Rhodium-Catalyzed Asymmetric Hydrogenation of α,β-Unsaturated Carbonyl Compounds via Thiourea Hydrogen Bonding

Article abstract of DOI:10.1021/acs.orglett.6b01812

The strategy of secondary interaction enables enantioselectivity for homogeneous hydrogenation. By introducing hydrogen bonding of substrates with thiourea from the ligand, α,β-unsaturated carbonyl compounds, such as amides and esters, are hydrogenated wi

Full text of DOI:10.1021/acs.orglett.6b01812

Letter
pubs.acs.org/OrgLett
Rhodium-Catalyzed Asymmetric Hydrogenation of α,β-Unsaturated
Carbonyl Compounds via Thiourea Hydrogen Bonding
Jialin Wen,†,§ Jun Jiang,‡,§ and Xumu Zhang*,†
†Department of Chemistry and Chemical Biology, Rutgers, the State University of New Jersey, 610 Taylor Road, Piscataway, New
Jersey 08854, United States
‡College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, China
S
* Supporting Information
ABSTRACT: The strategy of secondary interaction enables
enantioselectivity for homogeneous hydrogenation. By in-
troducing hydrogen bonding of substrates with thiourea from
the ligand, α,β-unsaturated carbonyl compounds, such as
amides and esters, are hydrogenated with high enantiomeric
excess. The substrate scope for this chemical transformation is
broad with various substituents at the β-position. Control
experiments revealed that each unit of the ligand ZhaoPhos is
irreplaceable. No nonlinear effect was observed for this Rh/
ZhaoPhos-catalyzed asymmetric hydrogenation.
s an important noncovalent interaction, hydrogen bonding
plays a crucial role in biosystem and enzyme catalysis.1
compounds.5 Asymmetric hydrogenation of unsaturated
carboxylic acids and esters has been developed with several
systems:6 Crabtree’s catalyst (iridium/P−N ligand) and the
Wilkinson−Osborn system (rhodium/bisphosphine ligand) are
successful representatives. To the best of our knowledge,
hydrogenation of unsaturated carboxamides, however, is still a
less explored field yet. Successful cases of asymmetric reduction
of α,β-unsaturated amides mainly engaged with transition-
metal-catalyzed conjugate addition of hydrides7 and iridium-
catalyzed direct hydrogenation by Ding.8 We seek an efficient
catalytic system to synthesize different types of chiral carboxylic
acid derivatives with high enantioselectivity.
We recently developed a bisphosphine−thiourea ligand,
ZhaoPhos:9 a covalent linker connects a ferrocene-based
bisphosphine unit with a thiourea moiety (Figure 1). Hydrogen
bonding of thiourea with substrates enables effective secondary
interaction in asymmetric catalysis. This bifunctional ligand has
successfully been applied in hydrogenation of nitroolefins,9,10
unprotected imines,11 isoquinolines, and quinolines12 with high
reactivities and high enantioselectivities.
A
From the inspiration of enzyme catalysis to the prosperity of
small-molecule catalysis, many studies have been elaborated in
the past two decades. This strategy of hydrogen bonding has
been successfully applied in numerous cases of organocatalysis,
which provide the synthetic community with many solutions
for enantioselective synthesis.2 Among these successful
catalysts, thiourea is a special motif for hydrogen bonding. As
a double hydrogen donor, thiourea could activate carbonyl
compounds by lowering their LUMO energy.3 Effective
bonding with neutral functional groups, potent binding affinity,
and high tunability make thiourea catalysts versatile for many
kinds of organic reactions.4 Originated in serine protease
(Figure 1) catalyzed hydrolysis of amides,1 the interaction of a
The binding affinity of (thio)urea with carboxylic acid
derivatives is in a range similar to that with nitro groups or
sulfonates,13 which inspires us to explore the application of
ZhaoPhos in homogeneous hydrogenation of unsaturated
carbonyl compounds. We envision that the secondary
interaction of hydrogen bonding between thiourea and
carbonyl substrates could play a dual role: (1) H-bond activates
the substrate by decreasing the LOMO; (2) the binding
between the ligand and substrate enhances the enantiomeric
control. We report herein a successful example of rhodium/
Figure 1. Double H-bonding with carbonyl.
