Unprecedented iron-catalyzed ester hydrogenation. Mild, selective, and efficient hydrogenation of trifluoroacetic esters to alcohols catalyzed by an iron pincer complex

Article abstract of DOI:10.1002/anie.201311221

The synthetically important, environmentally benign hydrogenation of esters to alcohols has been accomplished in recent years only with precious-metal-based catalysts. Here we present the first iron-catalyzed hydrogenation of esters to the corresponding alcohols, proceeding selectively and efficiently in the presence of an iron pincer catalyst under remarkably mild conditions. The replacement of precious-metal catalysts by an iron complex was accomplished for the synthetically important, environmentally benign hydrogenation of esters to alcohols under mild conditions. The iron pincer complex (see scheme) selectively and efficiently catalyzes the hydrogenation of trifluoroacetates under remarkably mild conditions (5-25 bar and 40 °C).

Full text of DOI:10.1002/anie.201311221

Angewandte
Chemie
DOI: 10.1002/anie.201311221
Iron Catalysis
Unprecedented Iron-Catalyzed Ester Hydrogenation. Mild, Selective,
and Efficient Hydrogenation of Trifluoroacetic Esters to Alcohols
Catalyzed by an Iron Pincer Complex**
Thomas Zell, Yehoshoa Ben-David, and David Milstein*
Dedicated to Professor Helmut Werner on the occasion of his 80th birthday
Abstract: The synthetically important, environmentally benign
hydrogenation of esters to alcohols has been accomplished in
recent years only with precious-metal-based catalysts. Here we
present the first iron-catalyzed hydrogenation of esters to the
corresponding alcohols, proceeding selectively and efficiently
in the presence of an iron pincer catalyst under remarkably
mild conditions.
this reaction have been developed. These bifunctional
catalysts either employ metal–ligand cooperation by aroma-
tization/dearomatization or a Noyori–Ikariya-type metal NH
bifunctional effect. However, most catalysts still require high
pressures and high catalyst loadings for an efficient reaction.
The Ikariya group recently reported the hydrogenation of
a-fluorinated esters using the Ru pincer complex [(dpa)-
Ru(H)(CO)(Cl)]
(dpa = bis-(2-diphenylphosphinoethyl)-
T
he reduction of esters to alcohols is an important reaction
amine) as catalyst.[3g] These reactions give, depending on the
reaction conditions, a-fluorinated alcohols or hemiacetals.
Shortly after, the same catalyst was used for hydrogenation
reactions of perfluoro methyl esters by Lazzari, Cassani, and
co-workers.[3n] Similar and remarkably efficient Ru catalysts
featuring NH-functionalized pincer ligands were recently
developed by Gusev and co-workers.[3p]
in organic chemistry.[1] This transformation traditionally
involves the use of stoichiometric amounts of metal hydride
reagents, such as LiAlH4, NaBH4, and their derivatives.
However, these reagents have poor compatibility with func-
tional groups and poor atom economy as a result of the
generation of stoichiometric amounts of waste. The catalytic
hydrogenation of esters to alcohols is, in contrast, an environ-
mentally benign, waste-free and atom-economical process,
which is used industrially on a large scale with fatty esters
under harsh conditions employing heterogeneous catalysts.
We[2] and others[3–5] have developed homogenous catalysts for
the hydrogenation of esters to alcohols. In 2006 we reported
the mild, low-pressure hydrogenation of non-activated aro-
matic and aliphatic ester catalyzed by the Ru pincer complex
The substitution of expensive and potentially toxic noble-
metal catalysts by inexpensive, abundant, and environmen-
tally benign metals is a prime goal in chemistry. In particular,
iron is an attractive alternative because of its high abundance,
low cost, and low toxicity. In recent reports, there is
a remarkable progress in the application of iron-based
catalysts for hydrogenation, dehydrogenation, and transfer-
hydrogenation reactions.[7] Iron catalysts have been success-
fully applied in hydrogenation reactions of various substrates,
such as alkynes,[8] alkenes,[8b,9] ketones,[10] aldehydes,[10e,11]
imines,[10f,12] and CO2.[13] However, although catalysts for the
hydrogenation of esters based on non-noble metals are highly
desirable, so far only Ru,[2,3] Ir,[4]and Os[5]-based catalysts have
been reported. Moreover, many iron-based hydrogenation
catalysts, such as Knçlker-type catalysts, bis(iminopyridine)–
iron catalysts, or Bellerꢀs dual iron catalyst for the hydro-
genation of a-keto- and a-iminoesters to a-hydroxy- and a-
aminoesters, respectively, are tolerant toward esters.[14] How-
ever, two-step strategies of iron-catalyzed ester reductions to
alcohols,[15] aldehydes,[16] and ethers[17] through hydrosilyla-
tion followed by acidic or basic workup were developed,
although they are not atom-economical.
