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Metal and Phosphine Mediated Transformations

Pincer Ligands

Functionalized allyl boronates are useful building blocks in natural product synthesis. Olsson et al. reported the use of a palladium pincer complex in combination with diboronic acid for the boronation of readily available allylic alcohols. Under mild conditions, a variety of allylic alcohols were reacted with 5 mol% catalyst to yield the corresponding boronic acids, which were converted to the more stable trifluoroborate salt derivatives in good yields. Considering the widely available nature of allylic alcohols, the mildness of the reaction conditions, and the potential utility in natural product as well as fine chemical synthesis, this conversion of the typically difficult-to-substitute alcohol moiety into a functionalized alkylboronate is a remarkably efficient method for the preparation of these reagents (Scheme 1).

Scheme 1.

The authors suggest the diboronic acid is behaving as a Lewis acid (Scheme 2); however, since it is not as strong a Lewis acid as alkyl- or haloboranes, they suggest participation by a MeOH molecule. The sixmembered transition state facilitates esterification of the boronic acid and consequently converts the hydroxyl moiety into a better leaving group.1

Scheme 2.

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Direct Arylation of Heterocycles

Lewis and co-workers have recently disclosed a highly functional-group compatible Rh-catalyzed C-H bond activation for the rapid synthesis of functionalized heterocycles. The method relies on the use of rhodium complexed with (Z)-1-tert-butyl-2,3,6,7-tetrahydrophosphepine, which behaves as a chelating ligand, addressing the sometimes slow arylations that occur due to dehydrogenation leading to aryl halide hydrohalogenation or reduction. This ligand is used as the tetrafluoroborate salt, which allows easy handling and storage and, when combined with the rhodium precatalyst, provides a highly robust and efficient catalytic system, in many cases performing arylations that were not possible using traditional catalytic methods. The scope of the reaction was examined and a variety of heterocycles were successfully arylated including benzimidazoles, benzoxazoles, benzothiazoles, as well as bisarylimidazoles, with a variety of functionalized aryl bromides (sulfinyl-, chloro-, acetamide-, hydroxy-, and amino-containing functionalities were suitable coupling partners) (Scheme 3).2

Scheme 3.

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Air-Stable Trialkylphosphine for Morita-Baylis Hillman Reactions

The use of amines and phosphines in nucleophilic catalysis is wellprecedented; however, arguably one of the severe limitations with respect to exploiting the more nucleophilic, yet less basic, phosphine in this regard is its air sensitivity. This is especially true for the most nucleophilic of this class, the trialkylphosphines. While utilization of these difficult-to-handle phosphines as their trifluoroborate salts has provided an excellent solution to handling limitations, there are circumstances where the use of base is not necessary or possible. He and co-workers have demonstrated the use of the known cage-like, air-stable trialkylphosphine, 1,3,5-triaza-7-phosphaadamantane (PTA), in organocatalysis, and specifically in the Morita-Baylis-Hillman (MBH) reaction (Table 1). Traditionally, MBH reactions are conducted using DABCO®, but slow reaction rates often hamper its utility. The authors’ use of PTA has addressed some of these difficulties, utilizing mild and environmentally friendly conditions, to provide the desired products in good to excellent yields. In addition, the use of PTA is also proving successful in historically challenging cases, such as MBH reactions using acrylate as the electrophile.

Table 1.

The authors also presented reasonable evidence implicating the phosphorus-bound Michael adduct 1 by preparation of species 3 via reaction of PTA with ethyl acrylate in THF-H2O (Scheme 4). Not only does formation of adduct 3 substantiate organocatalysis through the Michael adduct, but it also proves that the tertiary alkyl phosphine is behaving as the organocatalyst and not the nitrogen.3

Scheme 4.

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Despite a long-standing belief that formyl groups cannot be generated at quaternary carbon centers via hydroformylation, Clarke and Roff have developed a method utilizing 1,3,5,7-tetramethyl-6-phenyl-2,4,8- trioxa-6-phosphaadamantane, an air-stable phosphane ligand, which inhibited hydrogenation and provided excellent levels of regioselectivity (for quaternary versus linear regioisomer) (Scheme 5).4

Scheme 5.

