Tandem hydrogenation and condensation of fluorinated α,β-unsaturated ketones with primary amines, catalyzed by nickel

Article abstract of DOI:10.1039/c5dt02366a

A simple homogeneous catalytic system based on nickel phosphine complexes has been developed for the transfer hydrogenation and condensation of α,β-unsaturated ketones to yield saturated ones and saturated imines using primary amines as hydrogen donors. Thus, a wide range of fluorinated 1,5-diaryl-1,4-pentadiene-3-ones were allowed to react with substituted benzylamines in the presence of [(dippe)Ni(μ-H)]₂ (dippe = 1,2-bis-(diisopropylphosphino)-ethane) using ethanol as a solvent at 180 °C to give the corresponding saturated carbonyl compounds; here hydrogenation of the CC bond was preferred over the CO bond. Under the same reaction conditions but using an excess of benzylamine, a tandem process is then favoured, starting also with the reduction of the CC bond followed by a nucleophilic addition of the primary amine to yield valuable saturated imines with good to excellent yields (62%-91%).

Full text of DOI:10.1039/c5dt02366a

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Tandem Hydrogenation and Condensation of Fluorinated
α,β-Unsaturated Ketones With Primary Amines,
Catalyzed by Nickel
Nahury CastellanosꢀBlanco, Marcos FloresꢀAlamo and Juventino J. García*
Facultad de Química, Universidad Nacional Autónoma de México, Circuito Interior, Ciudad
Universitaria, Mexico City 04510, Mexico.
juvent@unam.mx
Keywords: α,βꢀunsaturated ketones / Fluorinated/ primary amines / nickel / transfer
hydrogenation / condensation / tandem.
ABSTRACT
A simple homogeneous catalytic system based on nickel phosphine complexes has been
developed for the transfer hydrogenation and condensation of α,βꢀunsaturated ketones to yield
saturated ones and saturated imines using primary amines as hydrogen donors. Thus, a wide
range of fluorinated 1,5ꢀdiarylꢀ1,4ꢀpentadieneꢀ3ꢀones were allowed to react with substituted
benzylamines in the presence of the [(dippe)Ni(ꢀꢀH)]2 (dippe = 1,2ꢀbisꢀ(diisopropylphosphino)ꢀ
ethane) using ethanol as solvent at 180 ºC to give the corresponding saturated carbonyl
compounds, here hydrogenation of the C=C bond was preferred over the C=O bond. In the same
reaction conditions but using an excess of benzylamine a tandem process is then favoured,
starting also with the reduction of the C=C bond followed by a nucleophilic adidition of the
primary amine to yield valuable saturated imines with good to excellent yields (62 % ꢀ 91 %).
1

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INTRODUCTION
The transfer hydrogenation of α,βꢀenones is an important chemical transformation since these
enones can be prepared by simple procedures1 and the corresponding products from
hydrogenation, such as saturated ketones, are of importance in the manufacture of value added
chemicals for pharmaceuticals and fragrance industry.2 The selective reduction of a carbonyl
group in α,βꢀunsaturated compounds has been reported.3 However, the transfer hydrogenation of
the C=C bond in enones is relatively scarce.4 The α,βꢀunsaturated ketones are widely used as
substrates for a number of reactions, such as hydrogenation,5 conjugate addition,6 alkylation,7
boration,8 and epoxidation.9 Specifically, 1,5ꢀdiarylꢀ1,4ꢀpentadieneꢀ3ꢀones and their analogs can
be applied in biochemistry since these compounds have a conjugate system that is expected to be
easily oxidized. Their general synthesis essentially involve an aldol condensation of the
appropriate aromatic aldehyde with acetone in an alkaline medium at room temperature.1a
Accordingly, 1,5ꢀdiarylꢀ1,4ꢀpentadieneꢀ3ꢀones are easily available either by isolation from
natural products or by methods of classical organic synthesis.1aꢀ1e Transfer hydrogenation of α,βꢀ
unsaturated ketones has been widely studied with a variety of different reducing agents. For
example, the use of silanes,10 alcohols,11 water,12 NaBH4,13 and Hantzsch esters14 can promote
reduction of α,βꢀunsaturated carbonyl compounds. However, although amines are one of the
most versatile and inexpensive reagents in organic synthesis, relatively little attention has been
paid to these compounds as hydrogen transfer reagents, and very few examples using amines in
this type of reaction have been reported.15ꢀ16 In 2011, Nakajima and coꢀworkers demonstrated
that the combination of bulky tertiary amines and trichlorosilyl triflate reduced α,βꢀunsaturated
ketones to yield the corresponding saturated ketones in good yields.15a However, the conversion
