A highly effective one-pot Friedländer quinoline synthesis using inexpensive reagents has been developed. o-Nitroarylcarbaldehydes were reduced to o-aminoarylcarbaldehydes with iron in the presence of catalytic HCl (aq.) and subsequently condensed in situ with aldehydes or ketones to form mono- or di-substituted quinolines in high yields (66-100%).
A highly effective one-pot Friedländer quinoline synthesis from o-nitroarylcarbaldehydes and ketones or aldehydes was developed and the scope and limitations of the method were examined. The o-nitroarylcarbaldehydes were reduced to o-aminoarylcarbaldehydes with iron in the presence of a catalytic amount of aqueous hydrochloric acid; the amino compounds were then condensed in situ with ketones or aldehydes to form mono-or disubstituted quinolines, respectively, in good-to-excellent yields (58-100%).Quinolines are an important class of heterocycles that have long been used antimalarial agents, 1 and more recently have been used as protein kinase inhibitors for the treatment of cancer. 2 These beneficial biological activities continue to make quinolines attractive targets for both synthetic and medicinal chemists. Among the many methods available for constructing the quinoline ring, the Friedländer quinoline synthesis has proven to be a very powerful tool. 3 This reaction typically requires two steps: reduction of an o-nitro aldehyde or ketone I into an o-amino aldehyde or ketone II followed by condensation of this intermediate with a ketone or aldehyde III (Scheme 1).Often the amino carbonyl intermediate II is unstable, especially when R 2 = H, and it may undergo self-condensation. To overcome this potential problem and make this century-old reaction more practical, several laboratories have attempted to develop one-pot procedures involving the use of II generated in situ. 4,5 Of particular interest is the one-pot method developed by Miller and McNaughton, 4a which uses a tin(II) chloride/zinc chloride system to convert o-nitro aldehydes or ketones into 2-monosubstituted or 2,3-disubstituted quinolines. This method works well with a range of aliphatic ketones but, unfortunately, it is not applicable to aromatic ketones such as acetophenone. 5 We therefore attempted to develop a method that would permit the preparation of 2-aryl-substituted quinolines. As reported in our previous preliminary communication, 5 we have discovered a practical one-pot Friedländer quinoline synthesis that uses inexpensive and readily available reagents such as iron powder, aqueous hydrochloric acid, and solid potassium hydroxide. Our method successfully condensed a variety of o-nitro aldehydes (or ketones) with various carbonyl co-reactants. Herein, we report a study of the scope and limitations of the one-pot Friedländer quinoline synthesis.In a typical operation, 2-nitrobenzaldehyde was reduced with 4.0 equivalents of iron powder in the presence of 5 mol% of aqueous hydrochloric acid in refluxing ethanol. The reduction was usually complete within 30-40 minutes (as monitored by thin-layer chromatography). After this time, 1.0 equivalents of a carbonyl compound and 1.2 equivalents of powdered potassium hydroxide were added. The mixture was then stirred at reflux for a further 40-60 minutes to complete the condensation reaction. A classical aqueous workup followed by chromatography over silica gel or by recrystallization afforded the desir...
Palladium‐catalyzed cyclizations of the 2‐bromo‐1,6‐diene 6 with an acetoxymethyl substituent on the bromoalkenyl moiety did not only lead to the expected 1‐acetoxymethyl‐1,3‐diene 40 but also to the bicyclic vinylcyclopropane 35, the 1,3‐diene 36 and the triene 37 (a dendralene). All these compounds result from an initial 5‐exo‐trig cyclization of the 2‐bromo‐1,6‐diene. By proper choice of the reaction conditions (ligand, base, allylic leaving group) each of these compounds could be formed selectively. Small amounts (3–5%) of the isomerized 1‐acetoxymethyl‐1,3‐diene 38 and the 6‐endo product 39 were also isolated. With the acetoxymethyl substituent on the alkenyl moiety (compound 27) only the 1,4‐diene 44 was formed. The related 1,6‐enyne 57 with a methoxycarbonyloxymethylene substituent on the triple bond gave in 36% yield the 2,3‐bis(bicyclo[3.1.0]hex‐1‐yl)‐substituted 1,3‐butadiene 63, which can be regarded as a dehydrodimer of the vinylcyclopropane 35. The presumption that the formation of 63 involves the alkenylpalladium species 65 was supported by its successful inter‐ as well as intramolecular trapping with formate as a hydride source to yield the vinylcyclopropane 35. The reaction pathways leading to the vinylcyclopropane derivatives 35 and 63 have in common that an alkylpalladium species rather undergoes a 3‐exo‐trig cyclization than an internal rotation followed by a β‐hydride elimination.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.