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N-Heterocyclic Carbene Catalyzed Switchable Reactions of Enals with Azoalkenes: Formal [4+3] and [4+1] Annulations for the Synthesis of 1,2-Diazepines and Pyrazoles Chang Guo, Basudev Sahoo, Constantin G. Daniliuc, and Frank Glorius J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja510737n • Publication Date (Web): 22 Nov 2014 Downloaded from http://pubs.acs.org on November 26, 2014
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Journal of the American Chemical Society
N-Heterocyclic Carbene Catalyzed Switchable Reactions of Enals with Azoalkenes: Formal [4+3] and [4+1] Annulations for the Synthesis of 1,2-Diazepines and Pyrazoles Chang Guo, Basudev Sahoo, Constantin G. Daniliuc, Frank Glorius* Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, Germany
Supporting Information Placeholder ABSTRACT: A regio- and enantioselective formal [4+3] annulation reaction between enals and in situ formed azoalkenes has been achieved. A diverse set of 1,2-diazepine derivatives were synthesized in good yields with excellent enantioselectivities (often 99% ee). Alternatively, modifying the standard NHC catalyst switched the reactivity toward a formal [4+1] annulation to afford functionalized pyrazoles. The electronic and steric properties of the N-heterocyclic carbene organocatalyst play a vital role in controlling the reaction pathway (homoenolate vs acyl-anion reactivity of enal), allowing selective access to diverse 1,2-diazepine and pyrazole derivates from identical substrates.
In the last decade, the N-heterocyclic carbene (NHC) catalyzed annulation reactions have emerged as powerful meth1 ods for the synthesis of various heterocycles. In 2004, the 2 3 Bode group and the Glorius group reported the NHCcatalyzed [3+2] annulation of enals with aldehydes to give γbutyrolactones, in which the enal β-carbon behaved as a reactive nucleophilic carbon. Consequently, the use of NHCs has introduced a variety of powerful and unconventional bond forming processes including reactions involving acyl 4 5-8 9 anion, homoenolate, and enolate equivalents. However, there are several challenges associated with the development of NHC catalyzed reactions, the most critical being the ability to control the reactivity modes of NHC (homoenolate vs acyl-anion reactivity). As documented in Bode’s study and indicated by reactions from others, an NHC catalyst with different electronics and steric demands could control the reactive NHC-intermediate to generate different prod4h,6f,10 ucts. We hypothesized that it might be possible to tune the desired selectivities through careful choice of NHC precursor. 11 12 Diazepines and styryl pyrazoles are important heterocycles, which are present in a wide range of natural products and bioactive compounds such as ACE inhibitors, analgesic agents, platelet aggregation inhibitors, and nonsteroidal antiinflammatory agents. Moreover, the 1,2-diazepine motif is 13 also an important scaffold in asymmetric synthesis. A limited number of methods have been developed to address this longstanding problem but they involve multistep synthetic sequences. Moreover, intermolecular reactions for the asymmetric synthesis of 1,2-diazepines have rarely been reported. Therefore, the development of more general strate-
gies for the construction of enantioenriched 1,2-diazepine derivatives with functional diversity is still highly desirable. Furthermore, it remains a challenge to selectively generate different products from identical substrates, utilizing catalyst rather than substrate control.
Scheme 1. NHC-catalyzed regioselective strategy
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Azoalkenes, which are readily generated in situ from αhalogeno hydrazones, have been commonly employed as key intermediates for the synthesis of various nitrogencontaining heterocyclic compounds. The Bolm group developed an elegant chiral copper complex-catalyzed enantioselective formal [4+1] annulation of azoalkenes with sulfur 15 ylides affording five-membered dihydropyrazole derivatives. Very recently, the Wang group reported the asymmetric AzaDiels-Alder reaction of indoles with azoalkenes to generate 16 17 fused indoline heterocycles. The Scheidt group and the Ye 18 group independently reported annulation reactions of α,βunsaturated aldehydes and ortho-quinone methides for the synthesis of benzoxopinones. Distinct from their findings, we envisioned that azoalkenes could be utilized as electrophiles with Breslow intermediates generated from enals for the construction of diverse 1,2-diazepines and pyrazoles derivatives. However, several challenges had to be overcome, such as (1) tolerance of the in situ generated azoalkenes under reaction condition of NHC catalysis (2) chemoselectivity i.e. selectivity for 1,2-diazepines over pyrazoles (3) to find reaction conditions which afford high ee’s. Herein, we reported a successful introduction of NHC catalyzed formal [4+3] and [4+1] annulation reactions, providing 1,2-diazepines and pyrazoles with good chemo- and regioselectivity (Scheme 1).
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Table 1. Optimization of the reaction conditionsa
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a regiochemical switch of the [4+1] cycloaddition, thus leading to the formation of the pyrazole 4ad in 64% yield. Based on these experiments, the change of annulation mechanism is believed to be due to the electronic and steric differences of the NHC catalysts (entries 6-12).
Table 2. Substrate scopea entry 1 2 3 4 5 6 7 8 9 10 11 12e
2 2a 2a 2a 2b 2c 2d 2d 2d 2d 2d 2d 2d
NHC 5a 5b 5c 5c 5c 5c 5d 5e 5f 5g 5h 5i
Yield (%)b trace trace 52 50 37 77 42 75 12 trace 52 64
3/4c 2:3 >20:1 4:1 9:1 8:1 1:2 6:1 6:1
