Unprecedented iron-catalyzed selective hydrogenation of activated amides to amines and alcohols

Article abstract of DOI:10.1039/c6cc01505k

The first example of hydrogenation of amides homogeneously catalyzed by an earth-abundant metal complex is reported. The reaction is catalyzed by iron PNP pincer complexes. A wide range of secondary and tertiary N-substituted 2,2,2-trifluoroacetamides were hydrogenated to form amines and trifluoroethanol.

Full text of DOI:10.1039/c6cc01505k

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Unprecedented Iron-Catalyzed Selective Hydrogenation of
Activated Amides to Amines and Alcohols
Received 00th January 20xx,
Accepted 00th January 20xx
Jai Anand Garg,† Subrata Chakraborty,† Yehoshoa Ben-David and David Milstein*
DOI: 10.1039/x0xx00000x
www.rsc.org/
The first example of hydrogenation of amides homogeneously first reported by our group.6 The chemoselective cleavage of the C-
catalyzed by an earth-abundant metal complex is reported. The N bond in preference to the C-O bond with no waste generation
reaction is catalyzed by iron PNP pincer complexes. A wide range render this methodology attractive. The reaction mechanism was
of secondary and tertiary N-substituted 2,2,2-trifluoroacetamides suggested to proceed via a bifunctional mode of activation by a
were hydrogenated to form amines and trifluoroethanol.
reversible aromatization-dearomatization sequence involving
pyridine-based pincer ligands. Several subsequent reports of
selective C-N bond hydrogenation of amides mainly by homogenous
precious metal catalysts were reported by the groups of Ikariya,7
Saito,8 Bergens,9 Mashima10 and Beller.11 Nevertheless, it is highly
desirable to develop selective homogeneous catalysts based on
cheap and abundant first row base metals for this difficult and
important transformation.12
The amide bond constitutes an important building block, ubiquitous
in chemistry and biology, making possible to realize compounds
such as peptides and synthetic polymers.1 The pervasive nature of
this functional group can be attributed to its relative chemical
inertness and bond strength made possible due to the amide-imide
tautomerization. Cleavage of the amide bond, selectively via either
C-N or the C-O bonds by an atom-economical catalytic
hydrogenation process is a desirable transformation in organic
chemistry (Scheme 1).2
Iron pincer catalysts have been successfully applied in homogenous
hydrogenation of ketones, carbon dioxide, alkynes, esters and
nitriles by several groups, including ours.13 However, to the best of
our knowledge, homogeneous hydrogenation of amides catalyzed
by base-metal complexes was not reported so far. Herein we report
the first selective hydrogenation of activated amides to their
corresponding amines and alcohols homogenously catalyzed by
pincer iron complexes.
Scheme 1 Possible pathways of amide hydrogenation.
Typically, stoichiometric metal hydride reagents, boranes or silanes
are routinely employed to reduce amides in industrial scale
operations, generating large quantities of toxic waste.3 Focusing on
At the outset of our study we explored pyridyl-based PNP iron
pincer catalysts [(tBu-PNP)Fe(H)2(CO)] (1), [(iPr-PNP)Fe(H)(BH4)(CO)]
(2) and [(iPr-PNP)Fe(H)(Br(CO)] (3) (Figure 1) developed in our
group13d,e,14 as potential candidates for hydrogenation of amides.
a
catalytic hydrogenation alternative, several heterogeneous
systems starting from the well-known Adkins copper-chromite
catalysts, Ni, PtO2, Cu, bimetallic catalysts (Rh-Re, Rh/Mo, Ru/Re,
Pt-Re/TiO2 and recently Pt/Re/graphite, Re/TiO2 have been
reported4 suffering from harsh reaction condition (high
temperature and pressure) and poor selectivity. Interesting
homogenous catalysts for amide hydrogenation based on
Ru(acac)3/triphos were reported by Cole Hamilton and coworkers.5
However, these catalytic systems are mainly aimed at C-O
hydrogenolysis of the carbonyl functionality to form amines, which
is of significant importance by itself ( Scheme 1).
Fig.
1 Fe-based PNP pincer catalysts explored for amide
hydrogenation.
The selective direct homogenous hydrogenation of amides to
primary amines and alcohols by a metal (ruthenium) complex was
While N-phenylacetamide and N-phenylbenzamide did not undergo
hydrogenation using catalyst 1 (10 mol%) at various conditions of
temperature and H2 pressure, selective hydrogenolysis of the C-N
bond of activated amides was successful. Encouragingly, employing
2,2,2-trifluoro-N-phenylacetamide and 1 (10 mol%) under 60 bar H2
at 140 °C in the presence of 10 mol% of KOtBu in dioxane as the
Department of Organic Chemistry, Weizmann Institute of Science,
76100 Rehovot (Israel)
E-mail: david.milstein@weizmann.ac.il
†J. A. G. and S. C. contributed equally to this work.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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solvent, resulted in 34% conversion after 36 h to trifluoroethanol Table 1 Optimization reactions for amide hydrogenation
and aniline with no trace of the carbonyl-reduced sec-amine (Table
1, entry 1). The products were analyzed by GC-MS and 1H/19F NMR.
