Mild and selective deuteration and isomerization of alkenes by a bifunctional catalyst and deuterium oxide

Article abstract of DOI:10.1021/ja903519a

(Figure Presented) H/D exchange is achieved at allylic positions of alkenes using D₂O in acetone and alkene isomerization catalyst 1, which features a bifunctional imidazolylphosphine. The basic nitrogen of the latter is thought to deprotonate an alkene substrate coordinated to the CpRu center; at this stage the protonated nitrogen could undergo H/D exchange with deuterium oxide. An exceptional degree of deuteration is achieved at positions accessible to isomerization, with a high degree of control. Using biphasic settings one can literally wash out reactive protons on the substrate without using organic solvents.

Full text of DOI:10.1021/ja903519a

Published on Web 07/08/2009
Mild and Selective Deuteration and Isomerization of Alkenes by a Bifunctional
Catalyst and Deuterium Oxide
Gu¨lin Erdogan and Douglas B. Grotjahn*
Department of Chemistry and Biochemistry, 5500 Campanile DriVe, San Diego State UniVersity,
San Diego California 92182-1030
Received April 30, 2009; E-mail: grotjahn@chemistry.sdsu.edu
Deuterium- and tritium-labeled compounds are valuable probes
in many studies, including reaction mechanisms, kinetics, drug
metabolism, and structural elucidation of biological macromol-
ecules.1 The heavy isotopes of hydrogen are often introduced
using multistep syntheses. This strategy involves several syn-
thetic operations with labeled reagents. In contrast, catalyzed
exchange of H for D or T is very attractive because it can be
done in one step, with unlabeled substrates.2,3 The great
challenges for catalyzed exchange are regio- and chemoselec-
tivity and functional group tolerance. Most of the methods
require high temperature and/or high pressure (in conditions
where D2 is the source of deuterium) or strongly acidic or basic
additives.2,3 Homogeneous metal catalysis can provide milder
conditions with greater functional group tolerance. Methods that
use deuterium oxide are especially attractive because of its lower
cost and toxicity and ease of handling. Although there are many
reports of H/D exchange at aromatic and aliphatic C-H
bonds,3,4a-f there are surprisingly few such reports for alkenes
and for these4g-l exchange at vinylic positions dominates. A
recent catalyst4l stands out for lack of alkene isomerization
during deuteration; the others do not control isomerization well
when it can occur.
Here we report H/D exchange at allylic positions of alkenes
catalyzed by recently reported alkene zipper catalyst 15 using
inexpensive deuterium oxide as the isotope source. We describe
homogeneous reactions with acetone cosolvent and biphasic
reactions which could allow one literally to wash out reactive
substrate hydrogens without using organic solvents.
Bifunctional catalyst 1 isomerizes many alkenes to (E)-isomer
products (upper part of Scheme 1) with low catalyst loading
(2-5 mol %) at moderate temperatures (25-70 °C). The
heterocyclic ligand is proposed to act as an internal base
facilitating the isomerization by deprotonating accessible allylic
position(s) of a coordinated alkene.5 In accord with the mech-
anism proposed in Scheme 1, adding deuterium oxide to the
isomerization reactions leads to useful H/D exchange. Substrate
scope (Scheme 2) was explored using representative hydrocarbon
chains. Substrates were dissolved in acetone-d6, and sufficient
deuterium oxide was added so as to provide 20 D per exchange-
able H. Assuming equal distribution of D among all exchange-
able positions, each such position should be 95% deuterated,
judged to be a synthetically useful goal. Deuteration of propene
C1 and C3 positions increased over time (Figure 1) reaching
97.5-98.5% of theoretical deuteration within 24 h.6 In stark
contrast, the single proton at C2 was retained6 after reaction
times as long as 60 d, in accord with the proposed mechanism.
Similar deuteration at only C1 and C3 was seen when 4-ally-
lanisole was heated with 1 and D2O at 70 °C. Isomerization of
diallyl ether gave (E,E)-dipropenyl ether without any detectable
(E,Z)- or (Z,Z)-isomer.7 In the presence of deuterium oxide, H/D
exchange is seen only at positions C1 and C3,7 consistent with
previous examples.
The observed selectivity makes the alternative mechanism
(metal hydride formation, alkene insertion, and ꢀ-hydride
elimination) seen for many other alkene isomerization catalysts8
highly unlikely.
In contrast to the case of substrates with isolated allyl groups,
when (E)-2-butene and 1-pentene were exposed to D2O and 1,
H/D exchange occurred at previously unreactive vinylic posi-
tions. Presumably η3-allyl intermediates formed along the chain,
allowing all positions to become allylic through isomerization.
Thus, full deuteration of these substrates can be achieved with
2 to 5 mol % catalyst loading and reasonable reaction times.
Catalyst 1 deuterates (E)-2-butene quickly (t1/2 ) ca. 1.2 h)
but only slowly (t1/2 > ca. 240 h) isomerizes it to the (Z)-isomer;
hence perdeuteration can occur without E/Z isomerization. These
features highlight the high kinetic selectivity of 1 in making or
acting on terminal or (E)-alkenes rather than on (Z)-alkenes.
Branched substrates provide additional examples of highly
selective deuteration. For example, 4-methyl-1-pentene isomer-
ized to (E)-4-methyl-2-pentene and deuteration was observed
only at C1 and C3, leaving the C2 proton intact.9 Further
isomerization was not observed even at elevated temperatures
over time. The natural product (+)-limonene underwent H/D
Scheme 1. Proposed Mechanism of Isomerization and Deuteration
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10354 J. AM. CHEM. SOC. 2009, 131, 10354–10355
10.1021/ja903519a CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Reactants and Productsa
Figure 1
Acknowledgment. We thank Reji Nair for early experiments,
Dr. LeRoy Lafferty for his assistance with NMR experiments, and
the NSF (CHE 0719575) for supporting this and related work.
Supporting Information Available: Details of reaction conditions
and results. This material is available free of charge via the Internet at
http://pubs.acs.org.
a Reactions carried out in acetone-d6 with enough deuterium oxide so
as to provide 20 D per exchangeable H present. The number in brackets
indicates the percentage of the theoretical amount (95%) of deuterium. b RT
with 2% catalyst. c 70 °C with 5% catalyst. d RT with 5% catalyst.
References
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exchange mainly at the exocyclic isopropenyl group. Deuterium
incorporation is observed at the endocyclic double bond but is
far from complete, which can be attributed to steric hindrance
to 1 forming an η3-allyl complex at this position. Deuteration
of (+)-valencene was even more selective. Exocyclic isopropenyl
groups are found in many terpenoid natural products; hence facile
pentadeuteration at such sites is of particular interest.
Biphasic reactions were performed on liquid substrate 4-al-
lylanisole by stirring it with only catalyst and D2O, avoiding
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to-handle D2O is the source of label.
The high steric selectivity of 1 for (E)-alkenes gives the
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expected to be especially useful in labeling complex substrates
either at a late stage of a synthesis or using material directly
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