Iridium-Catalyzed Alkene-Selective Transfer Hydrogenation with 1,4-Dioxane as Hydrogen Donor

Article abstract of DOI:10.1021/acs.orglett.9b01989

The iridium-catalyzed transfer hydrogenation of alkenes using 1,4-dioxane as a hydrogen donor is described. The use of 1,2-bis(dicyclohexylphosphino)ethane (DCyPE), featuring bulky and highly electron-donating properties, led to high catalytic activity. A polystyrene-cross-linking bisphosphine PS-DPPBz produced a reusable heterogeneous catalyst. These homogeneous and heterogeneous protocols achieved chemoselective transfer hydrogenation of alkenes over other potentially reducible functional groups such as carbonyl, nitro, cyano, and imino groups in the same molecule.

Full text of DOI:10.1021/acs.orglett.9b01989

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Iridium-Catalyzed Alkene-Selective Transfer Hydrogenation with
1,4-Dioxane as Hydrogen Donor
Deliang Zhang,† Tomohiro Iwai,*,† and Masaya Sawamura*,†,‡
†Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
‡Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo 001-0021, Japan
S
* Supporting Information
ABSTRACT: The iridium-catalyzed transfer hydrogenation of alkenes using
1,4-dioxane as a hydrogen donor is described. The use of 1,2-bis-
(dicyclohexylphosphino)ethane (DCyPE), featuring bulky and highly
electron-donating properties, led to high catalytic activity. A polystyrene-
cross-linking bisphosphine PS-DPPBz produced a reusable heterogeneous
catalyst. These homogeneous and heterogeneous protocols achieved chemo-
selective transfer hydrogenation of alkenes over other potentially reducible
functional groups such as carbonyl, nitro, cyano, and imino groups in the same
molecule.
ransition metal catalyzed transfer hydrogenations are
useful methods for reducing polar unsaturated bonds in
reasonably mild reaction conditions (bath temperature 120−
145 °C, 1−4 mol % Ir, Scheme 1b). Importantly, this transfer
hydrogenation was exclusively selective toward CC bonds
over CO bonds of ketones, which are the preferred
reduction sites under most transfer hydrogenation condi-
tions.2,3 Although a similar transfer hydrogenation of alkenes
with 1,4-dioxane catalyzed by the Wilkinson complex [RhCl-
(PPh3)3] had been reported in 1972, the reaction conditions
were harsh (170 °C), and the substrate scope was limited to a
few simple cycloalkenes.10 Therefore, we decided to investigate
the interesting Ir catalysis for ligand effects, substrate scope,
and chemoselectivity, having applications in organic synthesis
in mind. As a result, 1,2-bis(dicyclohexylphosphino)ethane
(DCyPE) was identified as an optimal ligand, which produced,
in combination with [IrCl(cod)]2, a catalyst that promoted the
highly chemoselective transfer hydrogenation of conjugated
polar alkenes and isolated nonpolar alkenes in the presence of
ketones or other potentially reducible functional groups. To
date, a broadly useful and versatile metal-catalyzed protocol
that enables selective transfer hydrogenation of isolated
nonpolar alkenes in the presence of ketones has not been
reported. Although Huang and co-workers recently realized a
similar transformation through the utilization of ethanol as a
hydrogen donor catalyzed by an Ir-NCP catalyst, only two
isolated nonpolar alkenes were used, and chemoselectivity was
not totally controlled.11
T
organic molecules due to their high chemoselectivity without
the need to use flammable hydrogen gas or complex
equipment.1 Furthermore, they have potential for enantiose-
lective catalysis. In fact, transfer hydrogenations of ketones2
and imines3 with protic H donor molecules such as 2-propanol
and formic acid have been well established (Scheme 1a).
