An iron variant of the Noyori hydrogenation catalyst for the asymmetric transfer hydrogenation of ketones

Article abstract of DOI:10.1039/d0dt01204a

We report the design of a new iron catalyst for the asymmetric transfer hydrogenation of ketones. This type of iron catalyst combines the structural characteristics of the Noyori hydrogenation catalyst (an axially chiral 2,2′-bis(phosphino)-1,1′-binaphthyl fragment and the metal-ligand bifunctional motif) and an ene(amido) group that can activate the iron center. After activation by 8 equivalents of potassiumtert-butoxide, (S_A,R_P,SS)-7aand (S_A,R_P,SS)-7bare active but nonenantioselective catalysts for the transfer hydrogenation of acetophenone and α,β-unsaturated aldehydes at room temperature in isopropanol. A maximum turnover number of 14480 was observed for (S_A,R_P,SS)-7ain the reduction of acetophenone. The right combination of the stereochemistry of the axially chiral 2,2′-bis(phosphino)-1,1′-binaphthyl group and the carbon-centered chiral amine-imine moiety in (S_A,R_P,RR)-7b′afforded an enantioselective catalyst for the preparation of chiral alcohols with moderate to good yields and a broad functional group tolerance.

Full text of DOI:10.1039/d0dt01204a

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DOI: 10.1039/D0DT01204A
ARTICLE
An Iron Variant of the Noyori Hydrogenation Catalyst for the Asymmetric
Transfer Hydrogenation of Ketones
Shangfei Huo, Qingwei Wang*, Weiwei Zuo*
Received 28th December 2019,
Accepted 00th December 2019
We report the design of new iron catalysts for the asymmetric transfer hydrogenation of ketones. This type of iron catalyst
combines the structural characteristics of the Noyori hydrogenation catalyst (an axially chiral 2,2’-bis(phosphino)-1,1’-
binaphthyl fragment and the metal-ligand bifunctional motif) and an ene(amido) group that can activate the iron center.
DOI: 10.1039/x0xx00000x
After activation by
8 equivalents of potassium tert-butoxide, (SA,RP,SS)-7a and (SA,RP,SS)-7b are active but
nonenantioselective catalysts for the transfer hydrogenation of acetophenone and α,β-unsaturated aldehydes at room
temperature in isopropanol. A maximum turnover number of 14480 were observed for (SA,RP,SS)-7a in the reduction of
acetophenone. The right combination of stereochemistry of the axially chiral 2,2’-bis(phosphino)-1,1’-binaphthyl group and
the carbon-centered chiral amine-imine moiety in (SA,RP,RR)-7b’ afforded a enantioselective catalyst for the preparation of
chiral alcohols with moderate to good yields and broad functional group tolerance.
reported the use of structurally well-defined achiral or chiral
Knölker’s iron complexes in the high pressure hydrogenation and
Introduction
transfer hydrogenation of a series of carbonyl derivatives by
mimicking the metal-ligand bifunctional pathway that occurs across
Chiral alcohols are important feedstocks in fields such as the
pharmaceutical, fragrance, and agrochemical industries. Asymmetric
reduction, including hydrogenation, transfer hydrogenation and
hydrosilylation of ketones catalyzed by homogeneous catalysts that
are mainly based on precious metals, is currently a powerful tool for
the metal center and the hydroxyl group in the cyclopentadiene
44
ligand.43,
Mezzetti et al. reported a series of macrocyclic
iron(II)/(NH)2P2 complexes that were sterically and electronically
tuned by bis(isonitrile) ligands for the highly enantioselective
transfer hydrogenation of aryl-alkyl ketones in isopropanol at
elevated temperature (40 – 75 °C); these catalysts offered both
outstanding enantioselectivities (up to 99% ee) and good catalytic
activities (up to 9430 h-1).45-49 Hydrido carbonyl iron complexes
bearing pyridine-based pincer ligands that are capable of metal-
ligand cooperation via aromatization/dearomatization were
reported by Milstein et al. for the hydrogenation of ketone and
aldehydes under mild conditions with good reactivity and turnover
numbers.50-52
2
accessing these important chiral compounds.1, However, their
limited availability and toxicity as well as the difficulty in removing
these species from the final product have hampered the wide
implementation of precious metal catalysts in industry. Iron could be
an inexpensive and environmentally friendly substituent because
iron is earth-abundant, nontoxic and essential to various biological