double hydrogen donor with an amide substrate became an
important paradigm for carbonyl activation in small molecule
catalysis. The hydrogen bonding of (thio)urea with ketones,
aldehydes, and carboxylic acid derivatives enables enantiose-
lective chemical transformations and, therefore, emerged as an
effective strategy in asymmetric catalysis.
Asymmetric hydrogenation, with 100% atom efficiency and
easy workup, serves as a practical method to synthesize chiral
Received: June 21, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01812
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Organic Letters
Letter
ZhaoPhos-catalyzed asymmetric hydrogenation of α,β-unsatu-
rated carbonyl compounds.
Table 2. Substrate Scope of Rhodium-Catalyzed Asymmetric
Hydrogenation of α,β-Unsaturated Amides
a
Initially, we chose trans-β-methylcinnamide as the target and
[Rh(COD)Cl]2 as the metal precursor since this rhodium(I)
dimer showed excellent performance in hydrogenation of
nitroolefins and (iso)quinolines with ZhaoPhos in our previous
studies. After screening of various types of solvent, we found
that dichloromethane gave the best enantioselectivity. Solvent
pairs were also tested. Solvent pairs were also tested, and we
finally selected a mixture of dichloromethane and 2-propanol
with a volume ratio 3:1 as the solvent (Table 1, entry9). When
a
Table 1. Condition Optimization
a
Reaction conditions: 1 (0.2 mmol) in 1.0 mL of solvent, 1/
[Rh(COD)Cl]2/L = 100/0.50/1.0; yields were obtained after
isolation; ee’s were determined by HPLC with a chiral stationary
phase.
b
c
entry
solvent
MeOH
ligand
conv (%)
ee (%)
1
2
3
4
5
6
7
8
9
ZhaoPhos
ZhaoPhos
ZhaoPhos
ZhaoPhos
ZhaoPhos
ZhaoPhos
ZhaoPhos
ZhaoPhos
ZhaoPhos
ZhaoPhos
L1
24
50
65
86
94
90
74
i-PrOH
DCM
42
With the success of hydrogenation of unsaturated amides in
hand, we sought an expansion of substrate scope into other
unsaturated carbonyl compounds. When the optimized
conditions were applied in reactions of esters, high conversions
with high enatioselectivities were obtained. The scope of β,β-
disubstituted ester substrates includes various substituents on
the β-phenyl ring with different electronic and steric effects,
which is in accordance with hydrogenation of unsaturated
amides. A broad substrate scope of this Rh/ZhaoPhos catalytic
system suggests its potential application in synthetic chemistry
(Table 3).
DCE
18
dioxane
<5
trace
36
acetone
ethyl acetate
DCM/Tol = 3:1
DCM/i-PrOH = 3:1
DCM/i-PrOH = 3:1
DCM/i-PrOH = 3:1
DCM/i-PrOH = 3:1
91
91
95
95
90
36
69
58
d
10
99
d
11
63
d
12
L2
38
a
Reaction conditions: 1a (0.1 mmol) in 1.0 mL of solvent, 1/
b
[Rh(COD)Cl]2/L = 100/0.50/1.0. Conversion was determined by
c
1H NMR analysis; no side product was observed. Enantiomeric excess
d
Table 3. Substrate Scope of Rhodium-Catalyzed Asymmetric
was determined by HPLC with a chiral stationary phase. Conducted
a
at 35 °C for 48 h.
Hydrogenation of α,β-Unsaturated Esters and Ketone
we increased the temperature and elongated the reaction time,
the desired conversion (99%) and high enantioselectivity
(95%) were obtained under 50 atm hydrogen gas pressure
(entry 10). Similar to the previous hydrogenation cases with a
Rh/ZhaoPhos system,9−12 this reaction is solvent-dependent.
