A Rh(I)-catalyzed direct arylation of pyridine and quinoline heterocycles has been developed. The method provides rapid entry into an important class of bis(hetero)aryl products employing inexpensive and readily available starting materials.The pyridine and quinoline nuclei are privileged scaffolds that occupy a central role in many medicinally relevant compounds. 1 Consequently, methods for their expeditious functionalization are of immediate interest. However, despite the immense importance of transition-metal catalyzed cross-coupling for the functionalization of aromatic scaffolds, general solutions for coupling 2-pyridyl organometallics with aryl halides have only recently been presented. 2 Direct arylation at the ortho position of pyridine would constitute an even more efficient approach because it eliminates the need for the stoichiometric preparation and isolation of 2-pyridyl organometallics. 3,4 Progress towards this goal has been achieved by activation of the pyridine nucleus for arylation via conversion to the corresponding pyridine N-oxide 5 or N-iminopyridinium ylide. 6 However, this approach necessitates two additional steps: activation of the pyridine or quinoline starting material, and then unmasking the arylated product. The use of pyridines directly would clearly represent the ideal situation both in terms of cost and simplicity. We now wish to document our efforts in this vein, culminating in an operationally simple Rh(I)-catalyzed direct arylation of pyridines and quinolines.We recently developed an electron-rich Rh(I) system for catalytic alkylation at the ortho position of pyridines and quinolines with alkenes. 7,8 Therefore, we initially focused our attention on the use of similarly electron-rich Rh(I) catalysts for the proposed direct arylation. After screening an array of electron-rich phosphine ligands and Rh(I) salts, only marginal yields (<20%) of the desired product were obtained. Much more efficient was an electron-poor Rh (I) system with [RhCl(CO) 2 ] 2 as precatalyst (Table 1). 9,10 For the direct arylation of picoline with 3,5-dimethyl-bromobenzene, addition of P(O i Pr) 3 afforded a promising 40% yield of the cross coupled product 1a (entry 1). The exclusion of phosphite additive proved even more effective, with the yield of 1a improving to 61% (entry 2). Further enhancement in yield was not observed upon the inclusion of other additives such as MgO (entry 3), various organic bases (entries 4, 5) and inorganic bases (entry 6), or a protic acid source (entry 7). Absolute concentration proved very important, with the best results being obtained at relatively high jellman@berkeley.edu, rbergman@berkeley.edu. concentrations of the aryl bromide (compare entries 8 and 9). A marginal improvement was observed upon running the reaction with 6 equivalents of 2-methyl pyridine (entry 10). 11,12 NIH Public AccessAuthor Manuscript J Am Chem Soc. Author manuscript; available in PMC 2009 November 12.The reaction temperature could also be increased to 175 or 190 °C while maintaining rea...
The copper-catalyzed electrophilic amination of diorganozinc reagents employing O-acyl N,N-dialkyl hydroxylamine derivatives as aminating agents is described. This reaction offers a general method for the preparation of tertiary amines in high yields and is noteworthy for its convenience both in terms of reaction conditions employed (room temperature, =1 h) and ease of product isolation (acid/base extractive workup).
A practical, functional group tolerant method for the Rh-catalyzed direct arylation of a variety of pharmaceutically important azoles with aryl bromides is described. Many of the successful azole and aryl bromide coupling partners are not compatible with methods for the direct arylation of heterocycles using Pd(0) or Cu(I) catalysts. The readily prepared, low molecular weight ligand, Z-1-tert-butyl-2,3,6,7-tetrahydrophosphepine, which coordinates to Rh in a bidentate P-olefin fashion to provide a highly active yet thermally stable arylation catalyst, is essential to the success of this method. By using the tetrafluoroborate salt of the corresponding phosphonium, the reactions can be assembled outside of a glove box without purification of reagents or solvent. The reactions are also conducted in THF or dioxane, which greatly simplifies product isolation relative to most other methods for direct arylation of azoles employing high-boiling amide solvents. The reactions are performed with heating in a microwave reactor to obtain excellent product yields in two hours.
[reaction: see text] This paper details new copper-catalyzed electrophilic amination reactions of diorganozinc reagents using O-benzoyl hydroxylamines as electrophilic nitrogen sources that may be accessed in one step. Simple and functionalized aryl, heteroaryl-, benzyl, n-alkyl, sec-alkyl, and tert-alkyl nucleophiles couple with R2NOC(O)Ph and RHNOC(O)Ph reagents in the presence of catalytic quantities of copper salts to provide tertiary and secondary amines, respectively, in generally good yields. In many cases, the product may be isolated analytically pure after a simple extractive workup. The amination process is shown to tolerate a significant degree of steric demand. The amination of nominally unreactive C(aryl)-H bonds via a sequential directed ortho metalation/transmetalation/catalytic amination reaction sequence is detailed. The direct Cu-catalyzed amination of Grignard reagents using cocatalysis by ZnCl2 is described.
It has been determined experimentally that a 3 ions are generally not observed in the tandem mass spectroscopic (MS/MS) spectra of b 3 ions. This is in contrast to other b n ions, which often have the corresponding a n ion as the base peak in their MS/MS spectra. Although this might suggest a different structure for b 3 ions compared to that of other b n ions, theoretical calculations indicate the conventional oxazolone structure to be the lowest energy structure for the b 3 ion of AAAAR, as it is for other b n ions of this peptide. However, it has been determined theoretically that the a 3 ion is lower in energy than other a n ions, relative to the corresponding b ions. Furthermore, the a 3 ¡ b 2 transition structure (TS) is lower in energy than other a n ¡ b nϪ1 TSs of AAAAR, compared with the corresponding b ions. Consequently, it is suggested that the b 3 ion does fragment to the a 3 ion, but that the a 3 ion then immediately fragments (to b 2 and a 3 *) because of the excess internal energy arising from its relatively low energy and the facile It has been shown that significant rearrangement can occur upon peptide dissociation, particularly in mass spectrometers with relatively long activation/dissociation times such as ion trapping instruments [23][24][25][26][27][28]. However, rearrangements are not limited to ion trapping mass spectrometers [29 -32]. In actuality even b and y ions are formed by rearrangements involving hydrogen atom transfers (y ions) or intramolecular cyclization (b ions). The ubiquitousness of the mechanism for formation of b and y ions has been shown through kinetic energy loss measurements [33].Initially it was thought that b ions had a simple acylium ion structure [5,34,35]. However, this theory was discredited because b 1 ions are not often observed in MS/MS spectra (i.e., these ions should also be acylium ions by the preceding rationale). The current consensus is that b ions most commonly have a protonated oxazolone structure [36 -39]. This has been demonstrated in gas-phase IR studies on the b 4 ions of YGGFL [38,40]. Additionally, recent experimental and theoretical data suggest that larger oxazolones can undergo head-to-tail cyclization to form cyclic-peptide isomers [32,40]. Further evidence supporting the conclusion that b ions have the protonated oxazolone structure is that the major dissociation products of b ions (a n and b nϪ1 ions) have product ion analogs in the MS/MS spectra of synthesized oxazolone compounds [37].Although formation of a n ions via the b n ¡ a n pathway is well understood [41], the actual mechanism of b nϪ1 formation is less clear. Two major mechanisms were considered here, the direct b n ¡ b nϪ1 [36] and indirect b n ¡ a n ¡ b nϪ1 [42] pathways. Metastable ion studies indicate that a n ions are formed with substantial release of kinetic energy (KER). On the other hand b nϪ1 fragments are formed from b n parents with small KER values [36,37]. This finding suggests that a direct b n ¡ b nϪ1 mechanism is preferred. Additionally, doubleresonance experimen...
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