Scheme 1. Catalytic Transfer Hydrogenations
Noyori−Ikariya-type transfer hydrogenation is a typical highly
enantioselective reaction.4 In contrast, the chemoselective
transfer hydrogenation of CC bonds in the presence of C
O bonds and other potentially reducible functional groups
such as benzylic ethers, nitriles, and imines is a long-standing
challenge. Although transfer hydrogenation protocols achieving
appreciable but incomplete chemoselectivities in favor of C
C bonds over ketoic CO bonds have been reported,5−7 the
substrates were restricted to conjugated enone derivatives or
the selectivities relied on careful control of the reaction
conditions.
Specifically, stirring and heating of a solution of cyclic
ketone 1a (1.1 g, 8.0 mmol) bearing a tert-alkyl-substituted
terminal alkene moiety, [IrCl(cod)]2 (26.8 mg, 0.04 mmol, 1
mol % Ir), and DCyPE (33.8 mg, 0.08 mmol, 1 mol %) in
refluxing 1,4-dioxane (10 mL) (bath temperature 120 °C)
under argon atmosphere over 4 h led to complete conversion
In our investigation of metal-catalyzed C(sp3)−H function-
alizations,8,9 we encountered a significant reduction of CC
bonds of alkenes with 1,4-dioxane as a two-H donor in the
presence of [IrCl(cod)]2 and some bisphosphine ligands under
Received: June 10, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01989
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Letter
of the starting material and afforded the corresponding
saturated ketone (2a) in 97% isolated yield (eq 1). Notably,
in the transfer hydrogenation of a conjugated polar alkene (see
SI).
Other phosphines were also examined for ligand perform-
ance in the transfer hydrogenation of 4-tert-butylstyrene (1b)
with 1,4-dioxane on a smaller reaction scale (1b, 0.2 mmol, 0.5
mol % Ir, Ir/L 1:1, 1,4-dioxane 1 mL, 120 °C in a sealed vial, 1
h). The results are summarized in Scheme 2. While
Scheme 2. Ligand Effect on Transfer Hydrogenation*
no other reduction products 3a and 4a were produced. The
protocol is operationally simple, and 1,4-dioxane serves as a
good solvent for a range of organic compounds, suggesting a
practical merit of this hydrogenation method.12,13
Monitoring reaction time courses by 1H NMR spectroscopy
clearly showed the difference between 1,4-dioxane and 2-
propanol as hydrogen donors (Figure 1). Thus, consistent with
*
Reaction conditions: 1b (0.2 mmol), [IrCl(cod)]2 (0.5 mol % Ir),
DCyPE (0.5 mol %), 1,4-dioxane (1 mL), 120 °C (Teflon-sealed
1
screw vial), 1 h. Yield was determined by H NMR analysis of the
crude product.
monodentate phosphine ligands and large-bite-angle bi-
sphosphine ligands such as Xantphos or DPPF were totally
ineffective (see SI), 1,2-bis(diphenylphosphino)benzene
(DPPBz) induced slight activity, giving 2b in 9% yield. The
yield of 2b was improved to 44% with a bulkier variant
(SciOPP) of DPPBz having P-3,5-di-tert-butylphenyl groups
instead of the P-Ph groups. Similarly, another bulkier variant
(DCyPBz) with P-Cy groups also gave an increased product
yield of 26%. Changing the 1,2-phenylene backbone of
DCyPBz to the 3,4-thiophene-diyl backbone (DCyPT) caused
a significant increase of the yield (45%). This may be
attributed to the higher electron-donating ability of the 3,4-
thiophen-diyl than the phenylene group.
Similar trends were observed in the examination of
bisphosphine ligands with saturated carbon backbones.
Namely, while a small-bite-angle ligand (DPPM) with P-Ph
groups did not induce the reaction, changing the P-Ph groups
to P-Cy groups (DCyPM) gave a highly active catalyst, leading
to 89% yield. Analogously, the replacement of the P-Ph groups
of 1,2-bis(diphenylphosphino)ethane (DPPE) with P-Cy
groups led to a dramatic increase in the product yield (from
5% to 99%), while the effect of the change to P-Et groups was
only marginal (12% yield). Overall, the reactivity of the
transfer hydrogenation was enhanced by steric bulk and more
electron-donating ligands.