of 1,5ꢀdiarylꢀ1,4ꢀpentadieneꢀ3ꢀones substrates only provided partially reduced products in good
2

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yields. Some other hydrogen transfer reagents containing NꢀH groups such as lithium amide,
imidazoline, and thiazoline have been investigated in similar reduction reactions.17ꢀ19 On the
other hand, the conjugate reduction of α,βꢀunsaturated ketones using tosylhydrazine as a
hydrogen source has also been investigated.20 More recently, Chen et al. developed a reduction
of chalcones to dihydrochalcones using tosylhydrazine as a hydrogen source.20 This method does
not require the use of transition metal; however, stoichiometric amounts of base (K2CO3) were
used. Normally, the reaction between amines with α,βꢀunsaturated ketones resulted in α,βꢀ
unsaturated imines (1,2ꢀaddition of an amine to the corresponding carbonyl compound) or the
competitive 1,4ꢀaddition product (Michael Addition).21 Despite numerous studies on that
chemistry, the reduction reaction of such enones using amines as hydrogen source has been
scarcely studied. We envisaged the transfer hydrogenation from amines to α,βꢀenones as a
feasible method of hydrogenation to yield saturated ketones and then with the use of additional
amounts of amine to produce the corresponding saturated imines.22 This tandem process requires
of easily available starting materials and the produced saturated imines may be useful in the
synthesis of anticancer and antiꢀinflammatory drugs, as well as in the preparation of building
blocks for not naturally occurring α,βꢀamino acids.23
Transition metal catalyzed transfer hydrogenation of α,βꢀunsaturated ketones has attracted
attention, and several reports have documented the use of organometallic complexes containing
metals such as cobalt,24 copper,25 iridium,26 palladium,27 rhodium,28 ruthenium,29 and nickel 30 as
catalysts in this type of reaction. Some of them present good regioꢀselectivity; for instance,
palladium and rhodium were selective for the reduction of the C=C bonds of enones to yield
saturated carbonyl compounds, and metals such as cooper and cobalt are particularly selective
for carbonyl reduction (1,2ꢀaddition) to give allylic alcohols.31 Recently, we reported the
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synthesis and structure of the nickel complexes [{(dippe)Ni}n(η2ꢀC
α,Cβꢀenone)] (dippe = 1,2ꢀ
bis(diꢀisopropylphosphino)ꢀethane); n = 1,2; enone:1,5ꢀdiarylꢀ1,4ꢀpentadieneꢀ3ꢀones using
complex ([(dippe)Ni(ꢀꢀH)]2) with all of them containing symmetrical dienones, which were
found to be an effective catalyst for the transfer hydrogenation and alkylation of α,βꢀunsaturated
ketones that allow the selective reduction of C=C bonds and methanol which act as hydrogen
donor and alkylating agent.7a Furthermore, our group recently disclosed the semihydrogenation
and hydroamination of diphenylacetylene and 2ꢀethynylaniline using primary amines and
aromatic Nꢀheterocycles as hydrogen sources catalyzed by ([(dippe)Ni(ꢀꢀH)]2).16b These findings
prompted us to assess the activity of primary amines in the transfer hydrogenation of α,βꢀ
unsaturated ketones using a nickel catalyst to achieve this transformation. Herein, we report the
reactivity of fluorinated 1,5ꢀdiarylꢀ1,4ꢀpentadieneꢀ3ꢀones with [(dippe)Ni(ꢀꢀH)]2, which gives
compounds of the type [{(PꢀP)Ni}n(η2ꢀC
α,Cβꢀenone)] (PꢀP = bidentate phosphine ligand), and
the catalytic activity of such compounds in the hydrogenation and subsequent condensation of
α,βꢀunsaturated ketones using primary amines as hydrogen donors. A variety of substituents in
the ortho and para position for the aryl ring were used to investigate the influence of steric and
electronic effects in this tandem process.
2. RESULTS AND DISCUSSION
2.1. Reactivity of Symmetrical Enones with [(dippe)Ni(ꢀ-H)]2
The reactivity of [(dippe)Ni(ꢀꢀH)]2 (dippe = 1,2ꢀbis(diisopropylphosphino)ethane) (2) in the
presence of symmetrical enones was previously explored in our group (vide supra).7a In order to
extend the scope of these results, particularly using aryl rings with orthoꢀCF3 and paraꢀF, i.e., to
assess the reactivity of (2) in the presence of α,βꢀunsaturated enones containing electron
4

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withdrawing groups in the aryl ring. In all cases, the reaction at room temperature of the nickel
dimer with fluoroꢀenones (1a, C19H12F6O = 1,5ꢀbis (2ꢀ(trifluoromethyl) phenyl) pentaꢀ1,4ꢀdienꢀ
3ꢀone and 1b, C17H12F2O = 1,5ꢀbis(4ꢀfluorophenyl)ꢀpentaꢀ1,4ꢀdienꢀ3ꢀone) in THFꢀd8 was fast
and exhibited a color change from wine red to brown along with evolution of H2 (Scheme 1).
