Copper-Mediated N-Alkynylation of Carbamates, Ureas, and Sulfonamides. A General Method for the Synthesis of Ynamides

Abstract

A general amination strategy for the N-alkynylation of carbamates, sulfonamides, and chiral oxazolidinones and imidazolidinones is described. A variety of substituted ynamides are available by deprotonation of amides with KHMDS followed by reaction with CuI and an alkynyl bromide.We report herein a convenient and general method for the synthesis of ynamides via the copperpromoted coupling of amides with alkynyl bromides. Interest in the application of ynamides in organic synthesis has increased enormously in recent years.1 Considerably more robust than simple ynamines, ynamides are more easily stored and handled and tolerate a variety of conditions destructive to typical ynamines. Ynamides have thus emerged as versatile building blocks in a wide range of useful synthetic transformations including Pauson-Khand reactions, 2 ring-closing metatheses, 3 cycloadditions (and other ring-forming processes), 4 and a variety of hydrometalation and hydrohalogenation reactions. 5 , 6In connection with our studies on [4 + 2] cycloadditions of conjugated enynes7 and heteroenynes,8 we required an efficient method for the preparation of a wide range of ynamides, preferably via the direct alkynylation of carbamates, sulfonamides, and other simple amide derivatives. Initially we focused our attention on the reaction of metalated amides with alkynyl (phenyl)iodonium salts (eq 1). 9 Stang 10 and Feldman 11 have shown that this process provides an excellent route to "push-pull"-type ynamides (4, Z = COR, CO 2 R, SO 2 Ar, etc.), and more recently Witulski and Rainier have extended this chemistry to the preparation of ynamides where Z = hydrogen, TMS, and phenyl.2a-d ,4b Unfortunately, this approach is not applicable to the synthesis of ynamides in which Z is a simple alkyl group. The addition of soft nucleophiles to alkynyl(phenyl)iodonium salts is believed to proceed via the rearrangement of alkylidenecarbene intermediates of type 3, and the requisite 1,2-shift only is a facile process when Z is a hydrogen atom or trialkylsilyl or aryl group. 12 In addition, whereas sulfonamide derivatives (e.g., 1, EWG = Ts) participate smoothly in the desired transformation, reactions of lactams, 1a oxazolidinones, 1a and acyclic carbamates 13 proceed at best in low yield. NIH Public Access Author ManuscriptOrg Lett. Author manuscript; available in PMC 2010 July 6. The aforementioned limitations of alkynyl(phenyl)iodonium methodology prompted us to consider alternative and potentially more general approaches to the synthesis of the ynamides required for our studies. Recent developments in the laboratories of Buchwald and Hartwig have revolutionized methodology for carbon-nitrogen bond formation. 14 Encouraged, in particular, by Buchwald's recent success in achieving copper-catalyzed amidation of aryl halides,15 , 16 we turned our attention to the coupling of amide derivatives with readily available alkynyl halides. 17 Initial results were disappointing. Application of Buchwald's catalyst system 15 to the coupling of acyclic carbamates w...

[2+2] Cycloaddition of ketenes with ynamides. A general method for the synthesis of 3-aminocyclobutenone derivatives

“…The ynamides employed in the present study were prepared as described in Table 1 using the N-alkynylation method recently developed in our laboratory. 9 The terminal ynamide 9 was obtained in 70% yield by desilylation of 7 as shown in Scheme 1. The conditions shown in Table 1 and detailed in Section 4 represent a minor modification of our original procedure.…”

“…11 Tam was motivated to introduce this variant following difficulties he encountered in reproducing results previously reported by both our group and that of Hsung. For example, Tam reported obtaining none of the desired ynamide from the reaction of 1-bromo-2-phenylacetylene with BnNHCO 2 Me using either our method 9 or the method of Hsung. 10b Hsung had previously reported obtaining this ynamide in 73% yield, and we had reported the synthesis of the corresponding Boc derivative in 61% yield.…”

“…Thus, the yields reported here were obtained using pyridine freshly distilled from CaH 2 or KOH as recommended in our original report. 9 When pyridine (Alfa Aesar, 99%, 0.1% water content) from a freshly opened bottle (without distillation) was used instead, the yield of ynamide product declined to 52%. Most significantly, when distilled pyridine that had then been exposed to the atmosphere for several days was used for the N-alkynylation, none of the desired ynamide was formed.…”

“…The septum was fitted with an outlet needle connected via tubing to a column of CaSO 4 leading to a trap of H 2 O. Ketene was bubbled into the reaction mixture at rt over a period of 5 h. The reaction mixture was then concentrated to afford 0.279 g of brown oil. Purification by column chromatography on 16 g of silica gel (elution with 25% EtOAc-hexanes) gave 0.184 g (94%) of 10 as a yellow oil: IR (CH 2 Cl 2 ) 2957, 2930,2858,1738,1611,1382,1326 160.4, 153.9, 127.3, 54.5, 51.0, 35.4, 32.0, 29.6, 29.4, 24.1, 23.0, and 14.5 9 (0.124 g, 0.34 mmol) in 0.7 mL of CH 3 CN with ketene over 6 h according to the general procedure 21 afforded 0.138 g of reddish-brown oil, which was dissolved in 1 mL of CH 2 Cl 2 and concentrated onto 1 g of silica gel. The free-flowing powder was added to the top of a column of 20 g of silica gel and eluted with 15% EtOAc-hexanes to provide 0.109 g (79%) of 17 as a pale yellow oil: IR (neat) 2928, 2856, 1753, 1602, 1380, and 1168 0, 157.7, 145.3, 136.0, 135.4, 130.3, 129.0, 128.0, 127.5, 126.8, 126.2, 52.6, 50.3, 31.4, 29.2, 28.3, 23.7, 22.5, 21.7 8, 157.9, 153.3, 134.6, 133.6, 127.9, 117.9, 117.8, 54.2, 51.1, 46.6, 32.9, and 22.3 5.…”

Synthesis of Highly Substituted Indolines and Indoles via Intramolecular [4 + 2] Cycloaddition of Ynamides and Conjugated Enynes.

“…As outlined in eq 1, 3-butynylamine serves as a synthetic linchpin in this divergent strategy. Sonogashira coupling of 4 with an alkenyl halide or sulfonate generates the requisite enyne moieties with a variety of substitution patterns, and our room-temperature copper-promoted Nalkynylation 8,9 reaction then provides access to the desired substituted ynamides. 10 (1) Tables 1 and 2 delineate the scope of the [4 + 2] cycloaddition.…”