Transfer hydrogenation promoted by N-heterocyclic carbene and water

Article abstract of DOI:10.1039/c5cc05117g

N-Heterocyclic carbenes (NHCs) promote the transfer hydrogenation of various activated C=C, C=N, and N=N bonds with water as the proton source. The NHCs act as reducing reagents to be converted into their oxides. A detailed reaction mechanism is proposed on the basis of deuterium-labeling experiments.

Full text of DOI:10.1039/c5cc05117g

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Transfer hydrogenation promoted by N-heterocyclic carbene and
water
Received 00th January 20xx,
Accepted 00th January 20xx
Terumasa Kato, Shin-ichi Matsuoka,* Masato Suzuki
DOI: 10.1039/x0xx00000x
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N-Heterocyclic carbenes (NHCs) promote the transfer Table 1 Transfer Hydrogenation of Dibutyl Fumalate (1a) Promoted by NHCsa
hydrogenations of various activated C=C, C=N, and N=N bonds
with water as the proton source. The NHCs act as reducing
reagents to be converted into their oxides. A detailed reaction
mechanism is proposed on the basis of deuterium-labeling
experiments.
The hydrogenation of unsaturated compounds by molecular
hydrogen is an important industrial chemical reaction. However,
the reaction using this flammable gas under pressurized conditions
is not operationally simple, and thus great care has to be taken. In
this respect, one of the most promising methods is transfer
hydrogenation, specifically using readily available, cheap, easy to
handle, and environmentally friendly reagents, such as water and
alcohols, as the hydrogen donors. Indeed, such hydrogenations
have been promoted by phosphines and transition metals. The
phosphine/H2O undergoes the Staudinger reaction, reported in
19191, and the reductions of TCNQ2 and α-keto esters.3 The
phosphine/alcohol systems reduced fumarates4, maleates4, and
maleimides5. In these reactions, phosphines serve as reducing
reagents to be converted into the phosphine oxides. In contrast, the
transition metal-catalyzed transfer hydrogenations using various
proton sources have been well-investigated.6 Among them,
however, there are only several examples of the transfer
hydrogenation of alkenes with water promoted by transition
Entry NHC
Baseb
Proton
Source
H2O
H2O
H2O
Solventc
Temp. Time
Yieldd
(%)
94
91
80
(°C)
150
150
120
80
(h)
2
1
2a
-
-
-
-
-
-
DME
DME
DME
DME
DME
DME
DME
DME
DME
toluene
DMF
n-BuOH
DME
2
2b
2
2
2
24
2
4
4
4
2
2
2
2
3
2b
4
2b
H2O
57
5
2a
H2O
30
15e
82
6
2b
H2Of
H2O
150
120
120
120
150
150
150
150
7
2c
DBU
DBU
DIPEA
-
-
-
-
31
0
0
41
64
91
trace
8
9
10
11
12
13
2d-2k
2c-2k
2b
2b
2b
H2O
H2O
H2O
H2O
H2O
n-BuOH
2b
a 1a; 0.25 mmol, NHC; 0.30 mmol, Base; 0.60 mmol, Proton Source; 0.90 mmol.
b DBU; 1,8-diazabicyclo[5.4.0]undec-7-ene, DIPEA; N,N-diisopropylethylamine. c
0.4 M, DME; 1,2-dimethoxyethane, DMF; N,N-dimethylformamide. d Isolated. e
oil bath heating. f H2O; 0.25 mmol (1.0 equiv.).
metals, i.e., Ti7, Rh8, Ti/Pd9 and Ni10
.
N-Heterocyclic carbenes11 (NHCs) have been widely used as the
ligands of transition metals and the main group element species,
and organocatalysts. For more than a decade, numerous NHC-
catalyzed reactions involving the umpolung of aldehydes have been
reported,12 while we and others have been developing the
umpolung of Michael acceptors.13 The NHCs show electronic
properties similar to the phosphines, which are well known to act as
oxygen acceptors to form phosphine oxide, enabling a wide variety
of transformations, e.g. the Wittig14, Mitsunobu15 and Appel16
reactions. The seminal study of the 1,2,4-triazol-5-ylidene NHC by
Enders et al. showed that the NHC reacts with oxygen to form the
corresponding NHC oxide.17 It has been reported that this oxide was
formed by the reaction of the NHC or the deoxy-Breslow
intermediate with oxidants18, and by the conversion of PhenoFluor,
a
2,2-difluoroimidazolidene, during the deoxyfluorination of
phenols and alcohols or during the dehydrative formation of alkyl
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Table 2 Substrate Scope
Entry
1
Substrate
Product
Yield (%)a
94
Entry
9
Substrate
Product
Yield (%)a
68
2
3
36b
85
10
11
51
55
O
H
O
CO2Et
H
3d
4
68
12
72
NC
H
N
5
6
65
79
13
14
80
Ph
H
3n
68
7
8
74
15
16
75c
MeOC
24b
88
CO2tBu
1i
a Isolated yield unless otherwise noted. b 1H NMR yield. c 1.0 equiv. of 2b.