processed.3-32
Therefore, many iron catalysts are currently being developed for
asymmetric, high pressure and transfer hydrogenations as well as
hydrosilylations.33-35 Gao’s group reported the in situ generation of
chiral and heterogeneous iron catalysts from trinuclear iron carbonyl
clusters with either tetradentate open-chain or macrocyclic
multidentate P,N ligands for both asymmetric hydrogenation and
transfer hydrogenation of a series of ketonic substrates with
enantioselectivities approaching or exceeding those obtained by
precious metal catalysts.36-38 Morris et al. reported the first
asymmetric hydrogenation and transfer hydrogenation with
Despite the significant advances made in the development of iron
catalysts for carbonyl reduction,37, 41, 48, 53-71 there is still need for the
development of new, reactive and stereoselective catalysts. For the
reduction of polar carbonyl groups, in addition to
aromatization/dearomatization pathways,50-52 the most widely used
approach to iron catalyst design is the involvement of a metal-ligand
bifunctional mechanism that involves cooperation between the
structurally defined iron complexes bearing tetradentate
diiminodiphosphine and diaminodiphosphine ligands.39,
Later, metal and the active sites of the ligand.2, 72 In addition, strong field
40
additional analogues of the tetradentate P-N-N-P iron complex
ligands, such as phosphine, CO and isonitriles, are frequently
introduced to keep the iron center in a low spin state to avoid the
catalysts were developed by the same group.41, 42 Casey and others
spin crossover-related reaction barriers that would otherwise
73
occur.5,
We have reported amido-ene(amido) diphosphine
carbonyl iron catalysts (A and B, Fig. 1)74 that possess carbon-
centered chirality derived from the S,S-1,2-diphenyl-1,2-
ethanediamine (S,S-dpen) skeleton for the efficient transfer
hydrogenation of a series of prochiral ketones and activated imines.
The turnover frequency was found to be as high as 242 s-1.
State Key Laboratory for Modification of Chemical Fibers and Polymer Materials，
College of materials science and engineering, Donghua University.
E-mail: wqwq888@dhu.edu.cn, zuoweiwei@dhu.edu.cn
Electronic Supplementary Information (ESI) available: Full experimental details,
additional figures, copies of NMR spectra and GC data. See
DOI: 10.1039/x0xx00000x
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ARTICLE
Journal Name
Ph
N
Ph
N
capabilities in various transition metal-catalyzed reactions. We
DOI: 10.1039/D0DT01204A
speculated that the combination of the 2,2’-bis(phosphino)-1,1’-
O
Ph
Ph
View Article Online
Ph
H
N
Ph
C
BF4
N
N
Fe
Fe
binaphthyl skeleton, the ene(amido) group and the metal-ligand
bifunctional structural motif may lead to the development of reactive
as well as enantioselective iron catalysts for asymmetric transfer
hydrogenations. We report here that when combined with the highly
stereo-inductive 2,2’-bis(phosphino)-1,1’-binaphthyl fragment, the
ene(amido) group, together with a carbonyl ligand, is able to activate
the iron center to achieve both reactivity and good enantioselectivity
in the asymmetric transfer hydrogenation of a series of ketone
substrates. The structure of this Noyori hydrogenation catalyst-type
iron catalyst is shown in Fig. 2.
N
Fe
P
Ph2
P
Ph2
P
Ph2
P
Ph2
C
O
C
O
P
Ph2
P
Ph2
Cl
A
B, active
C, not active
Fig. 1 Previously reported active iron catalysts with chiral ligands with
C-centered chirality. A, the amine(imine)diphosphine iron
complex precatalyst; B, the active amido-ene(amido) iron
catalyst; and C, the inactive bis(amido) iron complex.75
Results and discussion
The mechanistic study revealed the important role of the
ene(amido) group in enabling the high catalytic reactivity, as the
bis(amido) analogue (C, Fig. 1), produced by the reduction of the
ene(amido) group with isopropanol in the absence of an additional
base, is totally inactive.75 A recent study on the electronic structures
of the amido-ene(amido) diphosphine carbonyl iron complexes
revealed the presence of π-backdonation between the iron and the
ene(amido) group. This covalent metal-ligand bonding facilitates a
flexible electron density transfer between the iron center and the
ligands in the catalytic intermediates. Therefore, these reactive
species are stabilized against deactivation.
