that catalogs the substrates that proved inimical to reactivity (Table 1.5.3-5). These compounds show two general limitations to the substrate scope: (i) any substitution on the terminal alkene
prevents reactivity; and (ii) carbamates and sulfonamides are not effective nucleophiles. The attempted formation of 27 and 28 demonstrate the first limitation, as substitution of the alkene at the terminal or internal position is not tolerated. This limitation is likely the result of alkene substitution disfavoring coordination to the Rh catalyst, and subsequently preventing alkene activation. The limitations to the amine scope can be linked to the decreased nucleophilicity of carbamates and sulfonamides compared to alkyl- and arylamines. Attempted hydroamination with sulfonamide and carbamate nucleophiles was unsuccessful as both 29 and 30 failed to cyclize. The lack of conversion with these substrates shows the limit to amine nucleophilicity.
29 0% Yield 0% Yield30 28 0% Yield NBoc Me Ph Ph NTs Me Ph Ph NBn Me Ph Ph
Catalyst (5 mol %), AgBF4 (5 mol%); Additive (0.2 equiv) Solvent, Temperature, Time H N R2 R2 G NG R2 R2 R1 R1 27 0% Yield NBn Ph Ph Me Me
Scheme 1.5.3-5: Failed intramolecular hydroamination substrates.
Overall, the scope of intramolecular hydroamination with CDC-Rh complexes was very encouraging and closely mirrored the catalytic activity of 1 (Scheme 1.2.2-1),which is one of the most general late transition metal catalysts for intramolecular hydroamination (see Section 1.5.1).173 iPr
CDC-Rh-Cl catalyzed the addition of highly electron rich secondary and primary amines – which inhibit many electrophilic metal complexes used for alkene activation – while being equally effective with comparatively electron poor arylamines. This suggested that tridentate CDC-Rh complexes could tolerate an unusually broad range of nucleophiles. Furthermore, the catalysts were sufficiently electrophilic to allow for formation of both five and six membered heterocycles without the assistance of the Thorpe-Ingold effect.175
hydroamination proved to be a useful metric for gauging the reactivity of Ph
CDC-Rh-Cl and
iPrCDC-Rh-Cl, but was not sufficiently unique to warrant immediate publication.
1.5.4: Summary and Outlook
This unpublished work is, to the best of our knowledge, the first example of CDCs in catalysis. The reactions described above provided proof of concept that the designed ligand scaffolds could accomplish hydroamination. Furthermore, the brief substrate scope proved to be invaluable for gauging what types of substrates could react using Ph
CDC-Rh-Cl and iPr
CDC-Rh- Cl as catalysts. The CDC-Rh species favor electron rich primary and secondary alkylamine nucleophiles, but were also exceptionally tolerant of less nucleophilic arylamines. This broad substrate scope was our first clue that tridentate CDC-ligated Rh complexes might have special properties for hydroamination. Our goal was to develop catalytic methods that would have direct applications in the synthesis of natural products and bioactive molecules and, although this reaction is the first example of catalysis with CDC-ligated metal complexes, there are already a number of catalysts for intramolecular hydroamination. We chose to pursue more challenging intermolecular transformations to demonstrate that these complexes have unique properties that can overcome unsolved challenges in catalysis.
1.6: Intermolecular Hydroamination with Carbodicarbene-Ligated Rh Complexes
The results from our studies in intramolecular hydroamination were highly encouraging and hinted that carbodicarbene ligands could be used to access a broad scope of Rh catalyzed hydroamination substrates. However, our studies on the unique donor properties of these ligands would only be of interest to the synthetic community if we were able to apply CDCs to solving outstanding challenges in catalysis. Intermolecular hydroamination is substantially more
challenging than intramolecular hydroamination and comparatively few examples are known (see section 1.1.4). We chose to focus on addressing this gap in the state-of-the-art as a platform for introducing CDC catalysts to the literature. Intermolecular reactions must overcome a higher entropic barrier than intramolecular processes, and generally require more activating catalysts. Additionally, substrate inhibition is more problematic since the spatial assistance of having the alkene tethered to the amine can no longer assist in ligand substitution.173
We began our studies by screening a variety of amine and alkene analogs in order to determine if the CDC-Rh catalysts were capable of intermolecular hydroamination. The work discussed herein was published in 2014 and marks the first reported use of CDCs in catalysis.210
1.6.1 Screening for Intermolecular Hydroamination
A series of intermolecular test reactions were selected based on the reactivity observed for intramolecular hydroamination with Ph
CDC-Rh-Cl and iPr
CDC-Rh-Cl. N-
methylbenzylamine was selected as a test substrate for intermolecular hydroamination because we naively hypothesized that a stronger Lewis base would require less alkene activation. We did not anticipate catalyst inhibition being an issue since our intramolecular studies proved that nucleophilic alkylamines do not irreversibly inhibit the iPr
CDC-Rh-Cl catalyst. N- methylbenzylamine was paired with several alkene-derived π-electrophiles to explore alkene electrophiles with varied reactivity. Dodecene, styrene, allylbenzene, and phenylbutadiene were tested and we were pleased to discover that the reaction between N-methylbenzylamine and phenylbutadiene proceeded at 80 °C to provide 31 in 34% yield (Scheme 1.5.1-1). This yield nearly doubled to 61% when the catalyst was switched from iPr
CDC-Rh-Cl to the more active
Ph
Catalyst (5 mol %) AgBF4 (5 mol %) C6H5Cl, 80 °C, 24 h Ph Ph Me N (1 equiv) (1 equiv) + N H Me Bn Bn Me Entry 1 2 Yield (%) 34 61 Catalyst iPrCDC-Rh-Cl PhCDC-Rh-Cl
Scheme 1.6.1-1: Discovery of intermolecular hydroamination with CDC-Rh catalysts.