aryl ether.19 To the best of our knowledge, however, reactions Decreasing the reaction temperatures to 120, 80, and 30 °C led to
promoted by the oxidation of NHC remain unknown. In this lower yields (Entries 3-5), and no product was obtained at 0 °C. The
communication, we report the transfer hydrogenation of the hydrogenation similarly took place even in the presence of a
electron deficient C=C, C=N, and N=N bonds promoted by NHCs and stoichiometric or large excess amount (20 equiv.) of H2O, hardly
water, in which the NHCs work as reducing reagents for the first inducing other reactions (Entry 6 in Table 1 and Entry 2 in Table S1
time to be converted into the NHC oxides. The reaction mechanism in the Supplementary Information). The combination of 1,2,4-
is clearly proposed by the deuterium-labeling experiments using triazole type NHC precursor 2c with DBU or K2CO3 also produced 3a,
D2O for some substrates and the deoxy-Breslow intermediates. It accompanied by the formation of the corresponding oxide 4c (Entry
should be noted that there have been only several NHC-catalyzed 7 in Table 1 and Entry 3 in Table S1 in the Supplementary
reactions using water as the reagent.20
Information), while the hydrogenation did not proceed using other
We initially examined the transfer hydrogenation of dibutyl NHC precursors 2d-2k with DBU or DIPEA. Similar to the umpolung
fumarate (1a) with 1.2 equiv. of NHC 2a or NHC precursors 2b–2k reactions of Michael acceptors catalyzed by the NHCs, the effective
and 3.6 equiv of water using a sealed vial under microwave NHC promoters are very limited for this hydrogenation. The
irradiation to increase the reaction temperature above the boiling hydrogenation in toluene or DMF at 150 °C gave 3a in moderate
points of the solvents and water (Table 1). The reaction with the yields (Entries 10 and 11). n-BuOH is a good solvent, giving 3a in
isolated 1,2,4-triazol-5-ylidene NHC 2a in 1,2-dimethoxyethane 91% yield (Entry 12), but the hydrogenation using n-BuOH (3.6 eq.)
(DME) at 150 °C for 2 h resulted in the selective reduction of the as the proton source instead of water was ineffective (Entry 13).
C=C of 1a to give dibutyl succinate 3a in 94% isolated yield (Entry 1). When the hydrogenation using oil bath heating in the same type of
An equimolar amount of the NHC oxide 4a was precipitated in the a microwave vial was carried out at 120 °C for 2 h and at 80 °C for
reaction mixture and readily separated by filtration. The methanol 12 h, 3a was obtained in 91% and 81% yields, respectively. (Entries
adduct of NHC 2b, which is converted to 2a via the elimination of 8 and 9 in Table S1 in the Supplementary Information), indicating
MeOH by heating, showed a similar reactivity at 150 °C (Entry 2). that nonthermal microwave effects were not involved.
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Scheme 1. Transfer Hydrogenation of 1a, 1f, and 1m using 1.0 equiv of D2O.
With the optimized conditions in hand, we then examined the
substrate scope (Table 2). Similar to the hydrogenation of 1a, its cis
analogue, dibutyl maleate 1b, gave 3a in high yield. The
a
hydrogenation of the sterically-hindered trisubstituted alkene, 1c,
was also possible, though the yield is less than moderate. For the
functionalized fumarates, 1d and 1e, the hydrogenation selectively
took place at the electron deficient C=C bonds, and the allyl and
propargyl groups are tolerated. In addition, a variety of Michael
acceptors could be hydrogenated, which bear two electron-
withdrawing groups, such as ketone (1f, 1j), amide (1g, 1k), and
electron deficient aromatic groups (1h, 1i). Interestingly, the alkyl
Scheme 2. Transfer Hydrogenation of 1a using 30 equiv of D2O.
amide-functionalized
substrate
1k
underwent
tandem
hydrogenation and cyclization to give the succinimide 3k in a
moderate yield. N-Phenyl maleimide, 1l, and its methyl-substituted
analogue, 1m, also gave succinimides in moderate to good yields.
However, hexyl methacrylate, 2-methoxyethyl acrylate, t-butyl
crotonate, dimethylacrylamide, and dimethyl itaconate were not
hydrogenated under the same conditions (Figure S1 in the in the
Supplementary Information). This hydrogenation is also applicable
for the C=N and N=N bonds. The hydrogenations of the imines
bearing aromatic electron-withdrawing groups (1n, 1o),
a
carbodiimide, 1p, and an azodicarboxylate, 1q, under the same
conditions provided the corresponding products (3n-3q) in good
yields. One C=N bond of 1p was selectively hydrogenated without
further reactions of the produced imine, 3p.
selective deuterium incorporations with 2.0 D and 1.0 D for each of
the methylene carbons (Scheme 2(a)). In contrast, when the deoxy-
Breslow intermediate I generated in-situ from 1a and 2a17 was
subjected to the reaction with 30 equiv. of D2O, the α,α-
dideuterated product 3v was obtained in 80% yield (Scheme 2(b)).