Encouraged by the recent developments of iron pincer
complexes as catalysts for hydrogenation and dehydrogen-
ation reactions in our group,[8c,10c,d,13b,18] we investigated their
application as catalysts for the hydrogenation of fluorinated
esters. To our knowledge, no iron-catalyzed hydrogenation
reaction of esters or other carboxylic acid derivatives was
reported to date. Herein, we present an efficient and selective
method for the hydrogenation of trifluoroacetic esters to the
corresponding alcohols catalyzed by the iron pincer complex
[(PNN*)Ru(H)(CO)]
methyl)-6-diethylaminomethyl)pyridine));
(PNN = (2-(di-tert-butylphosphino-
the asterisk
denotes the dearomatized ligand).[2a] Based on stoichiometric
experiments, we suggested a mechanism that involves a new
type of metal–ligand cooperation,[6] which is based on the
aromatization/dearomatization of the pyridine-based pincer-
type ligand by protonation/deprotonation of the pyridinyl-
methylenic carbon atom. Since then, the catalytic hydro-
genation of activated and non-activated esters and lactones
has progressed rapidly and several bifunctional catalysts for
[*] Dr. T. Zell, Y. Ben-David, Prof. Dr. D. Milstein
Department of Organic Chemistry, Weizmann Institute of Science
76100 Rehovot (Israel)
E-mail: david.milstein@weizmann.ac.il
[**] This research was supported by the European Research Council
under the FP7 framework (ERC No. 246837) and by the MINERVA
Foundation. T.Z. received a postdoctoral fellowship from the
MINERVA Foundation. D.M. holds the Israel Matz Professorial
Chair. D.M. thanks the Humboldt Foundation for the Meitner–
Humboldt Research Award.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201311221.
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trans-[(tBu-PNP)Fe(H)2(CO)] (1, tBu-PNP =
2,6-bis(di-tert-butylphosphinomethyl)pyri-
dine, Scheme 1).
Complex 1 efficiently catalyzes the hydro-
genation of 2,2,2-trifluoroethyl trifluoroace-
tate to 2,2,2-trifluoroethanol (TFE) under
remarkably mild conditions (Table 1). Initially
a catalyst loading of 0.50 mol% of 1 and a KOtBu loading of
1.0 mol% (Table 1, entry 9). No poisoning of the catalyst was
observed in the presence of mercury (Table 1, entry 10) or
PMe3 (30% with respect to 1, entry 11), this indicates that
catalysis by nanoparticles is unlikely.[20]
Treatment of TFE with 2.0 mol% of complex 1 and
10 mol% of KOtBu at 408C and 1008C did not show any
reaction of the alcohol to a dehydrogenation product, such as
the corresponding aldehyde, hemiacetal, or ester after 24 h.
These results suggest that the hydrogenation reaction is
irreversible under these conditions.
Scheme 1.
Catalyst
1 (P=PtBu2).