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Amination of Aryl Halides


The Buchwald-Hartwig amination reaction, or the coupling between an aryl halide and an amine, is extremely important in various areas of both academic and industrial research. The amination of aryl chlorides with various amines can be notoriously difficult, usually requiring bulky phosphines to achieve reasonable yields. However, the scope of amination reactions using these bulkier phosphines is still somewhat limited with respect to the variety of aryl chlorides that can be employed. To address this limitation, Ackermann et al. synthesized a diaminophosphine ligand, which, when used with Pd(dba)2, afforded good yields for the catalytic amination of a wide variety of aryl chlorides with different primary and secondary amines (Scheme 6).5

Scheme 6.

BRIDP Catalysts

Researchers at Takasago developed two phosphine-based ligands for the Buchwald-Hartwig amination reaction with successful results for the cross-coupling of a wide array of amines and aryl halides. These ligands exhibit several noteworthy advantages, with regard to efficiency and turnover numbers, as well as the ability to access biaryls substituted with a nitrogen atom.

The development of a new ligand for efficient amination of a variety of aryl halides focused on optimizing the sterics and electronics and ultimately resulted in the development of a phosphinebased ligand consisting of two phenyl groups connected to a dicyclohexylphoshinylpropylidene (Cy-vBRIDP (Scheme 7)). N-Arylation using Cy-vBRIDP was exceptionally effective with aryl bromides and secondary amines.6a

Scheme 7.

After the report of Cy-vBRIDP incorporating a vinyl-based phosphine ligand, Suzuki and co-workers reported another amination ligand (cBRIDP) for use with more challenging coupling partners such as the reaction of aryl chlorides with primary and secondary amines.2 The vinyl component was replaced with a methylcyclopropane moiety and the cyclohexyl groups were replaced with t-butyl functionalities (the cyclohexyl version of this was also developed, Cy-cBRIDP). Improved catalytic activity was demonstrated with cBRIDP, with loadings as low as 0.2 mol% achieved and generating a variety of tertiary amines in good-to-excellent yields. In addition, cBRIDP proved to be a highly general ligand, facilitating couplings with different electron-poor and electron-rich aryl bromides and chlorides (Table 2 and Table 3). Additionally, sterically hindered couplings were effected such as the coupling between 2,4,6-trichlorobenzene and carbazole, yielding sterically congested products in good yields (Scheme 8).6b

Table 2.

Table 3.

Scheme 8.

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Ferrocenyl Based Ligands and Catalysts

Hartwig and co-workers have reported the use of the electron-rich and bulky ligand 1,1’-bis(di-tert-butylphosphino)ferrocene for the amination of aryl halides and for the first amination of aryl tosylates. The amination of various amines with aryl chlorides, iodides, and tosylates was effected using this novel ligand in combination with a palladium source affording the coupled products in excellent yield. This ligand is exceptionally effective and, though the electron density on the metal helps accelerate the oxidative addition (a necessity for unactivated aryl chlorides), the electron-richness does not negatively impact the reductive elimination since the steric bulk associated with this ligand facilitates this last step of the catalytic cycle (Table 4).7

Table 4.

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New Catalysts for Suzuki Coupling

Suzuki Coupling of Alkyl Chlorides

Gonzalez-Bobes and Fu reported the use of NiCl2•glyme in the presence of prolinol in the previously unprecedented Suzuki reactions of unactivated secondary alkyl chlorides. Both primary, secondary, cyclic and acyclic alkyl chlorides can be utilized in this transformation, as well as electron-rich and electron-poor arylboronic acids (Table 5).8

Table 5.

