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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Org Lett. Author manuscript; available in PMC 2010 April 28.
Published in final edited form as:
Published online 2008 February 7. doi:  10.1021/ol800159w
PMCID: PMC2860772

Iridium Catalyzed C-C Coupling via Transfer Hydrogenation: Carbonyl Addition from the Alcohol or Aldehyde Oxidation Level Employing 1,3-Cyclohexadiene


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Under hydrogen auto-transfer conditions employing a catalyst derived from [Ir(cod)Cl]2 and BIPHEP, 1,3-cyclohexadiene (CHD) couples to benzylic alcohols 1a-9a to furnish carbonyl addition products 1c-9c, which appear as single diastereomers with variable quantities of regioisomeric adducts 1d-9d. Under related transfer hydrogenation conditions employing isopropanol as terminal reductant, identical carbonyl adducts 1c-9c are obtained from the aldehyde oxidation level. Isotopic labeling studies corroborate a mechanism involving hydrogen donation from the reactant alcohol or sacrificial alcohol (i-PrOH).

As part of a broad program aimed at the development of methods for byproduct-free carbonyl and imine addition,1,2 we recently reported that carbonyl allylation may be achieved by simply hydrogenating allenes in the presence of aldehydes.2h Though effective for reverse prenylation, attempted crotylations and allylations using gaseous hydrogen as the terminal reductant suffered from over-reduction of the olefinic adduct. To address this limitation, allene-aldehyde reductive coupling was performed under the conditions of transfer hydrogenation using isopropanol as the terminal reductant.2i In the course of these studies, it was found that carbonyl allylation could be achieved directly from the alcohol oxidation level by way of allene-alcohol transfer hydrogenation,2i constituting a novel variant of hydrogen auto-transfer processes wherein hydrogen exchange between reactants is used to generate nucleophile-electrophile pairs (Scheme 1).2i, 3,4,5,6,7

Scheme 1
Carbonyl & Imine Addition via Hydrogen Auto-Transfer.

Through hydrogen auto-transfer, there exists the potential to develop a broad new family of byproduct-free catalytic C-C bond formations wherein alcohols and diverse π-unsaturated compounds are exploited as coupling partners. Motivated by this prospect, diene-aldehyde hydrogen auto-transfer was explored. Catalytic diene-aldehyde reductive coupling has been accomplished in both intra- and intermolecular settings. 8,9,10 Recently, the first examples of asymmetric diene-aldehyde intermolecular coupling were reported.9k,l Here, we disclose that 1,3-cyclohexadiene and aromatic alcohols 1a-9a engage in C-C coupling under the conditions of iridium catalyzed hydrogen auto-transfer. Additionally, we report the coupling of 1,3-cyclohexadiene to an analogous set of aldehydes 1b-9b under related transfer hydrogenation conditions employing isopropanol as the terminal reductant.

Initial studies focused upon the coupling of benzyl alcohol 1a to 1,3-cyclohexadiene (CHD) under the conditions of iridium catalysis. It was found that a catalyst derived from commercially available [Ir(cod)Cl]2 and BIPHEP delivers homoallylic alcohol 1c as a mixture of diastereomers, along with significant amounts of the regioisomeric product 1d.11 Notably, cationic iridium salts were almost completely ineffective for this process and basic additives were unnecessary. With the aim of minimizing isomer formation, a screen of additives was undertaken, leading to the discovery that Bu4NI had a small but significant effect on diastereoselectivity and the suppression of the regioisomeric product 1d. 12 Finally, formation of adduct 1c as a single diastereomer (> 95:5 syn:anti) is enabled using excess CHD (12 equiv.), which also suppresses further the formation of regioisomer 1d. Under these conditions, CHD couples to diverse benzylic alcohols 2a-9a, providing adducts 2c-9c in good to excellent yields as single diastereomers (Table 1, Left).

