Ligation catalyst

Although dirhodium(II) carboxamidates are less reactive toward diazo decomposition than are dirhodium carboxylates, and this has limited their uses with diazomalonates and phenyldiazoacetates, the azetidinone-ligated catalysts 11 cause rapid diazo decomposition, and this methodology has been used for the synthesis of the cyclopropane-NMDA receptor antagonist milnacipran (17) and its analogs (Eq. 2) [10,58]. In the case of R=Me the turnover number with Rh2(45-MEAZ)4 was 10,000 with a stereochemical outcome of 95% ee. 

The search for the racemic form of 15, prepared by allylic cyclopropanation of farnesyl diazoacetate 14, prompted the use of Rh2(OAc)4 for this process. But, instead of 15, addition occurred to the terminal double bond exclusively and in high yield (Eq. 6) [65]. This example initiated studies that have demonstrated the generality of the process [66-68] and its suitability for asymmetric cyclopropanation [69]. Since carbon-hydrogen insertion is in competition with addition, only the most reactive carboxamidate-ligated catalysts effect macrocyclic cyclopropanation [70] (Eq. 7), and CuPF6/bis-oxazoline 28 generally produces the highest level of enantiocontrol. 

Activated aryl chlorides, which are close in reactivity to unactivated aryl bromides, underwent reaction with the original P(o-tol)3-ligated catalyst.58 Nickel complexes, which catalyze classic C—C bond-forming cross-couplings of aryl chlorides, 9-64 also catalyzed aminations of aryl chlorides under mild conditions.65,66 However, the nickel-catalyzed chemistry generally occurred with lower turnover numbers and with a narrower substrate scope than the most efficient palladium-catalyzed reactions. 

In 1993 Burk, Brown, and coworkers confirmed that DuPHOS complexes exhibit the same anti-lock-and-key mechanistic motif as seen for aryl phosphine ligated catalysts [41], In 1998 by Burk and coworkers reported an unexpected and interesting result [34], With substrates having R<, = aryl, selectivity of 99% e.e. for the S product resulted from (S,S)-Me-DuPHOS-Rh hydrogenations, but the R product was obtained with similarly high enantioselectivity when Ra = t-Bu or adamantyl. In other words, the simple change of an aryl substituent to a bulky alkyl completely reverses the sense of enantioselection. 

We calculate only a 0.7 kcal/mol difference between R-DIHY-B and S-DIHY-B, with nearly identical migratory insertion barriers, so we would predict only modest enantioselectivity if a DuPHOS-ligated catalyst reacted along the hydride route. However, we are not aware of any evidence that a solvated Rh-DuPHOS catalyst reacts with hydrogen to form dihydrides. 

Copper catalysts were the first to be employed, and with the bis(oxazoline)-ligated catalyst 46 enantioselectivites up to 97% have been achieved (e.g.,... 

Metal complexation with RlifCOI))2 +HI 4 only gives the mono-ligated catalyst (.S)-94, unlike metal complexations with MiniPhos, which affords the bis-ligated complex [Rh(MiniPhos)2]+BF4, 114... 

Multiple arylations of polybromobenzenes have been conducted to generate electron-rich arylamines. Tribromotriphenylamine and 1,3,5-tribromobenzene all react cleanly with A-aryl piperazines using either P(o-tolyl)3 or BINAP-ligated catalysts to form hexamine products [107]. Reactions of other polyhalogenated arenes have also been reported [108]. Competition between aryl bromides and iodides or aryl bromides and chlorides has been investigated for the formation of aryl ethers [109], and presumably similar selectivity is observed for the amination. In this case bro-mo, chloroarenes reacted preferentially at the aryl bromide position. This selectivity results from the faster oxidative addition of aryl bromides and is a common selectivity observed in cross-coupling. Sowa showed complete selectivity for amination of the aryl chloro, bromo, or iodo over aryl-fluoro linkages [110]. This chemistry produces fluoroanilines, whereas the uncatalyzed chemistry typically leads to substitution for fluoride. 

Multiple arylations of polybromobenzenes were also conducted to generate electron-rich arylamines. Tribromotriphenylamine and 1,3,5-tribromobenzene all react cleanly with iV-aryl piperazines using either P(o-tolyl)3 or BINAP-ligated catalysts to form hexamine products [107]. Reactions of other polyhalogenated arenes have also been reported [108]. 

For the case of tri(o-tolyl)phosphine-ligated catalysts, the upper pathway appears to predominate. Oxidative addition occurs first via loss of a ligand from the bisphosphine precursor to form the oxidative adduct, which exists as a dimer bridged through the halogen atoms (equation 33). This dimer is broken up by amine, the coordination of which to palladium renders its proton acidic. Subsequent deprotonation by base leads to the amido complex, which can then reductively eliminate to form the product. When tert-butoxide is used as the base, the rate is limited by formation of and reductive elimination from the amido complex, while for the stronger hexamethyldisilazide, the rate-determining step appears to be oxidative addition. ... 

With fra 5-disubstituted allylic systems, the Rh2(MEPY)4 catalysts exhibit lower levels of stereo control. However, here again ligand switching corrects the efficiency since the steric bias imposed through the application of the W-acylimida-zolidinone-ligated catalysts raises enantioselectivity with trans systems to levels >95% ee. For example, the cinnamyl alcohol-derived diazoester in Eq. (24), with Rh2(4S-MPPIM)4 as catalyst, furnishes the bicyclic product with an ee of 96%. 

While phosphine-ligated catalysts like 77 and 81 are effective in thermo-morphic systems, the oxidation of phosphine ligands in the presence of transition metal compounds and especially in the presence of Pd(0) poses experimental and practical problems in recycling catalysts in batch reactions. Such issues can be handled with more rigorous inert atmosphere equipment. Alternatively, more stable catalysts can be used. In the case of Heck and Suzuki chemistry, very stable pincer-type catalysts are available. These include phosphine-ligated species like 112 and thioether-ligated species like 113 [152-154]. 

The polycycloalkenes produced with chiral, indenyl-ligated catalysts such as 6/MAO are insoluble in common hydrocarbons and are highly crystalline. The melting points of polycyclobutene, polycyclopentene, and polynorbomene are around or above 400 °C, close to their decomposition temperatures, rendering the polymers difficult to melt process. 

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