Highly Selective Hydrogenation of C═C Bonds Catalyzed by a Rhodium Hydride

Article abstract of DOI:10.1021/jacs.1c04683

Under mild conditions (room temperature, 80 psi of H₂) Cp*Rh(2-(2-pyridyl)phenyl)H catalyzes the selective hydrogenation of the C═C bond in α,β-unsaturated carbonyl compounds, including natural product precursors with bulky substituents in the β position and substrates possessing an array of additional functional groups. It also catalyzes the hydrogenation of many isolated double bonds. Mechanistic studies reveal that no radical intermediates are involved, and the catalyst appears to be homogeneous, thereby affording important complementarity to existing protocols for similar hydrogenation processes.

Full text of DOI:10.1021/jacs.1c04683

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Article
Highly Selective Hydrogenation of CC Bonds Catalyzed by a
Rhodium Hydride
Yiting Gu, Jack R. Norton,* Farbod Salahi, Vladislav G. Lisnyak, Zhiyao Zhou, and Scott A. Snyder
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ABSTRACT: Under mild conditions (room temperature, 80 psi of
H2) Cp*Rh(2-(2-pyridyl)phenyl)H catalyzes the selective hydro-
genation of the CC bond in α,β-unsaturated carbonyl
compounds, including natural product precursors with bulky
substituents in the β position and substrates possessing an array
of additional functional groups. It also catalyzes the hydrogenation
of many isolated double bonds. Mechanistic studies reveal that no
radical intermediates are involved, and the catalyst appears to be homogeneous, thereby affording important complementarity to
existing protocols for similar hydrogenation processes.
Scheme 1. (A) A Challenging Substrate for 1,4-
Hydrogenation, with Alternative Sites of Reaction; (B)
Chirik Proposal for Mechanism of Action of (η5-
C5Me5)Rh(ppy)H; (C) Homogeneous Hydrogenation of
α,β-Unsaturated Carbonyl Compounds and Isolated Olefins
Catalyzed by RhH-1
INTRODUCTION
■
The catalytic hydrogenation of unsaturated organic com-
pounds is a transformation of widespread importance in both
academia and industry, particularly as applied for the
preparation of pharmaceuticals, fragrances, and other fine
chemicals.1 The 1,4-reduction of α,β-unsaturated carbonyl
compounds has attracted particular attention, and much effort
has been devoted to its development.2 Hydrogen sources other
than molecular hydrogen,3 including silicon hydrides,4
formates,5 and alcohols,6 are often efficient and have become
widely used.7,8 To date, the majority of methods possessing
both high efficiency and selectivity have used transition metal
promoters (Ir,6 Pd,9 Co,10,11 Ni,12 and others13) with a variety
of supporting ligands,14,5 though there have also been recent
disclosures of transition-metal-free hydrogenation reagents
involving Se powder,15 borane,16 and electrons.17−19
Nevertheless, most 1,4-reductions still suffer from draw-
backs, such as poor tolerance of sensitive functional groups and
a lack of effectiveness with highly substituted, sterically
encumbered substrates. Indeed, such steric constraints can
sometimes lead to an undesired stereochemical outcome and/
or prevent hydrogenation entirely. Such issues arose in the
Snyder group’s recent total syntheses of the coccinellid
alkaloids, including targets such as exochomine,20 arborisi-
dine,21 and chilocorine C.22,23 For example, one of the final
steps in the exochomine work required the selective 1,4-
reduction of the hindered enone 1 to 2 (Scheme 1A).
However, the dithiolane group, benzylic ketone, and acyl
pyrrole all proved prone to reduction and/or side-product
formation; the desired product was best obtained by reducing
1 with silanes in the presence of stoichiometric Mn(dpm)3, a
procedure adapted from those reported by Magnus24 and
Shenvi.25 Given this, and other related, examples, a robust
catalytic procedure for the 1,4-reduction of α,β-unsaturated
carbonyl compounds using H2 was viewed as highly desirable.