More bulky substituents on phosphine do not bring higher
enantioselectivity but lower conversion (entry 11). Squaramide,
which usually plays a role as an alternative for (thio)urea in
hydrogen-bonding catalysis, fails to show any advantages over
thiourea (entry 12).
The substrate scope of Rh/ZhaoPhos-catalyzed hydro-
genation of α,β-unsaturated amides is shown in Table 2. β,β-
Disubstituted acrylamides were reduced with high enantiose-
lectivities. Various substituents with different electronic effects
do not bring significant changes in enantioselectivities. Steric
effects, however, show an influence on the reactivity of this
chemical transformation: compared to the meta- or para-
position, the methyl group at the ortho-position on the phenyl
slows the reaction rate significantly. The thienyl group, a
representative of heteroaryl, also works smoothly in this
homogeneous hydrogenation reaction.
a
Reaction conditions: 3 (0.2 mmol) in 1.0 mL of solvent, 3/
[Rh(COD)Cl]2/L = 100/0.50/1.0; yields were obtained after
isolation; ee’s were determined by HPLC with a chiral stationary
phase.
B
DOI: 10.1021/acs.orglett.6b01812
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Organic Letters
Letter
To investigate the cooperation of the thiourea moiety and
ferrocene-based bisphosphine skeleton, a series of analogues of
ZhaoPhos were prepared and applied in the model reaction.
(Experimental details are shown in the Supporting Informa-
tion.) In accordance with previous studies on hydrogenation of
nitroolefins,9 unprotected inmines,11 and (iso)quinolines,12
control experiments revealed that (1) each unit within
ZhaoPhos is irreplaceable for high conversion and high
enantioselectivity in catalytic chemical transformation and (2)
a covalent linker enables the incorporation.
We previously proposed a hydride-transfer mechanism for
asymmetric hydrogenation of (iso)quinolines with rhodium/
ZhaoPhos complex,12 which involves an outersphere model14
rather than the traditional innersphere mechanism.15 When
deuterium gas was used to conduct this hydrogenation, D
atoms were added at α- and β-positions. No obvious H atoms
were observed to be added to the CC bond (see the
Supporting Information). This result supports a traditional
innersphere mechanism, which has been well studied and
widely accepted in rhodium-catalyzed hydrogenation. Based on
these results, we propose a ligand−substrate coordinating
complex involving a secondary interaction between the thiourea
and the carbonyl substrate (Figure 2).
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xumu@rci.rutgers.edu.
Author Contributions
§J.W. and J.J. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the China Scholarship Council and the National
Natural Science Foundation of China (No. 201506270049) for
financial support.
REFERENCES
■
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A nonlinear effect, which can be observed in catalytic
asymmetric reactions, suggests potential dimerization or high-
order aggregation of catalysts.16 However, no nonlinear effect
was observed in hydrogenation of trans-β-methylcinnamide
(see the Supporting Information). It supports an assumption
that no catalyst self-aggregation or ligand−substrate agglomer-
ation occurs prior to the catalytic cycle.
In summary, we developed a synthetic method to approach
β-chiral carbonyl compounds. Catalyzed by a Rh/ZhaoPhos
complex, α,β-unsaturated carbonyl substrates were hydro-
genated with high enantioselectivities. A secondary interaction
between the thiourea ligand and carbonyl of the substrates is
believed to be crucial for the success. In addition, we did not
observe nonlinear effect in this catalytic chemical trans-
formation.
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(16) Guillaneux, D.; Zhao, S.-H.; Samuel, O.; Rainford, D.; Kagan, H.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01812.
Experimental procedures, characterization data (PDF)
C
DOI: 10.1021/acs.orglett.6b01812
Org. Lett. XXXX, XXX, XXX−XXX