Table 1: Hydrogenation of 2,2,2-trifluoroethyl trifluoroacetate to 2,2,2-
trifluoroethanol (TFE) catalyzed by iron pincer complex 1.[a]
Table 2: Hydrogenation of n-butyl trifluoroacetate to 2,2,2-trifluoroetha-
nol (TFE) and n-butanol catalyzed by iron pincer complex 1.[a]
Entry
1
KOtBu
[mol%]
p(H2)
[bar]
t
[h]
T
[8C]
Yield
[%]
[mol%]
1
2
3
4
5
6
7
8
0.50
0.50
0.50
0.50
0
0.25
0.05
0.50
0.50
0.50
0.50
0
10
10
10
10
10
10
10
10
5
16
16
1
40
40
40
40
40
40
40
24
40
40
40
2
>99
85
98
1
74
64
91
94
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2
Entry
Base ([mol%])
Solvent
t
[h]
T
[8C]
Yield
[%]
16
16
90
16
16
16
2
1
2
3
4
5
6
7
8
KOtBu (4.0)
KOtBu (4.0)
KOtBu (4.0)
KOtBu (4.0)
KOtBu (2.0)
KOtBu (10)
KOtBu (2.0)
KOtBu (4.0)
KOtBu (10)
KH (10)
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
16
16
16
16
16
16
66
66
66
16
16
16
16
16
16
16
16
24
40
70
100
40
40
40
40
40
40
40
40
40
40
40
40
40
30
48
25
16
32
55
31
57
66
52
1
68
59
59
69
46
1
9
10[b]
11[c]
10
10
>99
99
[a] Reaction conditions: ester (2.0 mmol), 1,4-dioxane (2 mL), per-
formed in a Fisher–Porter pressure vessel. Yields based on integration of
19F{1H} NMR spectra of the crude products. [b] Performed in the
presence of 0.9 g Hg. [c] Performed in the presence of PMe3 (0.15 mol%
with respect to 1).
9
10
11
12
13
14
15
16
17
KOH (10)
NaOMe (10)
NaOEt (10)
NaOiPr (10)
NaOMe (10)
NaOMe (10)
NaOMe (10)
the trans-dihydride complex 1 was investigated as a catalyst
for the hydrogenation of 2,2,2-trifluoroethyl trifluoroacetate
under base-free conditions. A reaction performed in a Fisher–
Porter pressure vessel with a hydrogen pressure of 10 bar and
a catalyst loading of 0.50 mol% in 1,4-dioxane as solvent
leads to the formation of TFE in an unsatisfactory yield of
2%, according to integration in the 19F{1H} NMR spectrum of
the crude product (Table 1, entry 1). The activity of the
catalyst increases significantly upon the addition of base. The
same reaction leads to full conversion to TFE in the presence
of 1.0 mol% of KOtBu after 16 h at 408C (Table 1, entry 2),
giving yields of 85% and 98% after 1 h and 2 h, respectively
(Table 1, entries 3 and 4). This corresponds to a turnover
frequency (TOF) of 170 hÀ1 for the first hour. No catalytic
conversion to TFE was observed in the absence of catalyst
1 (Table 1, entry 5).[19] When the same reaction was conducted
with half of the catalyst loading (0.25 mol%), a yield of 74%
was obtained after 16 h (Table 1, entry 6). Further reducing
the catalyst loading to 0.05 mol% resulted in a 64% yield
after a reaction time of 90 h (Table 1, entry 7), which
corresponds to a turnover number (TON) of 1280. The
catalytic system shows a significant activity even at ambient
temperature. A reaction with 0.50 mol% of 1 and 1.0 mol%
of KOtBu at 248C (Æ 18C) gave a comparatively good yield of
91% (Table 1, entry 8). Furthermore, the catalysis was
performed at even lower pressures of hydrogen. Reducing
the pressure to 5 bar gave TFE in 94% yield after 16 h with
toluene
MeOH
[a] Reaction conditions: H2 (10 bar), ester (1.0 mmol), 1 (2.0 mol%),
1,4-dioxane (2 mL), base, performed in a Fisher–Porter pressure vessel.
Yields based on integration of the 19F{1H} NMR spectra of the crude
products.
Catalyst 1 is less active for the hydrogenation of n-butyl
trifluoroacetate to TFE and n-butanol (Table 2). Experiments
at different temperatures were conducted using 10 bar of
hydrogen pressure, 2.0 mol% of catalyst 1, and 4.0 mol% of
KOtBu, and the yields of TFE were compared after 16 h
(Table 2, entries 1–4). The highest activity of 1 in the hydro-
genation reaction was observed at 408C (Table 2, entry 2),
resulting in a yield of 48%. Experiments performed at higher
or lower temperatures resulted in lower yields (Table 2,
entries 1, 3, and 4). We studied the effect of different KOtBu
concentrations on the reaction. Lowering the KOtBu loading
to 2.0 mol% resulted in a deceleration of the reaction
(Table 2, entries 5 and 7), whereas an increase of the KOtBu
loading to 10 mol% (Table 2, entries 6 and 9) gave the
products in higher yields.