The synthesis and characterization of the iron complexes
As shown in Scheme 1, the target iron complexes were synthesized
via a template reaction between the 2-phosphino substituted
acetaldehyde and chiral dpen in the presence of an iron cation,
forming the bis(acetonitrile) cationic iron(II) complex. This was
followed by a ligand substituent reaction between acetonitrile and
CO and a chloride anion. The key step is to obtain the 2-phosphino-
substituted acetaldehyde, which combines both the axial chirality of
the 1,1’-binaphthyl skeleton and a P-chirogenic76-84 moiety. This
includes two challenges: (1) the diastereoselective and clean
introduction of the P-chiral phosphino group into the axially chiral
binaphthyl scaffold with a high yield and (2) the introduction of an
aldehyde group in the presence of reactive phosphino groups. We
developed a new strategy to diastereoselectively and cleanly install
the P-chirogenic substituent into the 1,1’-binaphthyl scaffolds to
prepare new 2,2’-bis(phosphino)-1,1’-binaphthyl analogues that
possess both axial chirality and P-centered chirality. The proposed
mechanism is shown in the Electronic Supporting Information
(Scheme S1). We also developed a strategy that utilized a SnnBu3
group as the precursor of a lithium salt for the subsequent
introduction of an aldehyde group. This synthetic method has an
acceptable overall yield.
However, one shortcoming that prevents the previous iron
catalysts (A)74 from being practically useful is their relatively low
asymmetric induction capabilities. 2,2’-bis(phosphino)-1,1’-
binaphthyl ligands have exhibited excellent asymmetric induction
2, 72
Noyori & Morris
D
Metal-ligand bifunctionality
to impart high reactivity
Ar
Ar
H
Ph
Ph
P
N
Axially chiral fragment
to induce excellent
enantioselectivity
Fe
Ph
*
*
N
P
C
O
2
Noyori
The key starting material for the synthesis of the chirality-hybrid
compound (2) is (SA)-2-bromo-2’-phosphinyl-1,1’-binaphthyl (1). 1
was prepared by C-P nucleophilic substitutions between
chlorodiarylphosphine and (SA)-2-lithium-2’-bromo-1,1’-binaphthyl
and oxidation by H2O2, instead of the commonly utilized metal-
catalyzed C-P cross-coupling reactions.85-88 (SA)-2-Lithium-2’-bromo-
1,1’-binaphthyl was accessed by the reaction of (SA)-2,2’-dibromo-
1,1’-binathyl and 1.1 equivalents of n-butyl lithium at a low
temperature (-90 °C) in THF within 5 – 15 min. Fortunately, no
racemization of the axial chirality was observed during this lithium-
bromide exchange or during the following C-P bond formation step,
as indicated by high-performance liquid chromatography (HPLC)
analysis (see the Electronic Supplementary Information for details in
Chart S1, Fig. S3 and Table S1). A second lithium-bromide exchange
reaction on 1 and subsequent sequential quenching reactions with
-backdonation to activate iron
so that it reacts like ruthenium
This work
E
Ar
BF4
Ar
Cl
H2
N
Ph
Ph
P
Fe
Ph
*
*
N
P
C
O
Fig. 2 The structure of the Noyori hydrogenation catalyst-type iron
catalyst (D) and the precatalyst (E).
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0DT01204A
1) LinBu, -90 oC,
O
1) LinBu, -90 oC,
THF, 15 min
2) ClPAr2
O
P
1) HSiCl3, NEt3
THF, 80 oC, 3 h
2) BH3-THF, 45 oC
Ar
Ar
Ar
Ar
THF, 15 min
P
Br
Br
Ph
(S)
(S)
(S)
2) Cl2PPh
3) CH3MgBr
P
(R)
Br
3) H2O2
2a: Ar = Ph 71% yield
2b: Ar = p-OMeC6H4 79% yield
1a: Ar = Ph 90% yield
1b: Ar = p-OMeC6H4 92% yield
1) LisBu, -70 oC,
1) LinBu, -90 oC,
THF, 90 min
Ar
Ar
Ar
Ar
Ar
Ar
THF, 0.5 - 2 min
2) ClSnnBu3
P
P
P
P
Ph
Ph
BH3
Ph
2) HC(O)OEt
P
P
SnnBu3
CHO
3) HNEt2/THF,
40 oC, 12h
3) H2O
5a: Ar = Ph 46% yield
5b: Ar = p-OMeC6H4 47% yield
3a: Ar = Ph 73% yield
3b: Ar = p-OMeC6H4 74% yield
4a: Ar = Ph 29% yield
4b: Ar = p-OMeC6H4 41% yield
C
(BF4)2
BF4
N
Cl
Ar
Ar
Ar
Ar
H2
N
H2
N
1) (S,S) or (R,R)-dpen
2) Fe(H2O)6(BF4)2
Ph
Ph
P
P
CO, NaCl
Ph
Ph
Fe
Fe
*
*
*
*
P
P
N
N
CH2Cl2/CH3CN, r.t, 2 h
Acetone, r.t,
30 min
Ph
Ph
N
C
C
O
6a: Ar = Ph, (S, S)-dpen 71% yield
6a': Ar = Ph, (R, R)-dpen 73% yield
7a: Ar = Ph, (S, S)-dpen 55% yield
7a': Ar = Ph, (R, R)-dpen 50% yield
6b: Ar = p-OMeC6H4, (S, S)-dpen 75% yield
6b': Ar = p-OMeC6H4, (R, R)-dpen 78% yield
7b: Ar = p-OMeC6H4, (S, S)-dpen 57% yield
7b': Ar = p-OMeC6H4, (R, R)-dpen 55% yield
Scheme 1 The syntheses of iron complexes bearing axially chiral (SA)-2,2’-bis(phosphino)-1,1’-binaphthyl, imine, C-centered chiral amine
and carbonyl groups.