The isolated products contain two η2ꢀcoordinated (dippe)Ni(0) moieties for each ligand to the
C
α,C
β
ꢀ at the enone that were similar to those previously reported with nickel and palladium.7a, 32
Scheme 1. Reactivity 1a and 1b with 2.
As depicted in Scheme 1, dinuclear complexes 2a-2b were obtained as the main products on
using 1 equiv of enone and 1 equiv of 2. Nickel complexes 2a-2b were fully characterized by
NMR, Xꢀray crystallography, and EI+ꢀMS (see the Experimental Section). Complexes 2a-2b
typically display two broad doublet of doublets between 74ꢀ68 ppm with PꢀP coupling constants
in the range of 51ꢀ57 Hz in their 31P{1H}NMR spectra. The 2JPꢀP value is indicative of P bound
to a Ni(0) center and is in agreement with a η2ꢀcoordinated ꢀC
α,C
β
ꢀenone.7a In the 13C{1H} NMR
,C in 2a-2b were assigned in
spectrum, the corresponding signals for the coordinated carbons C
α
β
the range of 60ꢀ45 ppm (the corresponding signals for the free ligand 1a-1b were observed as
singlets in the region of δ 142ꢀ130) with 2JC ꢀP = 15 Hz and 2JC ꢀP = 15 Hz. The carbonyl signal in
β
α
both compounds 2a-2b are shifted to low field relative to the signals for the free enones 1a-1b
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( δ 189ꢀ188) and showed singlets in the range of 194 to 192 ppm. The 1H NMR spectrum for the
dinuclear complexes 2a-2b showed the signals for the η2ꢀC
α, Cβ olefinic protons shifted to high
field in the range of 4.4 ꢀ 4.2 ppm, while the olefinic protons of free enones typically resonate
between 8.1 and 7.0 ppm.
A thermolysis consisting of increasing the temperature from 25 to 100 ºC for 7 days and
monitoring complex 2a in THFꢀd8 shows the signals assigned to the original binuclear complex
and a singlet assigned to [(dippe)2Ni], δ 51.9, and light formation of metallic nickel (Scheme 2).
Compound 2a was also characterized in the solid state using singleꢀcrystal Xꢀray
crystallography. The ORTEP representation of complex 2a (Figure 1) confirmed the double
nickel coordination to the enone moiety in a η2ꢀC
α
,C way The CꢀC bond length of the olefin in
β
the unsaturated ketone is enlarged by 0.115 Å upon coordination in compound 2a (1.445 Å)
relative to the free ligand (1.330 Å). The C(15)ꢀC(16) and C(18)ꢀC(19) bond distances and the
C(15)ꢀNiꢀC(16) and C(18)ꢀNiꢀC(19) bond angles of the 1,5ꢀbis(2ꢀ(trifluoromethyl)phenyl)pentaꢀ
1,4ꢀdienꢀ3ꢀone ligand are similar to those observed previously in the [(dippe)2Ni(η2ꢀ(C
DBA)] complex.7a The two metal moieties [(dippe)Ni(0)] are arranged in a mutually trans
α,Cβꢀ
position with respect to the plane of ligand; each nickel center has a slightly distorted trigonalꢀ
planar geometry. An ORTEP representation of compound 2b is included in the Supporting
Information (See Figure S19). The planarity of the η2ꢀC
α,Cβ−1,5ꢀbis (2ꢀ(trifluoromethyl) phenyl)
pentaꢀ1,4ꢀdienꢀ3ꢀone ligand is significantly affected by the coordination to nickel(0) atoms. In
the supramolecular network, the intermolecular contacts of the van der Waals type F⋅⋅⋅H−C with
2
1
R2 (6) motif for C13−F(3)⋅⋅⋅H(46B)−C46−H(46A)⋅⋅⋅F(2), D1 (7) motif for C3−H3⋅⋅⋅F(1) and
1
D1 (10) H(25B)⋅⋅⋅F(5)−C14 mainly lead to infinite chains aligned with a axis.