Next, we applied 10 mol% of different bases in reactions
with 2.0 mol% of catalyst 1 and compared the yields after
16 h at 408C (Table 2, entries 6 and 10–14). These experi-
2
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Table 3: Hydrogenation of various esters to the corresponding alcohols
catalyzed by iron pincer complex 1.[a]
ments showed that the activity of the catalytic system depends
on the base. KH and alkoxide bases are suitable bases for the
reaction, whereas the use of KOH gives an unsatisfying yield.
An increase in activity was observed in the series KOH
(TON = 0.5), KH (TON = 26), KOtBu (TON = 27.5), NaOiPr
(TON = 29.5), NaOEt (TON = 29.5), and NaOMe (TON =
34). Additionally, the effect of various solvents on the
reaction was examined (Table 2, entries 12 and 15–17). A
series of reactions was performed using 2.0 mol% of 1 and
10 mol% of NaOMe under 10 bar of H2 pressure, and the
yields were determined after 16 h at 408C. The use of 1,4-
dioxane and THF as solvents gave practically the same yields
(68% and 69%, respectively), whereas the reaction in toluene
resulted in a slightly lower yield of 46%. Using MeOH as
solvent resulted in the deactivation of the catalyst, and TFE
was obtained in only 1% yield after 16 h.
Entry
Ester
Yield [%]
1
2
77
80
3
4
78
>99
The catalytic activity of catalyst 1 increased with higher
pressures of H2. A reaction with half the catalyst loading
(1.0 mol%) and half the amount of NaOMe (5.0 mol%) gave
TFE in 77% yield after 16 h with a H2 pressure of 25 bar
(Table 3, entry 1). Various trifluoroacetic esters were
smoothly hydrogenated under these mild conditions
(Table 3). Aliphatic, olefinic, and aromatic esters were
reduced with good to excellent yields and selectivity. Notably,
other functional groups, such as ethers (Table 3, entry 2), aryl
groups (entry 3, 7–10), and terminal (entry 5) and internal
5
6
95
84
7
8
>99
>99
=
(entry 6) C C bonds stayed intact during the catalytic hydro-
genation.
9
>99
The reaction proceeded more slowly for substrates with
bulky substituents at the ester alkoxy group, such as cyclo-
hexylmethyl trifluoroacetate (substituted at the b-carbon
atom; Table 3, entries 11 and 12) and isopropyl trifluoroace-
tate (substituted at the a-carbon atom; Table 3, entries 13 and
14). However, high yields were obtained after prolonged
reaction times. The same effect, a decrease in reaction rate for
substrates with an increasing steric demand on the ester
oxygen atom, was described very recently by Morris in
a comprehensive study.[3g] Notably, no catalytic hydrogenation
was observed for esters bearing only two fluoro substituents
at the methyl carbon atom of the acetate moiety. Reactions of
ethyl chlorodifluoroacetate, ethyl bromodifluoroacetate, and
ethyl difluoroacetate did not show any conversion to the
corresponding difluoroethanol using 2.0 mol% of 1, 10 mol%
of NaOMe, and 10 bar of H2 pressure at 408C after 16 h.
Similarly, under the same conditions, no formation of
corresponding nonfluorinated alcohol was observed for the
reaction of 2,2,2-trifluoroethyl acetate and 1,1,1,3,3,3-hexa-
fluoroisopropyl benzoate.
10
97
52
95
11
12[b]
13
25
77
14[c]
[a] Reaction conditions: H2 (25 bar), ester (2.0 mmol), 1 (1.0 mol%),
NaOMe (5.0 mol%), 1,4-dioxane (2 mL), 16 h, 408C, performed in an
autoclave. Yields based on integration of the 19F{1H} NMR spectra of the
crude products. [b] 48 h. [c] Ester (0.67 mmol), 1 (3.0 mol%), NaOMe
(15.0 mol%), 60 h.
In order to gain mechanistic understanding of the iron-
catalyzed hydrogenation of trifluoroacetates, complex 1 was
investigated in stoichiometric reactions (see the Supporting
Information). No reaction was observed between complex
1 and an excess amount of KOtBu, suggesting that a dearom-
atized anionic iron dihydride complex is not involved.
