A general protocol for the programmed synthesis of tetraarylthiophenes has been established. The utilization of three catalysts, RhCl(CO){P[OCH(CF(3))(2)](3)}(2), PdCl(2)/P[OCH(CF(3))(2)](3), and PdCl(2)/bipy, enables regioselective sequential arylations at the three C-H bonds of 3-methoxythiophene with iodoarenes. Interesting metal- and ligand-controlled regiodivergent C-H arylations have been uncovered during this study. The installation of fourth aryl groups to the thus-generated 2,4,5-triaryl-3-methoxythiophenes has been accomplished through a sequence of demethylation, triflation, and Suzuki-Miyaura coupling.

The ability to transform one functional group into another lies at the heart of organic chemistry. Such functional-group interconversions do not involve carbon-carbon bond-forming reactions and are thus seen as less efficient for the construction of complex molecules, however, these interconversions are often critical to "set up" a molecule for such a transformation. The oxidation of primary and secondary alcohols (1 and 3) to produce aldehydes (2) and ketones (4) prior to the addition of organometallic species is a prime example (Scheme 1). Although this reaction is often essential for the subsequent carbon-carbon bond-forming transformation, it does add an extra, linear step to the sequence. Thus, we imagined that performing the two steps, oxidation and addition, together would greatly simplify synthetic routes by essentially eliminating the need to carry out a preliminary oxidation before converting, for example, a primary alcohol (1) into a secondary alcohol (3), or similarly 3 into a tertiary alcohol (5).Numerous practical advantages are associated with such one-pot multistep alcohol-carbonyl interconversions, [1] but a uniform methodology has not been developed, partly because of the incompatibility of the reaction conditions. Whereas alcohol-to-carbonyl transformations are oxidative, the reverse processes such as carbonyl addition reactions are reductive in nature. Herein, we report that [Ni(cod) 2 ]/IPr (cod = 1,5-cyclooctadiene, IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) serves as a general catalyst for the controlled one-pot oxidation-addition of alcohols and carbonyl compounds. We demonstrate the feasibility of all possible multistep transformations in alcohol-carbonyl interconversions (Scheme 1). A one-pot nickel-catalyzed synthesis of flumecinol (a hepatic microsomal enzyme inducer) is also described.As an important progress toward controlled carbonylalcohol interconversions, we recently established that the [Ni(cod) 2 ]/IPr catalyst promotes the otherwise difficult intermolecular 1,2-addition of arylboronate esters to unactivated ketones and aldehydes.[2] Among the various arylboron reagents screened, arylboronic acid neopentyl glycol ester ArB(neo) turned out to be the most reactive. The advantage of our [Ni-IPr] catalytic system [2] over other transition-metalcatalyzed organoboron-based 1,2-additions is obvious from the viewpoint of the substrate scope. While other catalytic systems are generally only applicable to aldehydes [3] and some electronically and strain-activated ketones, [4] our [Ni-IPr] catalysis shows good reactivity not only toward aldehydes but also toward diaryl, alkyl aryl, and dialkyl ketones under mild reaction conditions.[2] The high reactivity of our [Ni-IPr] catalyst might be partly due to the unique Ni 0 /Ni II mechanism (right-hand catalytic cycle, Scheme 2).Since many transition-metal complexes are able to mediate the oxidation of alcohols to aldehydes or ketones, [5] we envisioned that our nickel catalysis could be extended to a controlled alcohol-carbonyl i...

The trifluoroacetic acid salt of 2-(pyrrolidinylmethyl)pyrrolidine was found to be an effective organocatalyst of an asymmetric intramolecular aldol reaction, affording bicyclo[4.3.0]nonane derivatives with a high enantioselectivity, in which the rare combination of aldehyde as a nucleophile and ketone as an electrophile was realized.

ABSTRACT:We previously reported the discovery of NCH-31, a potent histone deacetylase (HDAC) inhibitor. By utilizing our C−H coupling reaction, we rapidly synthesized 16 analogues (IYS-1 through IYS-15 and IYS-Me) of NCH-31 with different aryl groups at the C4-position of 2-aminothiazole core of NCH-31. Subsequent biological testing of these derivatives revealed that 3-fluorophenyl (IYS-10) and 4-fluorophenyl (IYS-15) derivatives act as potent pan-HDAC inhibitor. Additionally, 4-methylphenyl (IYS-1) and 3-fluoro-4-methylphenyl (IYS-14) derivatives acted as HDAC6-insensitive inhibitors. The present work clearly shows the power of the late-stage C−H coupling approach to rapidly identify novel and highly active/selective biofunctional molecules.

The ability to transform one functional group into another lies at the heart of organic chemistry. Such functional-group interconversions do not involve carbon-carbon bond-forming reactions and are thus seen as less efficient for the construction of complex molecules, however, these interconversions are often critical to "set up" a molecule for such a transformation. The oxidation of primary and secondary alcohols (1 and 3) to produce aldehydes (2) and ketones (4) prior to the addition of organometallic species is a prime example (Scheme 1). Although this reaction is often essential for the subsequent carbon-carbon bond-forming transformation, it does add an extra, linear step to the sequence. Thus, we imagined that performing the two steps, oxidation and addition, together would greatly simplify synthetic routes by essentially eliminating the need to carry out a preliminary oxidation before converting, for example, a primary alcohol (1) into a secondary alcohol (3), or similarly 3 into a tertiary alcohol (5).Numerous practical advantages are associated with such one-pot multistep alcohol-carbonyl interconversions, [1] but a uniform methodology has not been developed, partly because of the incompatibility of the reaction conditions. Whereas alcohol-to-carbonyl transformations are oxidative, the reverse processes such as carbonyl addition reactions are reductive in nature. Herein, we report that [Ni(cod) 2 ]/IPr (cod = 1,5-cyclooctadiene, IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) serves as a general catalyst for the controlled one-pot oxidation-addition of alcohols and carbonyl compounds. We demonstrate the feasibility of all possible multistep transformations in alcohol-carbonyl interconversions (Scheme 1). A one-pot nickel-catalyzed synthesis of flumecinol (a hepatic microsomal enzyme inducer) is also described.As an important progress toward controlled carbonylalcohol interconversions, we recently established that the [Ni(cod) 2 ]/IPr catalyst promotes the otherwise difficult intermolecular 1,2-addition of arylboronate esters to unactivated ketones and aldehydes.[2] Among the various arylboron reagents screened, arylboronic acid neopentyl glycol ester ArB(neo) turned out to be the most reactive. The advantage of our [Ni-IPr] catalytic system [2] over other transition-metalcatalyzed organoboron-based 1,2-additions is obvious from the viewpoint of the substrate scope. While other catalytic systems are generally only applicable to aldehydes [3] and some electronically and strain-activated ketones, [4] our [Ni-IPr] catalysis shows good reactivity not only toward aldehydes but also toward diaryl, alkyl aryl, and dialkyl ketones under mild reaction conditions.[2] The high reactivity of our [Ni-IPr] catalyst might be partly due to the unique Ni 0 /Ni II mechanism (right-hand catalytic cycle, Scheme 2).Since many transition-metal complexes are able to mediate the oxidation of alcohols to aldehydes or ketones, [5] we envisioned that our nickel catalysis could be extended to a controlled alcohol-carbonyl i...