials, bearing versatile functionality. In view of these challenging questions, to develop more general, viable, but complementary routes would be of great relevance to synthetic chemists. Nowadays, N-heterocyclic carbenes (NHCs) have emerged as powerful Lewis base catalysts to construct a vast array of carbocyclic, heterocyclic, and polycyclic compounds.13 Inspired by these elegant works, we here report a novel NHC-catalyzed intermolecular cross-coupling of organic azides with in situgenerated unsaturated acyl azoliums14 (Figure 1b, IV). To our knowledge, this is the first example of 1,2,3-triazole synthesis facilitated by carbene catalysis. Pleasingly, this catalytic reaction can not only provide a high regioselectivity but also assemble 1,4-disubsituted or 1,4,5-trisubstituted 1,2,3-triazole compounds. In addition, the ester moiety on the triazole core skeleton could readily convert to other useful functional groups for further applications. We initiated our reaction condition optimization through screening NHC catalysts building on the model reaction of acrolein (1a), phenyl azide (2a), and MeOH (Table 1). Interestingly, the reaction of 2a with 2.0 equiv of 1a, 5.0 equiv of MeOH, 0.2 equiv of K2CO3, and 0.1 equiv of oxidant DQ (3,3′,5,5′-tetra-tert-butyldiphenoquinone) in CHCl3 at 80 °C catalyzed by 20 mol % catalyst C-4 in a sealed tube, furnished 3a as a single regioisomer in moderate yield (Table 1, entry 4, 47%). The same reaction catalyzed by 20 mol % other NHC catalysts furnished 1,2,3-triazole 3a with low chemical yields (Table 1, entries 1−7). Switching the solvent to THF was successful in promoting the efficiency of the reaction (73%, entry 10). The choice of Cs2CO3 as the base resulted in the formation of 3a with excellent yield (Table 1, entry 9, 94%). It is worth noting that no product was observed in the absence of NHC catalysts (Table 1, entry 11). The effect of oxidant was also tested. Surprisingly, other commonly used oxidants (e.g., PCC or DDQ) gave no desire product. The feasibility of using 15 mol % C-4 was surveyed and resulted in a 91% yield (entry 10); however, the use of 10 mol % cat. C-4 caused a slight decrease in chemical yield (entry 12, 82%). In addition, lowering the amount of 1a led to a certain degree of loss in chemical yield (entries 13 and 14). To further clearly elucidate the oxidation process, an additional investigation on oxidation system was conducted, and the relevant results were shown in Table 1. We found that the combination of DQ (1.0 equiv) with air or oxygen is an effective oxidation system in achieving a high conversion (Table 1, air: 91%, 24 h; O2: 94%, 12 h). Surprisingly, when the reaction was conducted in a glovebox or under N2, almost no desire product 3a was obtained even with 2.0 equivent DQ as oxidant, but methyl acrylates were mainly formed in the above conditions. We envisioned that air or oxygen likely played an important role in triazole formation step. If DQ was removed from the system but oxygen remained in the sealed tube, no 3a was detected. In summary, a
entry
cat.
solvent
1 2 3 4 5 6 7 8 9 10c 11h 12d 13c,e 14c,f oxidanti
C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-4 C-4 C-4 -C-4 C-4 C-4
CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 THF THF THF THF THF THF THF solvent
DQ (1.0 equiv) no DQ DQ (1.0 equiv)
THF (degassing) THF (degassing) THF (degassing)
base
yield (%)b
K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 sealed tube
13 22 25 47 17 34 29 73 94 91 0 82 79 81 result
filled with O2 filled with O2 filled with N2
3a: 12 h, 94% 3a: 24 h,