Significantly, when the reaction of 1 with approximately
1.5 equivalents of benzyl trifluoroacetate was performed in
CD3CN at room temperature, transfer of one hydride of 1 to
the ester gave the monocationic acetonitrile complex [(tBu-
PNP)Fe(H)(CO)(MeCN)]+ (2).[21]
On the basis of the reactivity of complex 1 and precedents
regarding the non-innocent nature of the ligand,[6] a possible
bifunctional mechanism for the hydrogenation of trifluoro-
acetates catalyzed by complex 1 is presented in Scheme 2.[22]
We recently reported on the direct attack of CO2 on the Fe
hydride moiety of 1, forming the oxygen-bound formate
complex ([(tBu-PNP)Fe(H)(CO)(h1-OOCH)] (3),[13b] and we
showed by DFT calculations that this reversible reaction
proceeds through an outer-sphere mechanism.[18c] As shown
in Scheme 2, a direct attack of the carbonyl carbon atom of
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Scheme 2. Possible mechanism of the iron-catalyzed hydrogenation of
trifluoroacetate esters (P=PtBu2).
the ester on the Fe hydride moiety of 1 is also observed in the
case of the trifluoroacetate ester. This reaction likely pro-
ceeds via intermediate A, leading to oxygen-bound hemi-
acetaloxide intermediate B (which in acetonitrile forms
complex 2). The OH elimination of the hemiacetal through
metal–ligand cooperation generates the dearomatized inter-
mediate C. This step, the formation of the deprotonated
intermediate C, may be facilitated by the presence of
a catalytic amount of base.
The dihydride complex 1 is regenerated by addition of H2
through metal–ligand cooperation. This behavior was pre-
viously observed experimentally for dearomatized complexes,
such as the Ru complex [(PNN*)Ru(H)(CO)].[2a] The hemi-
acetal is in equilibrium with the trifluoroacetaldehyde, which
is likely to be readily hydrogenated through a similar cycle to
give TFE. The outer-sphere nucleophilic attack of the hydride
on the ester is obviously facilitated by the electron-deficient
character of the carbonyl carbon atom in the trifluoroacetates,
and is also in line with the lack of reactivity of the non-
=
polarized C C bonds (Table 3, entries 5 and 6).
In conclusion, we have demonstrated the catalytic hydro-
genation of a family of esters to alcohols without the use of
precious or toxic metals as catalysts. Thus, the iron pincer
complex [(tBu-PNP)Fe(H)2(CO)] (1) is an efficient catalyst
for the selective hydrogenation of trifluoroacetic esters to the
corresponding alcohols. These reactions proceed smoothly
under remarkably mild conditions (5–25 bar and 408C) to
give the products in good to quantitative yields. Further
studies on the scope and mechanism of Fe-catalyzed ester
hydrogenation are in progress.
Received: December 26, 2013
Revised: February 5, 2014
Published online: && &&, &&&&
Keywords: esters · homogenous catalysis · hydrogenation ·
iron complexes · pincer ligands
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[19] Minor amounts of side products from transesterification with the
base were observed occasionally in the hydrogenation reactions
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[21] Complex 2 was reported previously, see Ref. [18c]. Benzyl
alcohol was also formed, but the fate of the trifluoroacetyl group
of the ester is unclear (for details, see the Supporting Informa-
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[14] For selected examples, see references: [3j,8b,c,9,10a,e,f,11].
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Iron Catalysis
T. Zell, Y. Ben-David,
D. Milstein*
&&&& — &&&&
Unprecedented Iron-Catalyzed Ester
Hydrogenation. Mild, Selective, and
Efficient Hydrogenation of Trifluoroacetic
Esters to Alcohols Catalyzed by an Iron
Pincer Complex
The replacement of precious-metal cata-
lysts by an iron complex was accom-
plished for the synthetically important,
environmentally benign hydrogenation of
esters to alcohols under mild conditions.
The iron pincer complex (see scheme)
selectively and efficiently catalyzes the
hydrogenation of trifluoroacetates under
remarkably mild conditions (5–25 bar
and 408C).
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!