dichloroarylphosphine and methyl magnesium bromide afforded 2 in temperature (-90 °C) led to the formation of an important lithium
high yields, with only one diastereomer being formed. Similarly, no intermediate, which quantitatively affords the 2-phosphino-
erosion of the axial chirality was observed. Compound 2 can be substituted acetaldehyde (5) after sequential quenching reactions
deoxygenated by either a mixture of trichlorosilane and triethyl with excess ethyl formate at -90 °C for 5 min and H2O in THF at room
amine in a ratio of 1:20:5 at 80 °C in THF for 3 hours or by a temperature for 5 min. Notably, attempts to directly introduce an
combination of CeCl3/NaBH4/LiAlH4 in a ratio of 1:5:5:3 at low aldehyde group into the borane-phosphine adduct (3) led to
temperature (-90 °C) in THF.89 Negligible racemization of the P- reduction of the aldehyde group by the BH3 protecting group. The
chirality was observed in the trichlorosilane/triethyl amine process, aldehyde group of 5a shows a multiplet C-H signal at δ 9.28 ppm in
while the chirality of the phosphine group was unaffected when the its 1H NMR spectrum due to the coupling with both the geminal CH2
CeCl3/NaBH4/LiAlH4 reducing agent was employed. Deoxygenated protons and the P nuclei. The 31P{1H} NMR spectrum of 5a exhibits
product (SA,RP)-2-(methyl)(phenyl)phosphino-2’-diphenylphosphino- two phosphorus resonances at -15.31 and -38.06 ppm with a P-P
1,1’-binaphthyl was further reacted with one equiv. of BH3-THF coupling of 16.2 Hz. A similar NMR spectral pattern was observed for
adduct in THF overnight to afford borane-phosphine adduct 3 in 5b.
approximately 80% yield. The mono-phosphine protection of 3 was
Bis(acetonitrile) cationic iron(II) complex 6 was prepared by the
crucial for the following reaction, because the bis(boranato) adduct reaction of 5, Fe(H2O)6(BF4)2 and (S,S)-dpen or (R,R)-dpen in
does not give the target product but affords unknown side products. acetonitrile. Complex 6a was obtained as a single compound in
The deprotonation of the acidic CH3 group was facilitated by borane acetonitrile and showed two coupled 31P signals at 52.49 and 63.34
coordination, and the subsequent electrophilic quenching of the ppm with a PPJ coupling of 35.4 Hz in its 31P{1H} NMR spectrum.
reactive lithium intermediate with chlorotributyltin lead to the Complex 6a’ was obtained with two sets of phosphorus resonances
formation of important intermediate 4 in approximately 40% yield in its 31P{1H} NMR spectrum (53.73, 68.49, PPJ = 39.6 Hz; 52.97, 55.35,
after deboranation and purification by silica gel chromatography.
The lithium-tin exchange between 4 and n-butyl lithium in THF at low
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The catalytic results
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DOI: 10.1039/D0DT01204A
Catalysts 7a-7b’ were initially evaluated for the asymmetric transfer
hydrogenation of acetophenone using isopropanol as the solvent
and hydrogen source (Table 1). Precatalysts 7a-7b’ were all active for
the asymmetric transfer hydrogenation of acetophenone after being
activated with 8 equiv. of potassium tert-butoxide. Notably, for
(SA,RP,SS)-7a, a substrate/precatalyst ratio of 21300:1 and 42600:1
gave a maximum turnover number of 10650 and 14480 within 3
minutes, respectively. It was found that 7a was more active than our
previous active catalyst A74 under the same condition, but it stayed
active only for approximately 3 minutes. No further improvement on
the reaction yield was observed with longer reaction time.