Non-Proprietary Catalysts for Cross-Coupling

Great strides have been made in the development of catalysts for cross-coupling chemistry, particularly for Suzuki-Miyaura reactions. The cross-coupling reaction of heteroaryl halides is of particular interest to the pharmaceutical industry since many biologically active compounds are accessed through use of the Suzuki-Miyaura reaction. However, the efficient coupling of five-membered heteroaryl halides or six-membered heteroaryl chlorides bearing heteroatom substituents with boronic acids has not been well-developed. Catalysts are thought to form inactive complexes with many of these types of substrates, and thus, they typically require high catalyst loadings in order to achieve good yields.

The Guram group at Amgen has recently communicated the development of an air-stable palladium complex, (AtaPhos)2PdCl2, for Suzuki-Miyaura cross-coupling reactions (Table 6). The catalyst was very effective at coupling a wide variety of substrates with arylboronic acids, including amino-substituted 2-chloropyridines and fivemembered heteroaryl halides. The products are observed in excellent yields and high turnover numbers (up to 10,000 TON) are typically achieved.9

Table 6.

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Gold Catalysis

The Friedel-Crafts reaction is well-documented in organic chemistry; however, one major limitation is the common use of strong acids. There have been studies on the use of stoichiometric and catalytic metals to accelerate this important class of reactions. Since gold catalysts can be considered as metallic sources of H+, several research groups have successfully demonstrated the utility of Au(I) catalysts for Friedel-Craftstype reactions. Tarselli and Gagne recently reported an efficient and functional-group-tolerant method for the cyclization of 4-allenyl arenes to afford benzocycles in the presence of chloro(triphenylphosphite) gold. The reaction was generally amenable with electron-rich arenes, but heterocyclic aromatic compounds with coordinating abilities such as triazoles, isoxazoles, and oxazoles led to catalyst poisoning. On the other hand, the reaction was tolerant of functional groups and moieties such as ethers, acetals, and pyrroles (Scheme 9).10

Scheme 9.

Echavarren and co-workers used a Au(I) catalyst to effect the transformation of substrate 4 to 5. This reaction proceeds through a 5-exo-dig cyclization followed by trapping with MeOH (Scheme 10).11

Scheme 10.

Echavarren and co-workers have also reported the intermolecular addition reactions of nucleophiles, including electron-rich arenes and heteroarenes, allylsilanes, and 1,3-dicarbonyl compounds to 1,5- and 1,6-enynes. Using the electron-rich Au(I)-phosphite based catalyst below (6), the authors reacted 1,6-enynes with arenes and heteroarenes to afford carbocycles. This reaction occurs via 5-exo-dig cyclization to afford a cyclopropyl metal carbene species, which upon reaction with the nucleophile affords the carbocyclic product (Table 7).12

Table 7.

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  1. Olsson, V. J. et al. J. Am. Chem. Soc. 2006, 128, 4588.
  2. Lewis, J. C. et al. J. Am. Chem. Soc. 2008, 130, 2493.
  3. He, Z. et al. Adv. Synth. Catal. 2006, 348, 413.
  4. Clarke, M. L.; Roff, G. J. Chem.-Eur. J. 2006, 12, 7978.
  5. Ackermann, L. et al. Angew. Chem., Int. Ed. 2006, 45, 7627.
  6. (a) Suzuki, K. et al. Adv. Synth. Catal. 2007, 349, 2089. (b) Suzuki, K. et al. Adv. Synth. Catal. 2008, 350, 652.
  7. Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 7369.
  8. Gonzalez-Bobes, F.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 5360.
  9. (a) Singer, R. A. et al. Tetrahedron Lett. 2006, 47, 3727. (b) Singer, R. A. et al. Synthesis 2003, 1727. (c) Guram, A. S. et al. Org. Lett. 2006, 8, 1787.
  10. Tarselli, M. A.; Gagne, M. R. J. Org. Chem. 2008, 73, 2439.
  11. Nieto- Oberhuber, C. et al. Chem.-Eur. J. 2006, 12, 1677.
  12. Amijs, C. H. M. et al. J. Org. Chem. 2008, 73, 7721.

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