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Figure 1. ORTEP drawing of 2a, [{(dippe)Ni}2(η2ꢀCα ,Cβ –C19H12F6O)], showing 50%
probability ellipsoids. Selected bond distances (Å): C(19)ꢀC(18) 1.445(3), C(18)ꢀC(17) 1.475(3),
C(17)ꢀC(16) 1.477(3), C(16)ꢀC(15) 1.437(3), C(15)ꢀNi(2) 1.9860(19), Ni(2)ꢀP(3) 2.1554(6),
Ni(1)ꢀC(19) 1.9933(19) Ni(1)ꢀP(2) 2.1644(6). Selected bond angles (deg): C(16)ꢀNi(2)ꢀP(4)
112.08(6), C(16)ꢀNi(2)ꢀC(15) 42.54(8), P(4)ꢀNi(2)ꢀP(3) 91.96(2), C(15)ꢀNi(2)ꢀP(3) 112.91(6),
C(19)ꢀNi(1)ꢀP(2) 117.02(6), C(19)ꢀNi(1)ꢀC(18) 42.75(8), C(18)ꢀNi(1)ꢀP(1) 108.93(6), P(2)ꢀ
Ni(1)ꢀP(1) 91.44(2).
On the other hand, the reaction of complex 2 with fluorinated enones 1a-1b in a 0.5:1 ratio
dimerꢀtoꢀenone at room temperature (RT) resulted in the formation of mononuclear complexes
3a-3b. However, the dinuclear complexes 2a-2b were still observed at RT. The use of Tolꢀd8
instead of THFꢀd8 allowed reaching a higher temperature to yield the mononuclear complexes
3a-3b heating at 130 ºC for 15 hours (Scheme 2).
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Scheme 2. Formation of monoꢀ and binuclear [(dippe)Ni(η2ꢀC
α,Cβꢀ1,4ꢀpentadieneꢀ3ꢀone)]
complexes.
The 1H NMR spectra for the monometallic complexes 3a-3b displayed signals shifted to high
field assigned to the two protons in the η2ꢀC
=C coordination and displayed two doublets in the
α
β
region of 6.3 ppm and 5.5 ppm with 2JHꢀP of 15 Hz. The 31P{1H} NMR spectra displayed two
doublets located between δ = 75 ꢀ 68 with PꢀP coupling constants of 39 Hz, which is consistent
with two nonꢀequivalent phosphorous coordinated to a Ni(0). Single crystals for 3a were
obtained by cooling a Tolueneꢀd8 solution to ꢀ26 ºC. The corresponding ORTEP diagram of the
mononuclear complex 3a is shown in Figure 2.
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Figure 2. ORTEP drawing of 3a, [(dippe)Ni(η2ꢀCα ,Cβ –C19H12F6O)], showing 50% probability
ellipsoids. Selected bond distances (Å): C(25)ꢀC(24) 1.330(6), C(22)ꢀC(21) 1.421(5), C(22)ꢀ
Ni(1) 1.984(4), Ni(1)ꢀP(1) 2.1743(14), C(21)ꢀNi(1) 2.027(4), Ni(1)ꢀP(2) 2.1548(13). Selected
bond angles (deg): C(22)ꢀNi(1)ꢀP(1) 119.39(12), C(22)ꢀNi(1)ꢀC(21) 41.48(16), C(21)ꢀNi(1)ꢀP(2)
107.52(12), P(1)ꢀNi(1)ꢀP(2) 91.72(5).
As expected, the structure confirms a lengthening of the η2ꢀcoordinated C
α=Cβ bond (1.421(5)
Å) due to coordination to nickel compared with the free ligand C =C bond (1.330(6) Å) and
α
β
turns out to be intermediate between a typical C=C double bond (1.32 Å) and a single bond (1.54
Å).33
2.2. Catalytic Transfer Hydrogenation of Symmetrical Enones using Amines as Hydrogen
Donors
Considering the potential formation of dinuclear 2a and mononuclear 3a compounds in the
reaction of 1a with 2, the transfer hydrogenation process was initially investigated using a
variety of aliphatic amines. Thus, the treatment of 1a with catalytic amount of 2 with an excess
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of amine in toluene at 180 ºC for 48 h yielded the reduction products 3 and 4. This and other
selected results are summarized in Table 1. Compound 3 was obtained in low yield (14 %, entry
2) with the use of nꢀbutylamine. That yield was improved by using benzylamine (32 %, entry 4).
