Letter pubs.acs.org/OrgLett
Access to Cyclobutadienes via an Organocatalytic Dienamine− Iminium−Allenamine Cascade Approach Wenjun Li,† Ming Lang,† and Jian Wang* School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China S Supporting Information *
ABSTRACT: A new organocatalytic route to cyclobutadienes from α,β-unsaturated aldehydes and ynals is described. This protocol allows a broad substrate scope and mild conditions. Furthermore, a proposed mechanism of a dienamine−iminium− allenamine cascade process is discussed.
organocatalytic [2 + 2] cycloaddition reaction of α,β-unsaturated aldehydes with ynals might provide a novel route to construct the cyclobutadiene core. As part of our continued interest in this field, we herein reported our new discovery regarding the organocatalytic [2 + 2] reaction of ynals and α,β-unsaturated aldehydes to efficiently assemble cyclobutadiene skeletons (Scheme 1d). It is worth noting that utilizing a dienamine−iminium−allenamine cascade strategy to synthesize organic molecules has not yet been reported. We initiated our preliminary study with the model reaction of α,β-unsaturated aldehyde 1a and phenylpropargyl aldehyde 2a in the presence of L-proline as catalyst and K2CO3 as base. However, almost no desired product was obtained (Table 1, entry 1). With the initial experimental results in hand, we then turned our attention to other catalysts. The assessment of other catalysts indicated that catalyst V showed the highest conversion and gave the desired product 3aa in 65% yield (Table 1, entry 5). Further investigations revealed that the additive played a key role in this transformation. If the reaction was conducted in the absence of K2CO3, the yield would decrease to 13% remarkably (Table 1, entry 6). Other bases afforded 3aa in only moderate yields (Table 1, entries 7−11). Notably, only 14% yield was observed if we utilized acetic acid as the additive (Table 1, entry 12). After identifying base K2CO3 as the best additive, we then investigated the role of solvent in this process. The experimental results showed that toluene was the best medium in stabilizing and promoting the efficiency of the reaction (Table 1, entry 15). To further optimize the reaction conditions, we changed the reaction temperature and 78% yield was obtained when we conducted the reaction at 50 °C for 48 h (Table 1, entry 17). With the optimized reaction conditions in hand, we next examined the scope of α,β-unsaturated aldehydes 1. As indicated in Scheme 2, various substrates 1 bearing either electronwithdrawing or electron-donating groups in different positions
C
yclobutadiene, as an interesting precursor, has been utilized to construct natural products (e.g., (+)-Asteriscanolide1d) and many other useful materials.1 Although theoretic studies of cyclobutadienes have been well investigated,2 the unstable properties have largely restricted their application and development (Scheme 1a). In 1965, Pettit and co-workers reported the first preparation of cyclobutadiene−iron tricarbonyls that could efficiently transfer to cyclobutadiene precursors for further transformations (Scheme 1b).3a,b Shortly after, photolysis of α-pyrones was also found to be an efficient strategy to make stable cyclobutadiene−iron complexes.3c In 2001, Sekiguchi et al. first disclosed that cyclobutadiene dianions could be used to construct tetrasubstituted cyclobutadienes.3d Moreover, thermal [2 + 2] cycloaddition was also found to be an efficient method to synthesize cyclobutadienes (Scheme 1c). For example, the Peng and Maryanoff groups reported an intramolecular thermal [2 + 2] cycloaddition reaction of cyclobutadienes.4a,b Despite these progresses, some issues still need to be resolved: (i) high reaction temperature is normally required; (ii) substrate scope is relatively narrow; (iii) chemical yield is regularly low. Therefore, the development of an efficient catalytic system for rapid synthesis of cyclobutadienes still remains in high demand. Organocatalysis has become a powerful tool in organic synthesis.5 Aminocatalysis,6−11 as one of the most efficient organocatalytic strategies, has attracted much attention. Under aminocatalysis, substrates are normally motivated via HOMO,6−9 LUMO,10 or SOMO activation.11 In particular, the HOMO activation of α,β-unsaturated aldehydes via dienamine catalysis has made significant progresses in this field, as contributed by Jørgensen, Chen, Melchiorre, Uria, Liao, and others.12 It should be noted that our group successfully developed the first dienamine-mediated enantioselective 1,3-dipolar [3 + 2] cycloaddition of α,β-unsaturated aldehyde with C,N-cyclic azomethine imines.13 Moreover, our group also developed the dienamine-catalyzed 1,3-dipolar cycloaddition reaction of azides and α,β-unsaturated aldehydes.14 Building upon the significance of ynal in organocatalytic reactions,15 we envisioned that an © 2017 American Chemical Society
Received: July 15, 2017 Published: August 17, 2017 4564
DOI: 10.1021/acs.orglett.7b02161 Org. Lett. 2017, 19, 4564−4567
Letter
Organic Letters Table 1. Optimization of the Reaction Conditionsa
Scheme 1. Features and Strategies for Cyclobutadienes
entry
catalyst
solvent
base
yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17c
I II III IV V V V V V V V V V V V V V
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CHCl3 THF toluene DMSO toluene
K2CO3 K2CO3 K2CO3 K2CO3 K2CO3