Received: May 5, 2021
Published: June 18, 2021
https://doi.org/10.1021/jacs.1c04683
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© 2021 American Chemical Society
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The Norton group initially attempted to employ the Cr
[CpCr(CO)3H] and Co [Co(dmgBF2)2L2] (L = H2O, THF,
etc.) catalysts that they had used26−30 for H· transfer from H2
to solve this problem, but neither gave any 2 from 1. We then
considered (η5-C5Me5)Rh(ppy)H (ppy = 2-(2-pyridyl)-
phenyl), RhH-1, developed in the Norton laboratory and
shown to be a fast hydride and hydrogen atom donor, but a
relatively poor proton donor (Scheme 1B).31,32 Related
Cp*Rh systems have been shown to effectively catalyze
arene and olefin hydrogenation.33−35 Indeed, in 2019 the
Chirik group found that RhH-1 can catalyze the hydrogenation
to ammonia of amides,36 nitrides,37 and related ligands.38 Very
recently, the use of the same precatalyst for the hydrogenation
of N-heteroarenes has been reported by the same group.39
They have proposed that, upon heating or irradiation, the
reductive elimination of 2-phenylpyridine from RhH-1 can
lead to the formation of catalytically active multimetallic
clusters (and eventually nanoparticles), under varied H2
pressures (4−36 atm) at elevated temperatures (80−100 °C).
To our delight, we found that (η5-C5Me5)Rh(ppy)H (RhH-
1) does indeed show activity for the hydrogenation of the C
C bonds of enones. Herein we describe a highly selective and
mild procedure for catalyzing the CC hydrogenation of α,β-
unsaturated carbonyl compounds and isolated olefins (Scheme
1C) which works on an array of substrates with high
chemoselectivity and functional group tolerance. We follow-
up these studies of scope with mechanistic investigations which
reveal that our catalyst appears to be behaving in a
homogeneous, rather than heterogeneous, manner.
proved deleterious (entries 5−7). As shown by control
experiments, both the H2 gas and the rhodium promoter are
essential (entries 8 and 9).
As shown by the reaction scope in Table 2, the method
displays excellent chemoselectivity with various α,β-unsatu-
rated carbonyl compounds, which in all cases underwent 1,4-
reduction exclusively to form the indicated products in high
yields (with the colored bond marking the site of hydro-
genation). As can be discerned, chalcones containing both
electron-rich and electron-poor arenes are reduced appropri-
ately, to 4−9, and the reduction of the precursor to 5 can be
scaled up without compromising the overall yield. Related
substrates containing aromatic heterocycles such as imidazole
or thiophene also react smoothly, giving good yields of 10 and
11. Vinyl phenyl ketones with substituents at the α or β
position also undergo 1,4-hydrogenation, making 12 and 13 in
good yield. In addition, the vinyl methyl ketones in the
substrates leading to 14−16 are selectively reduced in excellent
yields, while the trisubstituted double bonds in 15 and 16
remain untouched. No 1,6-reduction product was detected
along with 16. Pleasingly, the α,β-unsaturated esters, vinyl
amide, and vinyl sulfones within products 17−22 all posed no
problems even with steric hindrance at the α position (as in
the precursor of 17). The substituted cyclic, α,β-unsaturated
ester in 22 was not reduced.
Critically, the scope of the Rh-catalyzed hydrogenation
extends to dienes and to cyclic enones. Both of the conjugated
double bonds leading to 23 and 24 were hydrogenated with
high efficiency, giving these materials in almost quantitative
yields. The CC bonds of cyclic enones are also hydro-
genated in 1,4-fashion (leading to 25−28). The cyclic enones
found in products 29 and 30, possessing β ethoxy substituents,
are not hydrogenated, although the isolated CC bonds are.
The chemoselectivity of the Rh-catalyzed hydrogenation is
further illustrated by the fact that acetals (24 and 26), esters
(22 and 25), aryl halides (21 and 23), and even unprotected
alcohol (6 and 28) are well tolerated, leaving ample room for
further derivatization, as desired.