Unfortunately, the 1-phenylethanol product was obtained as the
racemate instead of a highly enantioenriched one. Similar reactivity
and selectivity were observed for (SA,RP,SS)-7b. However,
fortunately, (SA,RP,RR)-7a’, having the dpen skeleton with the
opposite central chirality, stayed active for longer time
(approximately 3 hours) and produced enantioenriched (R)-1-
phenylethanol (82% ee), albeit with a much lower catalytic activity.
Precatalyst (SA,RP,RR)-7b’ showed much better enantioselectivity (R,
93%) than 7a’ but lower reactivity was seen. These results indicate
that when combined with metal-ligand bifunctional chemistry, the
ene(amido) group (together with a CO ligand) can activate iron to
efficiently catalyze asymmetric transfer hydrogenation reactions.
The homogeneity of this iron-catalysed reaction was assumed
based on several experimental observations. First, the addition of
either 300 equiv. of mercury or 0.5 equiv. of trimethylphosphine92 to
the reaction mixture of 7a’ after 1 h of reaction did not affect the
reaction and the analysis on the three-hour reaction showed the
same yield and enantioselectivity of (R)-1-phenylethanol to those
observed under the unmodified reactions (Table 1, entry 4). Second,
the 31P {1H} NMR spectrum of the one-hour catalytic reaction on 7a’
revealed the presence of one set of doublets at δ 82.90, 71.64 ppm
with a PPJ coupling constant of 48.6 Hz, although some other
unidentified signals that are derived from catalyst deactivation were
also observed (see the Electronic Supplementary Information for
details in Fig. S30). This is a typical resonance of either amido-
ene(amido) iron carbonyl complex (B, Fig. 1) or the corresponding
amino hydrido iron intermediate that have been observed in this
type of iron-catalysed reactions.74 The possibility of contaminations
of more active metals in this transformation was ruled out by a trace
metal analysis (ICP analysis) on complex 7a, where only iron was
detected (see the Electronic Supplementary Information for details
in Fig. S60). Different from the situation of transition metal catalysis
with P-chirogenic ligands,93-102 the influence of P-chirality on the
catalytic performances was indirect in the series of 7a-7b’. The aim
of introduction of a P-chirogenic centre in these iron complexes is to
construct a planar P-N-NH-P coordination plane that is structurally
reminiscent of either Noyori hydrogenation catalyst103-107 or the
previous amino(imino)diphosphine iron catalyst.74 The preliminary
results revealed that the inverse of the P-chirality in the P-N-NH-P
ligand will lead to the formation of a twisted P-N-NH-P coordination
Fig. 3 The molecular structure of (SA,RP,SS)-6a with the thermal
ellipsoids set at 10% probability. Aromatic ring protons and the two
BF4 counter anions have been omitted for clarity. Selected
interatomic distances (Å) and angles (deg): Fe1–N1 2.065(7), Fe1–N2
2.005(8), Fe1–N3 1.894(8), Fe1–N4 1.858(8), Fe1–P1 2.365(3), Fe1–
P2 2.235(3), C40–N2 1.313(11), P1–Fe1–P2 95.36(10), P1–Fe1–N1
98.8(3), P2–Fe1–N2 82.0(3), N1–Fe1–N2 83.6(4)
PPJ = 54.6 Hz) in a 1:2 ratio. Unlike our previous synthetic procedure,
which employed methanol as the solvent to accelerate the reaction,
complex 6 is only stable in acetonitrile. A single crystal of 6a suitable
for X-ray diffraction was obtained by slow diffusion of diethyl ether
into a dilute reaction solution. A further ligand exchange reaction of
6a was conducted in acetone under 1 atm of carbon monoxide and
in the presence of excess sodium chloride to afford complex 7a as a
single isomer. 7a exhibited 31P{1H} resonances at 62.01 and 58.18
ppm with a PPJ coupling of 55.7 Hz and showed a CO stretch at 1980
cm-1 in its FT-IR spectrum. Interestingly, the two sets of phosphorus
resonances of 6a’ gave only one set of phosphorus resonances of 7a’
after the ligand substitution reaction. Two doublets at 58.22 and
59.14 ppm with a PPJ coupling of 53.5 Hz were observed in the 31P{1H}
NMR spectrum of 7a’, and a similar CO stretching vibration at 1982
cm-1 was observed in the FT-IR spectrum. The structures of
complexes 7a and 7a’ were further confirmed by high-resolution
mass spectrometry. The fragmentation patterns and spectroscopic
data of the products of 6b, 6b’, 7b and 7b’ are similar to those of 6a,
6a’, 7a and 7a’, respectively. Complex 7 was purified by crystalization
in dichloromethane/diethyl ether.