Figure 1. Time courses of transfer hydrogenation of 1a. (a) Reaction
conditions: 1a (0.2 mmol), [IrCl(cod)]2 (1 mol % Ir), DCyPE (1 mol
%), 1,4-dioxane (1 mL), 120 °C (Teflon-sealed screw vial); (b)
Reaction conditions: 1a (0.2 mmol), [IrCl(cod)]2 (4 mol % Ir),
DCyPE (4 mol %), 2-propanol (1 mL), 60 °C (Teflon-sealed screw
vial).
With the optimized reaction conditions in hand, we then
explored the transfer hydrogenation of various simple alkenes
(Scheme 3). Styrene derivatives (1b−j) underwent transfer
hydrogenation smoothly. In general, substrates with an
electron-donating substituent at the para position of the
aromatic ring were more reactive and required lower reaction
temperature (120 °C) and catalyst loading (1 mol % Ir).
Remarkably, the benzyloxy group in 1c and the nitro group in
1f remained untouched. Substrates bearing either exocyclic
CC bonds (1h) or cyclic olefinic bonds (1j) were
hydrogenated in high yields. The protocol was also applicable
to various aliphatic alkenes including not only monosubsti-
the above-mentioned results from the gram-scale reaction, the
Ir-catalyzed transfer hydrogenation (1 mol % Ir) of 1a (0.2
mmol) in 1,4-dioxane heated at 120 °C in a sealed screw vial
was exclusively chemoselective throughout the reaction
(Figure 1a). However, the reaction in 2-propanol at 60 °C
(4 mol % Ir) was only alkene-selective from the initiation of
the reaction up to the half-conversion of the substrate (Figure
1b). After the brief appearance of enol 3a (40 min, 57% conv.
of 1a), overreduction product 4a started to form and became
the major component at 90 min. A similar trend was observed
B
DOI: 10.1021/acs.orglett.9b01989
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Letter
Scheme 3. Scope of Simple Alkenes*
Scheme 4. Alkene-Selective Transfer Hydrogenation*
*
Reaction condition A: 1 (0.2 mmol), [IrCl(cod)]2 (1 mol % Ir),
DCyPE (1 mol %), 1,4-dioxane (1 mL), 120 °C (Teflon-sealed screw
vial). Reaction condition B: 1 (0.2 mmol), [IrCl(cod)]2 (4 mol % Ir),
DCyPE (4 mol %), 1,4-dioxane (1 mL), 130 °C (Teflon-sealed screw
a
vial). Yields of isolated product are shown. Yield was determined by
1H NMR analysis of the crude product.
tuted or 1,1-disubstituted terminal alkenes (1k,m,n) but also
disubstituted or trisubstituted internal alkenes (1l,o,p), while
tetrasubstituted alkenes such as 2,3-dimethyl-1H-indene and
tetraphenylethylene did not participate in the present transfer
hydrogenation even at higher reaction temperature (140 °C).
Notably, the allyl and benzyl ether moieties of 1o were
innocent of hydrogenolysis reactivity.
*
Reaction conditions: 1 (0.2 mmol), [IrCl(cod)]2 (4 mol % Ir),
DCyPE (4 mol %), 1,4-dioxane (1 mL), 130 °C (Teflon-sealed screw
a
vial), 10 h. Yields shown are of isolated product. Run at 145 °C
b
(glass pressure tube) over 48 h. Run in 1,4-dioxane (1.5 mL) at 145
c
1
°C (glass pressure tube) over 48 h. Yield was determined by H
NMR analysis of the crude product.
Alkynes also underwent the transfer hydrogenation using
1,4-dioxane as H donor with the same catalyst. Diphenylace-
tylene (5) was converted to 1,2-diphenylethane (6) through
double transfer hydrogenation with 4 mol % Ir loading at 140
°C over 20 h (eq 2), while the reaction of a terminal alkyne
phenylacetylene suffered from significant oligomerization
under the same reaction condition.