RESULTS AND DISCUSSION
As shown in Table 1, we selected chalcone 3 as a test enone to
develop and optimize our rhodium-catalyzed 1,4-hydro-
■
a
Table 1. Optimization of the Reaction Conditions
Although we did not observe byproducts with 1,2-reduction
for any of the substrates used in Table 2, we did find that the
1,4-reduction products (34−36) from α,β-unsaturated alde-
hydes (31−33) undergo slow, further 1,2-reduction to afford
37−39 (Table 3). We note that both aliphatic and aromatic
substituents seem to be tolerated at the β position. Of
particular interest, the hydrogenation of the intermediate
aldehyde is considerably slower than the 1,4-hydrogenation of
the initial enone, as judged by the reaction times required.
With these initial results in hand, we then returned to the
highly substituted substrates that had caused difficulty for the
Snyder group in their exochomine synthesis (cf. Scheme 1A).20
For example, Stryker’s reagent (H6Cu6L6) had given a sluggish
reaction, with the principal product being the result of 1,6-
reduction across the pyrrole ring. A similar 1,6-reduction result
was obtained after one-electron reduction by SmI2; by contrast,
catecholborane and DIBAL-H gave the 1,2-reduction product,
while DIBAL-H with Cu(I), RedAl, Pd°/n-Bu3SnH, and
sulfonylhydrazides (NBSH) gave no reaction. Specifically, we
tried to hydrogenate somewhat simpler predecessors of 40 and
41 with our rhodium catalyst RhH-1 under our optimal
conditions, and found that selective 1,4-hydrogenation of the
CC bonds of these two enones could be achieved in the
presence of a dithiolane and a pyrrole, providing both 40 and
41 in high yields and diastereoselectivities (Table 3). The
a
3 (0.20 mmol), RhH-1 catalyst (3 mol %), H2 (80 psi), MeOH (4
b
mL) at room temperature, 24 h. NMR yields using CH2Br2 as
internal standard. Isolated yield.
c
genation method. With 3 mol % RhH-1 and 80 psi of H2
gas in MeOH (0.05 M) at 23 °C, the reaction took 24 h to
reach completion, affording reduction product 4 in 94%
isolated yield (Table 1, entry 1). Lowering the catalyst loading
or the pressure of H2 gas eroded the yield during the same time
period (entries 2 and 3). Further, changing the catalyst to the
benzo[h]quinoline derivative RhH-2 gave a slightly lower yield
(entry 4), while the use of solvents other than MeOH also
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a b
,
Table 2. Scope of the Rhodium-Catalyzed Hydrogenation of α,β-Unsaturated Carbonyl Compounds
a
b
c
d
Under the conditions of entry 1 in Table 1. Isolated yields, average of two independent runs. Using iPrOH as solvent instead of MeOH. Gram
scale (10 mmol reaction).
a b
,
a b
,
Table 3. Sequential Reductions & Synthetic Applications
Table 4. Hydrogenation of Isolated Olefins
a
b
Under the conditions of entry 1 in Table 1. Isolated yields, average
c
of two independent runs. Reaction time is 6 h.
brominated arene, an unprotected indole, and free alcohols
(both primary and tertiary). The trisubstituted CC bond
that belongs to the allylic alcohol precursor of 49 was reduced,
but the remote, trisubstituted double bond remained
untouched; in this case, the hydroxyl group might be serving
as a directing group. Complete reduction of diphenylacetylene
to 50 was observed in 6 h, while the terminal alkyne in
mestranol is hydrogenated to afford 51 in high yield (94%).