Next, we have examined the possibility of hydrogenation of 2,2,2-
trifluoro-N-phenylacetamide using 10 mol% of [(tBuPNP)FeBr2],
KOtBu (10 mol%) and NaHBEt3 (10 mol%), following conditions
which we have previously employed for hydrogenation of nitriles
catalyzed by dihalo- pincer complexes of iron13m and cobalt;15
however, no conversion was observed (Table 1, entry 2). Also,
employing just FeBr2 with NaHBEt3 had no effect, negating chances
of heterogeneous catalysis by this system (Table 1, entry 3). Having
Entrya
Cat
(mol%)
1(10)
1(10)
1(10)
1(10)
Base
(mol%)
Time
(h)
36
Convb
Yieldb
(%)
34
-
(%)
34
-
1
2c
3d
4
tBuOK (10)
tBuOK (10)
-
36
36
-
-
tBuOK (30)
36
67
67
5
6
7e
8f
9g
10h
1(5)
1(5)
1(5)
1(5)
1(5)
1(5)
tBuOK (15)
KHMDS (15)
KHMDS (15)
KHMDS (15)
KHMDS (15)
KHMDS (15)
18
18
36
36
36
36
21
46
6
21
46
6
seen that the dihydide PNP complex
1 can indeed catalyze
hydrogenation of activated amides, we then set out to optimize
conditions for better catalytic performance.
35
4
35
4
Initially, we observed that better conversion (67%) was obtained
upon increasing the amount of KOtBu (30 mol%) with respect to the
catalyst (10 mol%) (Table 1, entry 4). Also, the stronger base
KHMDS (potassium hexamethyldisilazane) was found to be superior
to KOtBu. After 18 h, with 5.0 mol% of 1 and 15 mol% of KHMDS
under the same conditions of pressure and temperature (60 bar H2
and 140 °C.), 46% of the amide was hydrogenated to aniline and
trifluoroethanol, whereas use of tBuOK as base under the same
condition gave only 21% conversion (Table 1, entries 5 and 6).
Decreasing either the pressure (Table 1, entries 7 and 8) or
temperature (Table 1, entries 9-12) led to a drop in the efficiency of
the catalysis. Dioxane was a better reaction solvent than THF or
toluene (Table 1, entries 13 and 14).
14
14
11i
12j
13k
14l
15
1(5)
1(5)
1(5)
1(5)
2(5)
3(5)
KHMDS (15)
KHMDS (15)
KHMDS (15)
KHMDS (15)
KHMDS (15)
KHMDS (15)
36
36
36
36
5
36
61
45
39
99
99
36
61
45
39
99
99
16
5
17
18
2(2)
3(2)
3(2)
2(5)
3(5)
3(2)
KHMDS (6)
KHMDS (6)
KHMDS (6)
-
5
5
29
33
99
32
-
29
33
99
32
-
19
12
24
24
7
20
21
22m
-
KHMDS (6)
-
-
Next, complexes 2 and 3 bearing iPr2P groups were examined. To
our delight, 2 and 3 showed a very significant rate enhancement in
the hydrogenation of 2,2,2-trifluoro-N-phenylacetamide, the
reactions being complete in 5 h with a catalyst loading of 5 mol% (2
or 3), 15 mol% KHMDS, 60 bar H2 at 140 °C, while 1 showed 61%
conversion after 36 h under similar reaction conditions (Table 1,
entries 12, 15 and 16). It is likely that the higher steric crowding of
the t-butyl groups as compared to isopropyl groups is the reason for
the difference in activity. Catalysts 2 and 3 displayed comparable
catalytic activity, with 3 being slightly better under exactly the same
conditions (Table 1, entries 17 and 18). In fact, the hydrogenation of
2,2,2- trifluoro-N-phenylacetamide achieved completion with just 2
mol% of catalyst 3 after 12 h under 60 bar H2 at 140 °C in dioxane
solvent in the presence of 6 mol% KHMDS (Table 1, entry 19).
