Letter pubs.acs.org/OrgLett
Gold-Catalyzed Intermolecular Ynamide Amination-Initiated AzaNazarov Cyclization: Access to Functionalized 2‑Aminopyrroles Chao Shu,† Yong-Heng Wang,† Cang-Hai Shen,† Peng-Peng Ruan,† Xin Lu,*,† and Long-Wu Ye*,†,‡ †
State Key Laboratory of Physical Chemistry of Solid Surfaces & The Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China ‡ State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China S Supporting Information *
ABSTRACT: A novel gold-catalyzed intermolecular ynamide amination-initiated aza-Nazarov cyclization has been developed, allowing the facile and efficient synthesis of various 2-aminopyrroles in moderate to good yields. Furthermore, a mechanistic rationale for this tandem sequence, especially for the observed high regioselectivity, is also well supported by DFT (density functional theory) computations. The high flexibility, broad substrate scope, and mild nature of this reaction render it a viable alternative for the construction of 2-aminopyrroles.
T
Scheme 1. Gold-Catalyzed Nazarov-Type Cyclization
he Nazarov cyclization is a stereospecific 4π-electrocyclization that, in its typical manifestation, converts divinyl ketones into cyclopentenones via a conrotatory cyclization. In the past decades, this cyclization has been proven to be a powerful method for the synthesis of fivemembered carbo- or heterocycles;1 however, metal carbene involved Nazarov-type cyclization is less explored.2 Recent rapid development in homogeneous gold catalysis offers a highly attractive approach for accessing this cyclization. For example, Liu et al. reported a gold-catalyzed formal [4 + 1] cycloaddition between 3-en-1-ynamides and quinoline oxide via oxa-Nazarov cyclization to afford various 2-aminofurans in 2012 (Scheme 1a).3 Simultaneously, Zhang et al. also demonstrated an elegant protocol for the efficient synthesis of substituted 2,3dihydro-1H-pyrrolizines through gold-catalyzed aza-Nazarov cyclization of linear azidoenynes, but requiring electronwithdrawing groups in the 5-position (Scheme 1b).4 Despite these significant achievements, it is still highly desirable to explore new reactions based on such a gold carbene5 involved Nazarov cyclization, especially in an intermolecular and atomeconomic way. In our recent study on the ynamide chemistry,6−8 we first disclosed that benzyl azides could serve as efficient nitrene transfer reagents to react with ynamides to intermolecularly generate the α-imino gold carbenes,9,10 allowing the site-selective synthesis of versatile 2-aminoindoles and 3-amino-β-carbolines.8b Inspired by these results, we envisioned that the gold-catalyzed intermolecular ynamide amination-initiated formal aza-Nazarov cyclization might be achieved by reaction of benzyl azides with 3-en-1-ynamides (Scheme 1c). Herein, we describe the realization of such a © 2016 American Chemical Society
formal aza-Nazarov cyclization, thus leading to the highly regioselective synthesis of various 2-aminopyrroles, which are common structural motifs found in a variety of bioactive molecules (Figure 1).11 Moreover, a mechanistic rationale for this tandem reaction, especially for the observed high regioselectivity, is also supported by DFT (density functional theory) calculations. At the outset, 3-en-1-ynamide 1a was chosen as a model substrate for our initial study, and some of the results are outlined in Table 1. To our delight, the expected 2Received: May 24, 2016 Published: June 22, 2016 3254
DOI: 10.1021/acs.orglett.6b01503 Org. Lett. 2016, 18, 3254−3257
Letter
Organic Letters Table 2. Reaction Scope Studya
Figure 1. Selected examples of bioactive 2-aminopyrroles.
Table 1. Optimization of Reaction Conditionsa
entry
gold catalyst
1 2 3 4 5 6 7 8 9 10c
IPrAuNTf2 SIPrAuNTf2 Me3PAuNTf2 Ph3PAuNTf2 XPhosAuNTf2 BrettPhosAuNTf2 (4-CF3C6H4)3PAuNTf2 IPrAuNTf2 IPrAuNTf2 IPrAuNTf2
yield (%)b
conditions 4 4 4 4 4 4 4 4 3 3
Å Å Å Å Å Å Å Å Å Å
MS, MS, MS, MS, MS, MS, MS, MS, MS, MS,
DCE, DCE, DCE, DCE, DCE, DCE, DCE, DCE, DCE, DCE,
80 80 80 80 80 80 80 60 60 60
°C, °C, °C, °C, °C, °C, °C, °C, °C, °C,
30 30 30 30 30 30 30 48 48 48
h h h h h h h h h h
65 60