The observed chemoselectivity of our Rh-catalyzed hydro-
genation reactions suggested to us that they may also be useful
in late-stage reductions during the synthesis of fine chemicals
and/or pharmaceutical agents. Indeed, we can carry out such
reactions (Scheme 2): for example, cyproheptadine is
exclusively hydrogenated at the less substituted double bond,
producing a good yield of the reduced pharmaceutical 52;
reduction of the trisubstituted olefin in brucine delivers 53 in
94% yield. The late-stage hydrogenation of levofloxacin was
similarly achieved with ease to give 54 in high yield, along with
decarboxylation of the β-keto acid that occurs with standard
hydrogenation protocols.40
a
b
Under the conditions of entry 1 in Table 1. Isolated yields, average
c
of two independent runs. Triethylamine (1.0 equiv) was added.
presence of the tert-butyl substituents caused no issues in these
transformations, and the addition of Et3N did not suppress the
formation of 40 (suggesting that the tertiary amine found in
exochomine itself would not be problematic if executed on
even more advanced intermediates).
In view of the hydrogenation of the isolated double bonds
leading to 29 and 30, we have further explored the utility of
RhH-1 as a catalyst for the hydrogenation of other such olefins
(cf. Table 4). As shown, carbon−carbon double bonds with a
variety of electronic and steric properties gave high yields of
the hydrogenated products 42−49. Functional groups that are
not affected under these conditions include a boronic ester, a
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Scheme 2. Late-stage Hydrogenation of Pharmaceuticals
MECHANISM
■
In order to probe the difference between the mechanism of
enones and that of isolated olefins, we have compared the
results of deuterium labeling experiments with the α,β-
unsaturated ketone in 61 with the results of such experiments
with the isolated terminal olefin in 63. The extent of label
incorporation is shown in Scheme 4. When CD3OD was used
as solvent, 0.75 D was transferred to the α position of 62, while
no deuterium was detected in 64. The protonation of a Rh-
enolate intermediate with methanol is faster than reductive
elimination of the enolate ligand with the H on rhodium.45
The H2 gas supplies the H atom added to the β carbon of 61,
and both of the H atoms added to 63; the solvent supplies only
the H atom found at the other α carbon of enone substrate 61!
Reaction of the same substrate 61 with D2 instead of H2 gas
resulted in 90% deuteration of 65 with only 0.25 hydrogen at
the β position. Given that both the H2 gas and the MeOH are
present in large excess relative to the substrate and the catalyst,
there is little scrambling between the H2/D2 and the solvent
during these experiments.46,47
In view of the effectiveness of RhH-1 in catalyzing the
hydrogenation of unactivated alkenes, we have attempted its
use on the exomethylene of 55, a substrate whose stereo-
chemical outcomes in catalytic hydrogenation have been
investigated in detail by Shenvi.25 As shown in Scheme 3, we
Scheme 3. Effect of Solvent on Exomethylene Reduction
Mechanisms that explain the results in Scheme 4 are shown
in Scheme 5, with substrates bearing enones on the left and
those with isolated olefins on the right. The generation of the
active catalyst probably begins with the reductive elimination
of phenylpyridine from RhH-1 (as suggested by Chirik),39
followed by the addition of H2 to the Cp*Rh(I). The resulting
Cp*RhH2 has been drawn by the Maitlis,33 Finke,34 and
Chirik39 groups in catalytic cycles, but to our knowledge has
never been isolated or identified.
To determine if the generation of carbon-centered radicals
by MHAT (metal hydrogen atom transfer) was involved in this
RhH-1 catalyzed hydrogenation, we treated 71 and 74 with H2
in the presence of RhH-1. Although RhH-1 has a low bond
dissociation free energy (BDFE = 52.3 kcal/mol)32 no trace of
the radical cyclization products 73 or 76 was observed (the
predominant products are shown in Scheme 6, i.e. 72 and 75).