Scheme 4 also shows the scope of functionalized nonpolar
alkenes. Terminal alkenes bearing an acetophenone or
cyclohexanone (1ah−al) underwent site-selective reduction
at the alkene moiety. Tolerance toward nitro and cyano groups
was confirmed in the reaction of the biphenyl derivatives 1am
and 1an. The CN bond in N-sulfonyl ketimine 1ao also
remained untouched. The chemoselective transfer hydro-
genation of an estrone derivative (1ap) highlights the synthetic
utility of this hydrogenation method.
To gain insight into the mechanism, the effects of deuterated
1,4-dioxane were investigated. Thus, the Ir-catalyzed transfer
hydrogenation of 1c (0.1 mmol, 4 mol % Ir) in a mixed solvent
system composed of 1,4-dioxane (0.3 mL) and 1,4-dioxane-d8
(0.3 mL) conducted at 130 °C proceeded at a much reduced
rate than in the single component nondeuterated 1,4-dioxane,
resulting in the formation of 2c in only 48% yield after 24 h
with no D-incorporation in the product (eq 3). When the
The chemoselectivity of this protocol toward CC
hydrogenation was further examined with various function-
alized alkenes as showcased in Scheme 4. Benzylideneacetone
and its derivatives (1q−w) bearing electron-donating or
withdrawing groups on the aromatic ring were suitable
substrates, providing the desired products with excellent yields
and exclusive chemoselectivity. The protocol was applicable to
the sulfide-functionalized enone (1v), although a higher
reaction temperature and longer reaction time were required.
The aromatic ring could be polycyclic (1x, 1y) or S-
heterocyclic (1ab). An aliphatic conjugated enone (1z) and
chalcone (1aa) also underwent clean CC reduction. The
protocol was also applicable to more sterically hindered enones
such as 4,4-dimethyl-2-cyclohexene-1-one (1ac) and (E)-4-
phenylpent-3-en-2-one (1ad). Conjugated enoates (1ae, 1af)
and an enamide (1ag) were also reduced at the CC bond.
C
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reaction was performed in the single component deuterated
solvent 1,4-dioxane-d8 (0.3 mL) under the same reaction
conditions, the deuterated product was obtained in 13% yield
with 82% D-incorporation in the methylene group and 118%
D-incorporation in the methyl group (eq 4). These results
prove that 1,4-dioxane is the hydrogen donor. The unusually
high kinetic isotope effect suggests that dissociations of two
different C(sp3)−H bonds in 1,4-dioxane, one at C(2) and the
other at C(3), doubly affect the rate of the catalysis. Namely, it
is suggested that both C(2)−H oxidative addition to an Ir
center forming an Ir-monohydride species and the subsequent
β-hydride elimination giving an Ir(III) dihydride species may
contribute to the total kinetics of the catalysis. Furthermore,
the unequal D-incorporation at C(α) and C(β) of 2c is
suggestive of the occurrence of β-hydride elimination of a
benzylic alkyliridium intermediate.
Scheme 6. Heterogeneous Transfer Hydrogenation of 1a
with 1,4-Dioxane and the [Ir-(PS-DPPBz)] Catalyst
System*
*
Reaction conditions: 1a (1 mmol), [IrCl(cod)]2 (0.005 mmol, 1 mol
% Ir), PS-DPPBz (0.1 mmol/g, 0.01 mmol, 1 mol %), 1,4-dioxane
On the basis of the above experimental results, a catalytic
reaction pathway for the transfer hydrogenation of an alkene
with 1,4-dioxane can be proposed as outlined in Scheme 5.
1
(0.33 M), 145 °C (glass pressure tube). Yield was determined by H
NMR analysis of crude product.
Scheme 5. Proposed Reaction Pathway
and PS-DPPBz (Ir/L 1:1, 1 mol % Ir) was complete at 4 h
1
(98% yield by H NMR analysis) (Scheme 6, first cycle). The
[Ir-(PS-DPPBz)] catalyst in a form of orange-colored beads
could be reused until the third reaction cycle without a
significant reduction of the product yield under the identical
reaction conditions (4−5 h), while the catalytic efficiency was
gradually reduced after the third cycle.