Exploring the role of base, complexes 2 (5.0 mol%) and 3 (5.0 mol%)
were used without the addition of the base. As expected the
dihydride 2 was still active, showing 32% conversion after 24 h
(Table 1, entry 20), while the hydridobromo complex 3 showed
practically no conversion (Table 1, entry 21). This demonstrates the
essential part of base in deprotonation of 3 to the followed by
hydrogenation to the trans-dihydride complex. However,
comparing the conversions using 2 as catalyst, with and without the
base, it is clear that the base has an additional significant effect on
the rate of the reaction, although its role is unclear at this stage. A
control experiment in the absence of H2 with a loading of 2 mol%
catalyst 3, 6 mol% KHMDS at 140 °C using dioxane as solvent did
not show any conversion of 2,2,2-trifluor-N-phenylacetamide after
7 h, as revealed by the GC-MS analysis, indicating that base attack
on the amide to generate aniline does not occur under the reaction
conditions (Table 1, entry 22).
aConditions: amide (0.5 mmol), catalyst (10-2 mol%), base and dry 1,4-dioxane (1.5
mL), heated in an autoclave at 140 °C bath temperature under 60 bar H2. byields and
conversions determined by GC-MS analysis and yield based on aniline. c10 mol%
(tBuPNP)FeBr2 was used as catalyst and 10 mol% NaHBEt3 as hydride source. d10 mol%
FeBr2 and 10 mol% NaHBEt3 was used.e10 bar H2.f30 bar H2. gRT h60 °C 100 °C 140°C.
kTHF used as solvent ltoluene used as solvent. mThe reaction was carried out in a
pressure tube in the absence of H2.
i
j
Considering the fact that complexes 2 and 3 have comparable
activities, we chose to use complex
3 for further catalytic
examination due to is easier preparation. Employing complex 3 (2.0
mol%), KHMDS (6 mol%), H2 (60 bar) and 140 °C we have examined
the substrate scope of this reaction using various substituted 2,2,2-
trifluoro-N-phenylacetamides. The electronic nature of the arene
seemed to have little influence on the reactivity. 2,2,2-trifluoro-N-
(4-fluorophenyl)-acetamide, bearing a fluoro substituent at the para
position was completely hydrogenated in 12 h (Table 2, entry 1),
and complete selective hydrogenation was also observed with the
isopropyl-
substituted
2,2,2-trifluoro-N-(4-isopropylphenyl)-
acetamide (Table 2, entry 2), using a loading of only 2 mol%
complex 3 in the presence of 6 mol% KHMDS. The substrate 2,2,2-
trifluoro-(4-N,N-dimethyphenyl)-acetamide showed 58% conversion
(Table 2, entry 3) after 12 h, while the amide with a p-nitro
substituent (Table 2, entry 4) showed only 25% conversion after 24
h. The reason for the retardation effect by the nitro group is not
clear at this stage. Initial evaluation of RNHCOCF3 (R= alkyl,
cycloalkyl) substrates showed very low conversions at 2.0 mol% of
complex 3 at the end of 24 h. Better conversion was observed with
a loading of 5.0 mol% catalyst and longer reaction time (36 h).
Methyl (26%) and long chain aliphatic (23%) and cyclohexyl (35%)
substituted trifluoroacetamides showed moderate conversions
2 | J. Name., 2012, 00, 1-3
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Table 2 Hydrogenation of activated amides catalyzed by 3a
the mechanism previously suggested by us for the hydrogenation of
trifluoroacetic esters.13f As observed in that case, complex 1 does
not react with excess of KOtBu, suggesting that a dearomatized
anionic iron dihydride complex is not involved in the catalytic cycle.
In addition although complex 1 does not react with 2,2,2-trifluoro-
N-phenylacetamide at room temperature in 1, 4-dioxane, possibly
due to steric reasons, complex 2 reacted with 3 equivalents of
2,2,2-trifluoro-N-phenylacetamide at room temperature in dioxane
as shown by the appearance of a triplet hydride signal at -18.4
ppm, upfield shift in comparision to 2, and a 31P NMR signal at δ =
88 ppm (see supporting information). This is very likely
intermediate C (Scheme 2). A reported iron complex very closely
related to C (P=iPr2P), bearing a diphenylmethylalkoxide ligand
trans to H instead of the N-phenylalkoxide ligand in C, gives rise to
very similar chemical shifts of δ = 90.01 and -19.94 for 31P- and
1HNMR, respectively.13d A broad B-H signal at δ = -5.7 ppm was
also observed, which might indicate BH3 coordinated to solvent or
excess substrate (see Supporting Information).
Entry
Substrate
Mol%
Time
(h)
Conv
(%)[b]
Productsb
Amine
(%)
99
(%)
1
2
2
2
2
2
5
5
5
5
5
5
5
5
12
12
12
24
36
36
35
36
36
36
36
36
99
99
58
25
35
23
26
58
62
46
99
48
p-F-aniline
(99)
99
52
25
36
23
26
44
61
42
99
45
Isopropyl
aniline (99)
NN-
Dimethylaniline
(58)
H
N
CF3
3
O
N
4
p-Nitroaniline
(25)
Cyclohexyl
amine
5
(34)
6
Hexylamine (22)
Based on the aforementioned observation and on the basis of
precedents regarding the non-innocent nature of the ligand,12d,16 a
possible mechanism involving metal-ligand cooperation for the
hydrogenation of activated amides catalyzed by complexes 1-3 is
depicted in Scheme 2.