Heterogeneous and homogeneous catalysis have been
established by Finke and Chirik in related Cp*Rh
systems,33−35,39,48−51 but it appears that our catalyst is
homogeneous. All materials dissolved with our reactions
being clear and red within 20 min. We observed no precipitates
even after 24 h of reaction time, and the kinetic plot in Scheme
7 suggests a clean first-order transformation of the tested
substrate (S15, it is the precursor to compound 15) to product
with a rate constant of about 2.3 × 10−5 M−1 s−1. A sigmoidal
curve is typical of metal-particle formation. Furthermore, we
found the addition of excess mercury after 200 min did not
change the observed rate constant, a result typical of a
homogeneous catalyst. Finally, TEM analysis (see the
obtained in THF mostly the cis-disposed reduction product 56
(which is also the predominant product with traditional
catalysts).41−43 We obtained a near-equimolar mixture of the
epimers 56 and 57 when the reaction was conducted in
MeOH. Under no conditions did our catalyst prefer to form
the more stable product 57, one which Shenvi has found to be
the kinetic product with Mn(dpm)3 or Co(dpm)2 as the
catalyst.44
The outcome of such hydrogenation reactions is determined
by both substituent effects and by solvent. With β-pinene (58),
for example, there is no hydrogenation in MeOH, but in THF
the equatorial methyl product 59 is obtained in 56% yield
along with 44% of the isomerization product 60. The
isomerization surely arises from the reversibility of the olefin
insertion.
Scheme 4. Deuterium Labelling Experiments
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Scheme 5. Mechanistic Proposal
Scheme 6. Evidence against MHAT and Radical Formation
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c04683.
■
sı
Experimental procedures, spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Jack R. Norton − Department of Chemistry, Columbia
University, New York City, New York 10027, United States;
orcid.org/0000-0003-1563-9555; Email: jrn11@
columbia.edu
Scheme 7. Mercury Poisoning Study
Authors
Yiting Gu − Department of Chemistry, Columbia University,
New York City, New York 10027, United States;
orcid.org/0000-0002-7748-1506
Farbod Salahi − Department of Chemistry, University of
Chicago, Chicago, Illinois 60637, United States;
orcid.org/0000-0003-3577-6813
Vladislav G. Lisnyak − Department of Chemistry, University
of Chicago, Chicago, Illinois 60637, United States;
orcid.org/0000-0002-4406-8440
Zhiyao Zhou − Department of Chemistry, University of
Chicago, Chicago, Illinois 60637, United States;
orcid.org/0000-0002-2792-8429
Scott A. Snyder − Department of Chemistry, University of
Chicago, Chicago, Illinois 60637, United States;
orcid.org/0000-0003-3594-8769
Supporting Information section for full details) of the residue
when solvent was removed after the reaction showed neither
heterogeneous metal particles nor rhodium clusters.52
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c04683
CONCLUSION
■
In summary, (η5-C5Me5)Rh(2-(2-pyridyl)phenyl)H (RhH-1)
catalyzes the selective 1,4-reduction of α,β-unsaturated
carbonyl compoundseven ones with bulky substituents
under H2. It also catalyzes the hydrogenation of many isolated
alkenes under mild reaction conditions. The system shows
excellent selectivity and functional group compatibility, and
appears to operate mechanistically under conditions that are
homogeneous. The rhodium catalyst is a significant comple-
ment to the existing toolbox for metal-catalyzed selective
hydrogenations and offers an opportunity to overcome
longstanding challenges in the hydrogenation of polyfunction-
alized molecules.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Sara Triana Hamilton and Prof. Ah-Hyung (Alissa)
Park for helping with the TEM analysis. We are grateful to
BASF for providing RhCl3. Dr. Jiawei Chen is acknowledged
for helpful discussions, and members of the Snyder group are
thanked for their contributions of additional α,β-unsaturated
substrates which were explored in the course of these studies.
We also thank Dr. Hunter B. Vibbert for the calculation of the
equilibrium constant of 56/57. This research has been
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Friedfeld, M. R.; Sheng, H.; Pierson, N. A.; Hoyt, J. M.; Campeau,
L.-C.; Chirik, P. J. Nickel-Catalyzed Asymmetric Alkene Hydro-
genation of g,,-Unsaturated Esters: High-Throughput Experimenta-
tion-Enabled Reaction Discovery, Optimization, and Mechanistic
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supported by the National Institute of General Medical
Sciences of the National Institutes of Health under Award
R01-GM124295.
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