A general strategy for the synthesis of 3,4-dioxygenated quinolin-2-one natural products is reported. The key step is a regioselective insertion of arynes into unsymmetric imides. When performed in continuous flow, the reaction proceeded within minutes. The resulting N-acylated 2-aminobenzophenones were transformed to (±)-peniprequinolone, (±)-aflaquinolones E and F, (±)-6-deoxyaflaquinolone E, (±)-quinolinones A and B, and (±)-aniduquinolone C in 1-3 steps. 4 d MeCN CsF 3.7:1 33 5 d,e MeCN KF 4.0:1 20 a Reaction conditions: 4a (0.26 mmol, 1 equiv.), 3a (0.39 mmol, 1.5 equiv.), Fsource (0.52 mmol, 2 equiv.), solvent (2.0 mL), 60 °C, 16 h; b ratios were determined by 1 H NMR integration; c isolated yield; d conducted at 80 °C for 4 h; e 18-crown-6 (1 equiv.) and 4 Å mol sieves were used as additives. ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website.

A scalable access to functionalized 1,1'and 1,2-ferrocenyl azides has been realized in flow. By halogen-lithium exchange of ferrocenyl halides and subsequent reaction with tosyl azide, a variety of functionalized ferrocenyl azides was obtained in high yields. To allow a scalable preparation of these potentially explosive compounds, an efficient flow protocol was developed accelerating the reaction time to minutes and circumventing accumulation of potentially hazardous intermediates. Switching from homogeneous to triphasic flow amidst process was key for handling a heterogeneous reaction mixture formed after a heated reactor section. The corresponding and synthetically versatile ferrocenyl amines were then prepared by a reliable reduction process.Since the discovery of ferrocene in 1951, [1] its derivatives have found innumerable applications in chemistry. The intriguing redox properties of ferrocenes led to applications in coordination chemistry, [2] inorganic materials, [3] molecular wires and sensors. [4] Their unique stability make ferrocenes useful in medicinal research [5] and as privileged ligands in many catalysts. [6] Frequently, these ferrocene based compounds are derived from ferrocenyl azides [7] or amines. [8] As organic azides can be readily reduced to the corresponding amines, ferrocenyl azides are the access hub to a large number of N-substituted ferrocenes. Owing to thermal lability and shock-sensitivity, [9] the obvious synthetic potential of ferrocenyl azides has not been fully realized. For their preparation, copper mediated substitution of ferrocenyl bromides [9a,10] and boronic acids [11] with sodium azide (Scheme 1A) was employed, however, requiring the use of explosive copper azide. Alternatively, ferrocenyllithiums, prepared by lithiation of C-H bonds in ferrocenes, are reacted with aryl sulfonyl azides (Scheme 1B). [6f,12] While for the former process inconsistent yields were reported, the latter suffers from low functional group tolerance. [10] More recently, a single functionalized ferrocenyl azide was prepared by halogen-lithium exchange of the corresponding ferrocenyl halide. [13] The azidation of aryl halides through bromine-lithium exchange and trapping with tosyl azide has been realized in flow very recently by Yoshida and Nagaki. [14,15] Fast chemical transformations immensely benefit from precise reaction control in a continuous flow setup. [16] Enhanced heat and mass transfer has enabled organic reactions previously viewed impossible. [14,15,17] Vice versa, slow reactions can be significantly accelerated by fast heating, frequently rendering a flow process more efficient and sustainable than a batch process. [18] Herein, we describe the flow-enabled development of a general method for the safe and scalable synthesis of functionalized ferrocenyl azides (Scheme 1C) through azidation of ferrocenyllithiums. Scheme 1. Synthesis of functionalized ferrocenyl azides: A) Copper-mediated azidation of ferrocenyl halides or boronic acids. B) Introduction of azides using stoichi...

A general strategy for the synthesis of 3,4-dioxygenated quinolin-2-one natural products is reported. The key<br>step is a regioselective insertion of arynes into unsymmetric imides in flow.<br>

A general strategy for the synthesis of 3,4-dioxygenated quinolin-2-one natural products is reported. The key<br>step is a regioselective insertion of arynes into unsymmetric imides in flow.<br>

A scalable access to functionalized 1,1’- and 1,2-ferrocenyl azides has been realized in flow. By halogen‒lithium exchange of ferrocenyl halides and subsequent reaction with tosyl azide, a variety of functionalized ferrocenyl azides was obtained in high yields. To allow a scalable preparation of these potentially explosive compounds, an efficient flow protocol was developed accelerating the reaction time to minutes and circumventing accumulation of potentially hazardous intermediates. Switching from homogeneous to triphasic flow amidst process was key for handling a heterogeneous reaction mixture formed after a heated reactor section. The corresponding and synthetically versatile ferrocenyl amines were then prepared by a reliable reduction process.