The structure of the (SA,RP,SS)-bis(acetonitrile) complex 6a was
determined by single-crystal X-ray diffraction, and the molecular
structure of the cation is shown in Fig. 3. This is the first example of
a BINAP mononuclear iron complex and the second example of an
iron complex chelating with BINAP-derived phosphorus ligands.90
The iron is coordinated in a distorted octahedral fashion, and both
the (SA)-2,2’-bis(phosphino)-1,1’-binaphthyl
ligands were coordinated in a δ conformation.91
and the S,S-dpen
plane in the new iron complex which has
a cis-located
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bis(acetonitrile)
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Table 1 Precatalyst screening and reaction condition optimization for the asymmetric transfer hydrogenation of acetophenone using
potassium tert-butoxide as the base.a
Precatalyst
Substrate
/precatalyst
Time at
maximum
yield
3 min
10 min
3 min
3 h
Maximum
yield and TON
Enantiomeric
Excess at
Maximum yield
0%
60%, (R)
0%
82%, (R)
0%
93%, (R)
7a
A
7a
7a’
7b
7b’
21300
21300
42600
21300
21300
21300
50%, 10650
72%, 15300
34%, 14480
9%, 1870
41%, 8650
8%, 1620
3 min
3 h
aGeneral conditions: [precatalyst]= 6.02 × 10-5 M, [KOtBu] = 4.82 × 10-4 M, [isopropanol] = 11.1 M, 25 °C.
109
ligands.108,
In this case, the stereo induction behaviour will acetylindan was hydrogenated to the R-alcohol with an ee of 97%.
otherwise be determined by the steric bulkiness on the chiral P- The reduction of 2-acetyl-5,6,7,8-tetrahydronaphthalene with
donor and the chirality on the diamine moiety, and the chirality (SA,RP,RR)-7b’ afforded (R)-5,6,7,8-tetrahydro-α-methyl-2-
induction capability of the binaphthyl ligand was lost. naphthalenemethanol with 43% yield and an ee of 94%. Subjecting
In addition to acetophenone and similar to the case of A,74 2-acetonaphthone to the same catalytic reaction conditions
(SA,RP,SS)-7a can also mediate the reduction of aldehydes with high furnished (R)-1-(2-naphthyl)-1-ethanol in 93% ee, which is
reactivity and high turnover numbers. The exclusive preferential significantly improved compared to the results with our previous
reduction of C=O over C=C was observed in the reduction of α,β- PNNP iron catalyst (A).74
unsaturated aldehydes (cinnamaldehyde and citral) to afford
A series of industrially and synthetically useful chiral alcohols can
unsaturated alcohols that are important starting materials in the be prepared with good enantiopurities using our iron-catalyzed
perfume and pharmaceutical industries.110-112 This beneficial process. For example, (R)-1-(1-Napthyl)ethanol, which can be used
chemoselectivity was attributed to the known metal-ligand for the synthesis of (+)-compactin and 1233A, was obtained in an ee
bifunctional mechanism that was operative in our previous processes of 96%.114-116 Furthermore, (R)-1-[3’-(trifluoromethyl)phenyl]ethanol
and was not observed in related iron catalytic systems, which are and (R)-1-[3’,5’-bis(trifluoromethyl)phenyl]ethanol, which are the
mechanistically heterogeneous or undefined.110 (SA,RP,RR)-7b’ was staring materials for the industrial synthesis of fungicides117, 118 and
found to be enantioselective for
a
series of substituted NK1 antagonists,119 could be produced with 97% and 97% ee,
acetophenones, and the corresponding R-enriched alcohols were respectively. Chiral β-amino alcohols are important building blocks in
generally obtained with moderate to good turnover numbers and industrial scale syntheses of physiologically active compounds120 and
enantiomeric excess of >90%, which is significantly improved are widely used as chiral auxiliaries.121 This catalytic system is also
compared to the results obtained with A.74 The standard conditions compatible with a dimethylamino group at the 2-position of 2-
employed 0.023 mol% of the iron complex precursor and 8 (dimethylamino)acetophenone and gave (R)-2-(dimethylamino)-1-
equivalents of KOtBu with a catalyst concentration of 3.00 × 10−4
M
phenylethanol in an ee of 87% with a TON up to 500. Importantly,
in isopropanol at 25 °C. In general, the introduction of bulky under similar conditions (SA,RP,SS)-7a allows the smooth transfer