H
N
CF3
7
Methylamine
(undetected)
O
8
Benzylamine
(58)
p-Fluoro
benzylamine
(62)
9
10
11
12c
p-Methylbenzl
amine (46)
Ph
N
CF3
Ph
Diphenylamine
(99%)
O
Fluoroaniline
(47)
aUnless and otherwise stated, reaction conditions were 2-5 mol% catalyst 3, 3 equiv.
KHMDS relative to catalyst, 60 bar H2, 140 °C and 1,4-dioxane as solvent. bconversions
and amine yields were determined by GC using mesitylene as internal standard and TFE
yield is based on 19F NMR. ctrifluoromethylbenzylalcohol was obtained as alcohol and
quantified by GC.
(Table 2, entries 5-7). Various 2,2,2,-trifluoroacetamides bearing
para substituted benzyl groups (N-benzyl-2,2,2-trifluoroacetamide
(58%), 2,2,2-trifluoro-N-(4-fluorobenzyl)acetamide (62%) and 2,2,2-
trifluoro-N-(4-methylbenzyl)acetamide (46%) showed improved
yields compared to aliphatic substrates (Table 2, entries 8-10).
The hydrogenation reaction is not limited to secondary amides. The
tertiary amide 2,2,2-trifluoro-N,N-diphenylacetamide which has a
relatively low C-N bond dissociation energy underwent quantitative
conversion (99%) to diphenylamine and trifluoroethanol (Table 2,
entry 11). In order to examine the efficacy of the catalyst beyond
the trifluoracetamide substrates, we tested activated substrates
with substituted phenyl substituents attached on the carbonyl
carbon and the nitrogen. Encouragingly, N-(4-fluorophenyl)-4-
Scheme 2 Possible mechanism for the amide hydrogenation.
As shown in Scheme 2, the trans dihydride complex 1 is very likely
an actual intermediate. In case of complex 2, A is generated by
removal of BH3 by adduct formation with dioxane and for 3, the
base leads to dehydrobrominaton followed by H2 addition via metal
ligand cooperation (MLC)16 generating the trans dihydride
intermediate A. Outer-sphere attack of the carbonyl carbon atom of
the amide on the Fe-H moiety of A via transition state B leads to the
alkoxide intermediate C, which we have very likely observed, as
described above. This can be followed by elimination of
a
hemiaminal through metal–ligand cooperation (MLC) generating
the dearomatized intermediate D, which may be facilitated by the
presence of a catalytic amount of base. The dihydride A is then
regenerated by addition of H2 to D through MLC. The hemiaminal is
in equilibrium with the product amine and trifluoroacetaldehyde,
the latter being readily hydrogenated via a similar cycle to give
TFE.17 The outer-sphere nucleophilic attack of the hydride on the
(trifluoromethyl)benzamide
showed
48%
conversion
to
corresponding p-fluoraniline (47%) and p-trifluormethyl benzyl
alcohol (Table 2, entry 12). However, activated primary amine
substates such as 2,3,4,5,6-pentafluorobenzamide did not show any
conversion after 36 h.
We believe that the mechanism of the hydrogenation of activated
amides catalyzed by complexes 1-3 reported here is analogous to
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amide is obviously facilitated by the electron-deficient character of
the carbonyl carbon atom in the trifluoroacetamides.
In conclusion, we have demonstrated for the first time catalytic
hydrogenation of a family of activated amides to alcohols and
amines by applying pincer complexes based on an earth-abundant,
low toxicity, first row transition metal. Thus, the iron pincer
complexes [(iPr-PNP)Fe(H)(BH4)(CO)] (2) [(iPr-PNP)Fe(H)(Br(CO)] (3)
are effective pre-catalysts for the selective hydrogenation of a wide
range of N-substituted 2,2,2,-trifluoroacetamides and N-(4-
fluorophenyl)-4-(trifluoromethyl)benzamide to trifluoroalcohol and
6
7
8
9
the corresponding amines.
A plausible mechanism has been
proposed. Further investigation regarding the extension of the
scope of the reaction, and elucidation of a detailed mechanism is
currently underway in our group.
(a) J. M. John and S. H. Bergens, Angew. Chem. 2011, 123,
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This research was supported by the MINERVA Foundation, by the
Israel Science Foundation, and by the Peter Cohn Catalysis Research
Fund. D.M. holds the Israel Matz Professorial Chair of Organic
Chemistry. J. A. G. and S. C. thank the Swiss Friends of the
Weizmann Institute of Science for generous postdoctoral
fellowships.
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