Table 1
Left: Iridium catalyzed coupling of 1,3-cyclohexadiene to alcohols 1a-9a via hydrogen auto-transfer.a Right: Iridium catalyzed coupling of 1,3-cyclohexadiene to aldehydes 1b-9b via transfer hydrogenationb

The very same products 1c-9c are accessible through the coupling of CHD to aldehydes 1b-9b under the conditions of iridium catalyzed transfer hydrogenation employing isopropanol as the terminal reductant. Conditions similar to those described in Table 1 are used, but with lower loadings of 1,3-cyclohexadiene (4 equiv.). Thus, carbonyl addition products 1c-9c are accessible from the alcohol or aldehyde oxidation level (Table 1, Right).

In light of previous results,2i a plausible general mechanism for catalytic C-C coupling under hydrogen autotransfer conditions is proposed in Scheme 1. Iridium-catalyzed dehydrogenation of the alcohol followed by hydrometallation of 1,3-cyclohexadiene results in the generation of a nucleophile-electrophile pair. The iridium σ-allyl species engages the aldehyde in a closed six-centered transition state, to furnish the syn-adduct. Cleavage of the iridium-alkoxide delivers the alcohol product and releases the catalyst to close the cycle. Formation of regioisomers 1d-9d is attributed to metal-hydride mediated olefin isomerization subsequent to C-C coupling. This interpretation is supported by the fact that decreased levels of this component are observed at lower conversion. Under the conditions of transfer hydrogenation, iridium-monohydride generation is accomplished by employing isopropanol as a sacrificial alcohol.13

To gain further insight into the catalytic mechanism, isotopic labeling studies were performed. Thus, exposure of deuterio-1a to standard conditions results in the formation of deuterio-1c which incorporates deuterium in the benzylic position (95 %), and, to a limited extent (ca. 15 %), in the cyclohexene ring (eq. 1). Incomplete deuterium incorporation is possibly a result of deuterium-hydrogen exchange with cyclohexadiene (12 equiv.) in advance of C-C coupling. Indeed, when the reaction is run using only 2 equivalents of 1,3-cyclohexadiene, an increase in deuterium incorporation in the cyclohexene ring (ca. 40 %) is observed. Here, positional analysis by NMR is complicated by the presence of significant amounts of 1d and anti-1c/1d. Similarly, coupling of 1b using d8-isopropanol, results in the formation of deuterio-1c’, where deuterium incorporation (ca. 25 %) is observed solely in the cyclohexene ring (eq. 2). These data do not preclude alternative mechanisms involving diene-aldehyde oxidative coupling (Scheme 2).

Scheme 2
Isotopic labeling experiments.

In summary, we demonstrate that diene-alcohol hydrogen auto-transfer enables byproduct-free carbonyl addition from the alcohol oxidation level. Under related transfer hydrogenation conditions employing isopropanol as terminal reductant, identical carbonyl adducts are obtained from the aldehyde oxidation level. These studies suggest the feasibility of developing a broad new class of catalytic C-C bond formations, wherein alcohols and π-unsaturated reactants are exploited as coupling partners.

Supplementary Material

Supplementary Data


Acknowledgment is made to the Robert A. Welch Foundation, Johnson & Johnson, Merck, and the NIH-NIGMS (RO1-GM69445) for partial support of this research. Dr. Oliver Briel of Umicore is thanked for the generous donation of [Ir(cod)Cl]2.


Supporting Information Available. Experimental procedures and spectral data for all new compounds (1H NMR, 13C NMR, IR, HRMS). This material is available free of charge via the internet at


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(11) The stereochemical assignment of 1c was made by comparison with the corresponding literature NMR data.9j The stereochemical assignment of products 2c-9c was made in analogy to 1c. That 1c and 1d are regioisomers (and not diastereomers) was confirmed by oxidation (Dess-Martin periodinane) to the corresponding mixture of ketones and comparison with relevant literature NMR data. See Supporting Information for details.
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(13) In the absence of isopropanol, benzaldehyde 1b is converted to 1c in 5% yield.