substituents at the meta-position of the phenyl group of hydrogenation of an α-keto acetal (2,2-dimethoxyacetophenone) to
acetophenone led to some reactivity and good enantioselectivity, give a chiral α-hydroxyl acetal [(R)-2-(dimethoxy)-1-phenylethanol]
similar to what is observed with iron catalysts having bis(isonitrile) in a moderate optical purity of 54% ee. Despite the relatively low
ligands.113 The catalytic performances in terms of reactivity and enantioselectivity, this is the first example of the preparation of this
enantioselectivity were less influenced by the electronic properties highly value-added chiral alcohol by an iron-catalyzed process. After
of the substituent at that position, as both electron-donating groups, initial hydrolysis of the acetal group, this versatile α-hydroxyl acetal
such as NMe2 and OMe, and electron-withdrawing groups, including synthon could be transformed into a variety of highly value-added
chloride, bromide and nitrile, provided similar results. The relatively chiral products, including 1,2-diols, α-hydroxyl acids, and β-amino
lower TON observed with 3’-CN acetophenone was due to the lower alcohols, which are useful chiral building blocks for the synthesis of
solubility of the substrate in isopropanol. Thus, 3’- biologically active natural products, pharmaceutically important
methylacetophenone yield the corresponding R-enriched alcohol molecules, chiral ligands and fine chemicals.122-125 Higher optical
with 55% yield and an ee of 96% under the standard conditions. The purities have been reported with heterogeneous Pt catalysts126
tolerance of nitrile groups in the synthesis of (R)-1-(3’-cyanophenyl) modified with chiral cinchonidine ligands or by biocatalytic
ethanol makes the current iron-catalyzed process versatile in the process.127
Homogeneous
catalytic
precedents
with
preparation of a series of functionalized chiral alcohols by further enantioselectivity were mediated by ruthenium catalysts ligated by
functionalization of the nitrile group. With (SA,RP,RR)-7b’, 5- pyrrolidinebisphosphine ligands.128 Interestingly, an excellent
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a
DOI: 10.1039/D0DT01204A
Table 2 Transfer hydrogenation of ketones and aldehydes catalyzed by complexes (SA,RP,RR)-7b’ and (SA,RP,SS)-7a. General conditions for
(SA,RP,RR)-7b’: [7b’] = 3.00 × 10−4 M, [KOtBu] = 2.40 ×10−3 M, [ketone] = 1.28 M, [iPrOH] = 11.1 M, 25 °C. The absolute configurations were
determined by gas chromatography or HPLC by comparison to known standards.
7a
7b'
or 0.023 mol%
0.0047 mol%
O
R2
H
0.192 mol% KOtBu
HO
R1
R1 R2
iPrOH, 25 o
3 min - 3 h
C
c
d
CH2OH
b
HO
HO
HO
Me
H
Me
H
Me
H
O
Br
N
Alcohol
product
OH
(R)
(R)
(R)
TON
ee
2400
2000
12000
N.A.
4900
N.A.
74
98%
74%
3 h
92%
57%
3 h
96%
46%
3 h
Yield
Time
58%
>99%
3 min
3 min
d
Me
d
Me
e
HO
HO
HO
HO
HO
Me
Me
H
Me
Cl
NC
Alcohol
product
H
H
H
H
(R)
(R)
(R)
(R)
(R)
3000
900
1800
75
TON
ee
44
90%
72%
3 h
99%
90%
3 h
97%
44%
3 h
94%
43%
3 h
93%
75%
3 h
Yield
Time
d
Me
HO
d
Me
O
Me
HO
HO
(R)
HO
F3C
HO
NMe2
F3C
H
O
(R)
Alcohol
product
H
H
(R)
H
(R)
H
(R)
CF3
1700
86
39
400g,h
54%g (90%h)
98%g (>99%h)
TON
ee
500f
f
87%
97%
39%
3 h
97%
86%
3 h
96%
f
Yield
Time
56%
39%
3 h
3 h
3 min
d
d
d
Cl
HO
HO
Me
HO
(R)
HO
HO
HO
Me
Me
Et
H
Me
H
Me
Alcohol
product
H
H
H
H
(R)
(R)
(R)
(R)
(R)
2500
90%
59%
3 h
50
2400
96%
55%
3 h
2200
62
26
TON
ee
94%
97%
50%
3 h
95%
97%
Yield
Time
51%
3 h
26%
3 h
62%
3 h
bConditions for (SA,RP,SS)-7a: [7a] = 5.95 × 10−5 M, [KOtBu] = 4.76 ×10−4 M, [ketone] = 1.27 M, [iPrOH] = 11.1 M, 25°C. cConditions for (SA,RP,SS)-
7a: [7a] = 6.67 × 10−5 M, [KOtBu] = 5.34 ×10−4 M, [ketone] = 0.33 M, [iPrOH] = 12.4 M, 25°C. dConditions for (SA,RP,SS)- 7b’: [7b’] = 3.00 × 10−4
e
M, [KOtBu] = 2.40 ×10−3 M, [ketone] = 0.03 M, [iPrOH] = 11.1 M, 25°C. Conditions for (SA,RP,SS)- 7b’: [7b’] = 3.54 × 10−4 M, [KOtBu] = 2.83
f
×10−3 M, [ketone] = 3.54 × 10−1 M, [iPrOH] = 12.4 M, 25°C. Conditions for (SA,RP,RR)-7b’: [7b’] = 2.55 × 10−4 M, [KOtBu] = 2.04 × 10−3 M,
g
[ketone] = 0.26 M, [iPrOH] = 12.4 M, 25°C. Conditions for (SA,RP,SS)-7a: [7a] = 2.55 × 10−4 M, [KOtBu] = 2.04 ×10−3 M, [ketone] = 0.10 M,
[iPrOH] = 12.4 M, 25°C. hConditions for A: [A] = 2.55 × 10−4 M, [KOtBu] = 2.04 ×10−3 M, [ketone] = 0.10 M, [iPrOH] = 12.4 M, 25°C.
