Organic Letters
Letter
deuterium incorporation results suggest the involvement of a bis-
hydride species in the catalytic cycle in order to allow
equilibration of the hydrogen sources. The observed preference
for hydrogen versus deuterium implies a kinetic isotope effect in
the rate-determining step.14 Based on these observations, a
potential catalytic cycle consistent with these observations can be
proposed (Figure 3). The catalytic cycle is initiated by
discussions. Mark Saulnier (Bristol-Myers Squibb), Nick Mean-
well (Bristol-Myers Squibb), Eric Gillis (Bristol-Myers Squibb),
and John Kadow (Bristol-Myers Squibb) are thankfully acknowl-
edged for reading the manuscript. Dieter Drexler (Bristol-Myers
Squibb) is gratefully acknowledged for deuterium isotopic
analysis. This paper is dedicated to the memory of Prof. David
Y. Gin (1967−2011).
REFERENCES
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Figure 3. Proposed catalytic cycle of alkene hydrogenation.
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conversion of Ru catalyst 4 into bis-hydride 16a. Following
complexation of the alkene, 16b, the Ru hydride adds across the
alkene to form alkyl ruthenium 16c. Next, protonation by
methanol provides 16d and finally reductive elimination delivers
product and ruthenium 16e. Hydride transfer to 16e from
sodium borohydride would then reform ruthenium hydride 16a.
All interconversions in the catalytic cycle prior to the irreversible
reductive elimination of 16d to 16e are all likely reversible under
the reaction conditions allowing for alkene isomerization
commonly observed during Ru-catalyzed transfer hydrogenation
reactions. However, further work is needed to clarify the
mechanism.
In conclusion, a simple and practical hydrogenation protocol
for alkenes has been demonstrated. The method works well
coupled with Ru-catalyzed metathesis allowing for a convenient
tandem RCM/transfer hydrogenation sequence. The hydro-
genation process has high functional group tolerance, a notable
advantage over more common Pd-catalyzed hydrogenations.
The selective and practical nature of the tandem metathesis/
hydrogenation sequence provides a useful addition to the
pantheon of Ru metathesis chemistry.
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Org. Biomol. Chem. 2014, 12, 5082.
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(12) Schmidt, B. Eur. J. Org. Chem. 2004, 1865.
(13) Execution of the double labeling experiment NaBD4/CD3OD
under rigorously dry conditions should increase deuterium incorpo-
ration into the product. This experiment, however, has not been run.
(14) In the double labeling experiment NaBD4/CD3OD, the isolated
product yield was only 20% further supporting a kinetic isotope effect.
ASSOCIATED CONTENT
* Supporting Information
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S
Experimental procedures and product characterization (1H and
13C NMR, MS). This material is available free of charge via the
AUTHOR INFORMATION
Corresponding Author
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Prof. Phil Baran (the Scripps Research Institute) and Eric Gillis
(Bristol-Myers Squibb) are gratefully acknowledged for helpful
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dx.doi.org/10.1021/ol5019739 | Org. Lett. XXXX, XXX, XXX−XXX