In conclusion, we have developed a new operationally simple
method for the transfer hydrogenation of alkenes with 1,4-
dioxane as a hydrogen donor. The commercially available
bulky and electron-rich ligand DCyPE was identified to be a
particularly high-performing ligand. A polystyrene-cross-linking
bisphosphine PS-DPPBz produced a reusable heterogeneous
catalyst. In contrast to the transition metal catalyzed transfer
hydrogenation with protic hydrogen donor reagents or
solvents, the present hydrogenation protocol is alkene selective
in the presence of polar unsaturated bonds such as CO, C
N, and CN bonds. Mechanistically, this hydrogenation is
triggered by oxidative addition of a 1,4-dioxane C(sp3)−H
bond. We anticipate this method to find widespread
application in organic synthesis. Studies toward developing
an asymmetric version of this transformation are underway.
Oxidative addition of a C(sp3)−H bond in 1,4-dioxane to the
Ir(I) center in A yields Ir(III) monohydride B. Subsequent β-
hydride elimination generates Ir(III) dihydride species C,
which, depending on the nature of the phosphine ligand bound
to the Ir atom, should be in equilibrium with hydride-bridged
dimeric iridium complex C-dimer as an off-cycle species.14 The
alkene coordinates to C to form D. This is followed by
insertion of the alkene to the Ir−H bond of D to form Ir-alkyl
complex E, which undergoes reductive elimination to produce
the 1,2-hydrogenation product 2 with regeneration of A.15,16
According to this C(sp3)−H activation triggered reaction
pathway, the ligand electronic effect favoring the electron-rich
nature may be due to the promotion of oxidative addition of
the C(sp3)−H bond of 1,4-dioxane in A to form B, while the
favorable effect of the sterically hindered bisphosphine ligands
can be ascribed to an inhibitory effect for the dimerization of
C.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01989.
Experimental procedures and the characterization of all
new compound (PDF)
This mechanistic consideration prompted us to use a
polystyrene-cross-linking bisphosphine PS-DPPBz17,18 as an
effective ligand for a reusable heterogeneous catalyst system
(Scheme 6), as its excellent ligand performance has been
demonstrated for some heterogeneous transition metal
catalysis. The characteristic ligand property was due to spatial
isolation of the bisphosphine unit in the polymer matrix,
inhibiting the formation of a bischelated metal complex or a
dimer of a monochelate complex (cf. C-dimer in Scheme 5).
Specifically, the hydrogenation of 1a (1 mmol) with 1,4-
dioxane (0.33 M) at 145 °C in the presence of [IrCl(cod)]2
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: iwai-t@sci.hokudai.ac.jp.
*E-mail: sawamura@sci.hokudai.ac.jp.
ORCID
Masaya Sawamura: 0000-0002-8770-2982
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.9b01989
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Letter
Science and Opportunities. Angew. Chem., Int. Ed. 2002, 41, 2008−
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ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI Grant Number
JP17H04877 in Young Scientists (A) to T.I., and by JSPS
KAKENHI Grant Number JP15H05801 in Precisely Designed
Catalysts with Customized Scaffolding and JSPS KAKENHI
Grant Number JP18H03906 in Grant-in-Aid for Scientific
Research (A) to M.S. D.Z. thanks JSPS for a scholarship
support.
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1
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hydride species (F), which may offer a route for outer-sphere
concerted transfer of proton and hydride. This would be responsible
for the reactivity of the CO bonds.
̈
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(18) While PS-DPPBz gave 2b in a yield (11%) comparable to that
with the corresponding homogeneous ligand DPPBz (9%) under the
otherwise same conditions as Scheme 2 (0.5 mol% Ir, 120 °C, 1 h),
the polymer effect was significant at a longer reaction time (9 h, 1 mol
% Ir): 97% yield with PS-DPPBz, 48% yield with DPPBz.
F
DOI: 10.1021/acs.orglett.9b01989
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