enantioselectivity of 90% was obtained using our previous less- achieve both high reactivity (up to 9430 h-1) and excellent
enantioselective iron catalyst (A).74
enantioselectivity (up to 99%) in the asymmetric transfer
When ligated with macrocyclic chiral ligands, iron catalysts, either hydrogenation of
a
series of aromatic ketones at elevated
generated in situ with triiron carbonyl clusters or with well-defined temperatures (40
– 75 °C). Although slightly inferior, the
structures, reported by Gao37, 38 and Mezzetti et al.,45, 46, 49 could enantioselectivity (>90% in most cases) exhibited by (SA,RP,RR)-7b’ is
6 | J. Name., 2012, 00, 1-3
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also good and of synthetic relevance. In addition, (SA,RP,RR)-7a was 2
orders of magnitude more active and chemoselectively
2.
R. Noyori, Angew. Chem., Int. Ed., 2002, 41, 2008-
2022.
View Article Online
DOI: 10.1039/D0DT01204A
hydrogenated α,β-unsaturated aldehydes to the corresponding 3.
unsaturated alcohols, which are important feedstocks in industry,
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with high turnover numbers. In addition, (SA,RP,RR)-7b’ and our
previous PNNP iron precatalyst (A)74 have potential practical
applicability in catalytic asymmetric transfer hydrogenations of
functionalized ketonic substrates to produce a series of highly value-
added chiral alcohols that are important building blocks for various
industries with good to excellent enantioselectivities.
Conclusions
A new strategy to the stereoselective synthesis of chirality hybridized
2,2’-bis(phosphino)-1,1’-binaphthyl ligands was developed. Based on
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the asymmetric transfer hydrogenation of ketones. These new iron
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catalysts contain 1,1’-binaphthyl axial chirality, P-centered chirality
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ethanediamine. For precatalysts (SA,RP,SS)-7a and (SA,RP,SS)-7b, it
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structural motif and the ene(amido) group (as well as carbonyl) could
activate the iron for the fast transfer hydrogenation of acetophenone
and α,β-unsaturated aldehydes, although the catalysts decomposed
rapidly and were not enantioselective. For precatalysts (SA,RP,RR)-7a’
and (SA,RP,RR)-7b’, however, the right matching of the axial chirality
and the carbon-centered chirality was important to confer iron
catalysts good stereoselectivity. With 7b’, a series of ketone
substrates were reduced to the corresponding chiral alcohols,
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enantioselectivities.
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Conflicts of interest
There are no conflicts to declare.
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conformation of the coordinated ligands. This work was
sponsored by Natural Science Foundation of China (21772021),
“Shanghai Rising-Star Program” (16QA1400100), The Program
for Professor of Special Appointment (Eastern Scholar) at
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Dalton Transactions
Page 10 of 10
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DOI: 10.1039/D0DT01204A
A new type of iron catalyst that structurally mimics the Noyori hydrogenation catalyst can
catalyze asymmetric transfer hydrogenation of ketones.
Metal-ligand bifunctionality
to impart high reactivity
Ar
Ar
H
Ph
Ph
P
N
Axially chiral fragment
to induce excellent
enantioselectivity
Fe
Ph
*
*
N
P
C
O
Ene(amido) & CO groups to
effectively activate iron
O
HO
Fe catalyst, KOtBu
isopropanol as H source
H
R2
R1
R1
R2