Based on these results, we propose the reaction mechanism
shown in Scheme 3. NHC 2a reacts with 1a to generate the
zwitterionic intermediate II. In the presence of an excess amount of
D2O, the intermolecular H-D exchange forms the mono-deuterated
deoxy-Breslow intermediate III (Scheme 3(a)), which then
undergoes the addition of D2O to generate IV. Since IV has a weak
C-C bond between the quaternary carbon derived from the carbene
and the α-carbon activated by the ester carbonyl, the C-C bond
To elucidate the reaction mechanism, deuterium-labeling
experiments were performed. The hydrogenations of the substrates
1a, 1f and 1m using an equimolar amount of D2O at 120 °C provided
3r, 3s and 3t, with deuterium incorporations of 2.0 D, 1.6 D, and 1.4
D, respectively (Scheme 1). It is clear that water acts as the
hydrogen donors. The 13C NMR and ESI-MS analyses indicated that
these three products were a mixture of isotopic isomers, for
instance, showing four ESI-MS signals at m/z = 253 (0 D), 254 (1 D),
255 (2 D), and 256 (3 D) for 3r. These results suggest that complex
intermolecular H-D exchange reactions are involved. We then used
a large excess amount (30 equiv.) of D2O for the hydrogenation of
1a and obtained the trideuterated product, 3u, in 80% yield with
Scheme 3. Proposed reaction mechanism of the transfer hydrogenation of 1a, 1l, and 1m with D2O.
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6
For reviews, see; (a) G. Brieger, T. J. Nestrick, Chem. Rev.,
cleavage and the deuterium transfer are possible, leading to the
elimination of 4a to produce 3u. This bond cleavage is
understandable by assuming a relatively stable ion pair V composed
of the triazolium cation and the ester enolate. Scheme 3(b) shows
the mechanism of the reaction of I with D2O to give 3v. Importantly,
this clear difference in the deuterium incorporation between 3u
and 3v supports the fact that the reaction mechanism, involving the
D2O addition to III or I and the subsequent deuterium transfer, is
reasonable. This proposed mechanism indicates that two electron-
withdrawing substituents at the 1,2 positions of the unsaturated
substrates are required to promote the initial Michael addition and
the C-C bond cleavage, which is consistent with the experimental
results. If the reaction of II with D2O generates VIII (Scheme 3(c)),
the α,β-dideuterated product, 3w, would be obtained, but this is
not the case. Thus, this result also supports the fact that the
hydrogenation of fumarates goes through the deoxy-Breslow
intermediate.
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The mechanism of the hydrogenation of maleimides was
found to be different from that of the fumarates (Scheme 3(d)). In
contrast to the reactions of I and III derived from 1a, the reactions
of the deoxy-Breslow intermediates XI from maleimides (1l and 1m)
with water did not give the hydrogenated products (3l or 3m). In
addition, the hydrogenation of 1m with D2O gave the hydrogenated
product 3t and deoxy-Breslow intermediate 5t in comparable yields
(Scheme 1). Accordingly, in the case of the maleimides (1l and 1m),
the zwitterionic intermediate X undergoes proton transfer to give XI
but no further addition of water. Instead, X also reacts with water
to directly generate the hydroxyl-functionalized intermediate XII,
resulting in the production of 3l or 3m. Since the formation of
deoxy-Breslow intermediate from a carbodiimide (1p) and an azo
compound (1q) is impossible, it is reasonable to assume that the
mechanism of the transfer hydrogenations of 1p and 1q is similar to
those of 3l and 3m.
13 (a) C. Fischer, S. W. Smith, D. A., Powell, G. C. Fu, J. Am.
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,
In conclusion, we have developed the transfer hydrogenations
promoted by 1,2,4-triazol-5-ylidene NHC and water. The substrate
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scope includes
a variety of electron deficient unsaturated
compounds, such as Michael acceptors, imines, a carbodiimide, and
an azo compound. The deuterium-labeling experiments using D2O
and the reactions of the deoxy-Breslow intermediates clearly
propose the detailed reaction mechanism including the proton
transfer process. It depends on the substrates as to whether or not
the deoxy-Breslow intermediates are involved. This hydrogenation
is the first reaction promoted by the oxidation of NHC, and also first
reaction of deoxy-Breslow intermediates or the zwitterionic
intermediates derived from NHC with water. Reaction discoveries
using this concept will be highly expected.
,
19 (a) P. Tang, W. Wang, T. Ritter, J. Am. Chem. Soc. 2011, 133
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