Benzene construction via organocatalytic formal [3+3] cycloaddition reaction

ARTICLE Received 23 Jul 2014 | Accepted 18 Aug 2014 | Published 25 Sep 2014 DOI: 10.1038/ncomms6027 Benzene construction via organocatalytic formal [3 þ 3] cycloaddition reaction Tingshun Zhu1, Pengcheng Zheng1,2, Chengli Mou1,2, Song Yang2, Bao-An Song2 & Yonggui Robin Chi1,2 The benzene unit, in its substituted forms, is a most common scaffold in natural products, bioactive molecules and polymer materials. Nearly 80% of the 200 best selling small molecule drugs contain at least one benzene moiety. Not surprisingly, the synthesis of substituted benzenes receives constant attentions. At present, the dominant methods use pre-existing benzene framework to install substituents by using conventional functional group manipulations or transition metal-catalyzed carbon-hydrogen bond activations. These otherwise impressive approaches require multiple synthetic steps and are ineffective from both economic and environmental perspectives. Here we report an efficient method for the synthesis of substituted benzene molecules. Instead of relying on pre-existing aromatic rings, here we construct the benzene core through a carbene-catalyzed formal [3 þ 3] reaction. Given the simplicity and high efficiency, we expect this strategy to be of wide use especially for large scale preparation of biomedicals and functional materials. 1 Division of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore. 2 Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Guiyang 550025, China. Correspondence and requests for materials should be addressed to B.-A.S. (email: ) or to Y.R.C. (email: ). NATURE COMMUNICATIONS | 5:5027 | DOI: 10.1038/ncomms6027 | www.nature.com/naturecommunications & 2014 Macmillan Publishers Limited. All rights reserved. 1 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms6027 M ulti-substituted benzenes are widely present in natural products. In industry, these benzene frameworks are nearly unavoidable in preparing most of today’s biomedicals, fine chemicals and polymer materials. The functions of the benzene-containing molecules are determined by the identity and substitution patterns of the substituents installed on the benzene unit. Exemplified in Fig. 1a are one natural product (salvadorin)1 and two synthetic bioactive molecules2,3 containing a benzene core bearing four substituents. Most synthetic methods in synthesizing such multi-substituted aromatics start with preexisting benzene unit by replacing hydrogen with other functional groups. The classic approach relies on stepwise electrophilic substitution (such as Friedel–Crafts reaction) or electrophilic halogenation and successive transition metal-catalyzed couplings. However, regio-selectivity and chemo-selectivity normally require rather tedious functional group (including protecting group) manipulations. For example, the classic synthesis of a 2,4,6trisubstituted benzoate needs the introduction of a temporary amine group to ensure selectivities in a key bromination reaction step4, and the overall synthesis requires over eight steps (Fig. 1b). Another approach for access to substituted benzenes is based on transition metal-catalyzed direct C–H activations5–8. While providing impressive shortcuts for benzene substitutions, this C–H activation method has its own limitations. For example, the presence of directing groups (for coordination with the metal catalyst) is often necessary and the instruction of multiple substituents is difficult (in part due to steric congestion). In a Bn different direction for substituted benzene synthesis, the benzene core is newly formed. Representative methods include transition metal-catalyzed [2 þ 2 þ 2] or [4 þ 2] reactions such as acetylene trimerizations developed by Reppe et al.9–11 In this cycloaddition approach, partial or complete intramolecular reaction is usually indispensable to ensure the regio-selectivity. Here we report a new strategy for highly effective access to multi-substituted benzenes through the construction of the benzene core via a formal [3 þ 3] cycloaddition reaction (Fig. 1d). Our approach uses enals readily prepared in three steps and unsaturated ketones as the starting material and N-heterocyclic carbene (NHC) as the organic catalyst12–24. It is a single-step reaction that affords tetra-substituted benzenes (2,4,6trisubstituted benzoate and its analogues) with high yield. In comparison, previous approaches to this class of molecules typically need seven steps with less than 10% overall yields25 (Fig. 1d). A plausible pathway of our NHC-catalyzed [3 þ 3] cycloaddition reaction involving formal a-, and g-carbon activations of enal is illustrated in Fig. 2. Briefly, addition of the carbene catalyst to the aldehyde moiety of enal followed by deprotonation forms Breslow intermediate I26–28. This process is followed by oxidative transformation29–33, and former enal g-CH deprotonation33 leads to vinyl enolate intermediate III. Notably, similar vinyl enolate intermediate could also be accessed from ketenes34 by Ye or esters in our laboratory35. Nucleophilic Michael-type addition of the g-carbon of III to enone 2 affords intermediate IV bearing a NHC-bound a,b-unsaturated ester H3C O O Ph O O CH3 H3C O O O CH3 H3C CH3 CH3 Salvadorin CH3 CH3 CH3 CH3 CH3 CO2CH3 H2N TRPA1 & TRPM8 modulator HMG-CoA reductase Inhibitor CH3 COOH H2N CO2CH3 Br Br CO2CH3 Ar H CH3 Ar CH3 H CO2H Ar O CHO + Ar H3C CH3 Ar' CH3 CO2Et NHC organocatalysis [O] Ar' Ar = C6H5, Ar' =p-F-C6H4 Ar' CO2H CO2H Br O Ar Single key step, 70% yield (ref.25) (Previous synthesis, 7 steps, ~10% yield) CO2Et Ar' Figure 1 | Multi-substituted benzenes and their synthesis. (a) examples of natural products and bioactive synthetic compounds containing multi-substituted benzene. (b) it took about eight steps for the classical substitution methods to synthesize a 2,4,6-trisubstituted benzoate. (c) transition metal-catalyzed C–H activation methods provides a shortcut (about five steps) for the synthesis. (d) this work: single key step reaction to afford tetra-substituted benzenes via organocatalyzed formal [3 þ 3] cycloaddtion. 2 NATURE COMMUNICATIONS | 5:5027 | DOI: 10.1038/ncomms6027 | www.nature.com/naturecommunications & 2014 Macmillan Publishers Limited. All rights reserved. ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms6027 CHO 1 O O Mes OH CH3 Ar N CH3 O X MesN MesN CH3 NMes Ar Ar Ar' NHC cat. NHC+ CH3 O VIII NHC+ X Ar Ar' Ar γ-CH deprotonation CH3 VI O– Aldol reaction Ar' NHC+ III CH3 O 3 Ar' V 2 X O NHC+ Ar O H3C Ar' O (X=alkyl or O-alkyl) X γ-CH deprotonation O H3C –O X Ar' O Michael reaction O H3C O X Ar CH2 Ar [O] NHC+ II MesN CH3 Ar CH3 O O X Ar –O N+ O –CO2 Mes O [ (...truncated)