Additionally, with the use of benzylamine, a product derived from a dehydrogenationꢀ
transamination process was also produced (SI section, Figure S23).16b, 34 The condensation
products 5-7 were also produced (entries 1ꢀ4). Generally, α,βꢀunsaturated imines are prepared by
1,2ꢀaddition of an amine to the analogous α,βꢀunsaturated carbonyl compound. It is noteworthy
that high amounts of saturated imine 7 were obtained (53 %, entry 4). The formation of saturated
imine 7 produced by this method has been relatively unexplored.21, 24b
A complete conversion of the starting material with the use of cyclohexylamine and benzylamine
was achieved (entries 3ꢀ4) but only with moderate selectivity. Therefore, we decided to
investigate the effect of solvents and other reaction conditions in this tandem process and to
extend the scope to other α,βꢀunsaturated ketones.
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Table 1. Reduction of 1a by [(dippe)Ni(ꢀ-H)]2 Using Amines a
Yield (%) b
Conv 1a
Entry
Amine
(%)
3
4
5
6
7
1
61
21
ꢀ
ꢀ
8
32
2
3
4
74
42
ꢀ
14
22
32
18
10
ꢀ
ꢀ
ꢀ
100
100
35
33
ꢀ
15
53
a Reaction Conditions: 1a (0.15 mmol), Amine (1.5 mmol), 2 (1 mg, 1.55*10ꢀ3 mmol), toluene
(3 mL), 180 ºC, 48 h. b All yields were measured by GCꢀMS.
The effect of the solvent and amount of benzylamine were assessed; the main results for these
experiments are summarized in Table 2. As shown, initial studies were carried out at 180 ºC, 48
h, and using 1 mol % of catalytic precursor 2. All reactions produced the saturated imine 7 in low
to high yields (5% to 80 %, entries 1ꢀ8) along with low yields of saturated ketone 4 (9 % to 32
%, entries 1ꢀ8). Toluene was again a useful solvent for the hydrogenation and condensation of
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enone 1a; however, we found that decreasing the amounts of benzylamine to 100 equivalents in
Toluene produced a low yield of saturated products (entry 1). When the amounts of benzylamine
were increased to 500 equivalents (entry 2), a better yield of saturated imine 7 was produced (68
%, entry 2). Note that the catalytic conversion and yield of saturated products are enhanced with
a more polar solvent such as ethanol (entry 5) to produce 7 in a good yield (80 %, entry 5).
Nevertheless, the yield of saturated product 7 decreases dramatically when increasing the amount
of amine (22 %, entry 6) probably due to coordination of this amine to nickel.35 Additionally, the
use of alcohols as a hydrogen source for the reduction of α,βꢀunsaturated enones is well known11
where they are oxidized to the corresponding aldehydes.7a In these experiments, the crude was
analyzed by 1H NMR and GCꢀMS, acetaldehyde was not detected.
Thus, ethanol was chosen as the optimal solvent since the reaction in this solvent led to complete
conversion in 48 h and exhibited an improved selectivity of 7 (80 %, entry 5). Other solvents,
(e.g., THF, water, or neat benzylamine) proved to be less efficient in this reaction (entries 3, 4
and 8); under these conditions, the products 4ꢀ7 were obtained in low yields.
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Table 2. Optimization of Reaction Conditions in Reduction and Condensation of Enone 1a
with Benzylamine a
Yield (%) b
6
Equivalents
Amine
Conv 1a d
(%)
Entry
Solvent
4
7
1
Toluene
Toluene
THF
100
500
14
9
ꢀ
21
ꢀ
5
2
100
100
94
11
ꢀ
68
33
16
80
22
53
29
3
500
4
Water
500
25
14
13
32
ꢀ
ꢀ
5
Ethanol
Ethanol
Toluene
Neat
500
100
100
100
100
6
6
1000
1000
10000
10
15
8
7
8 c
a
Reaction Conditions: 1a (0.15 mmol), 2 (1 mg, 1.55*10ꢀ3 mmol), Solvent. (3 mL), 180 ºC, 48
h. b All yields were measured by GCꢀMS. c Benzylamine (2 mL). d Complete conversion of 1a is
calculated by summing 4, 6, 7 and additional product 5 (α,βꢀunsaturated imine).
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We further investigated the formation of saturated products to understand the relative rates and
selectivity of saturated ketone 4 vs. saturated imine 7 (Table 3). Simple reaction time monitoring
proved to be useful for this purpose (Table 3, entries 1ꢀ3). Formation of the saturated ketone
reached a maximum within 36 h (45%, entry 2); at this time, the saturated imine formation is low
(17%, entry 2). At 48 h, the conversion of 1a was complete, but the yield of 4 was significantly
reduced (14%, entry 3), while the yield of saturated imine 7 was increased to 80% (entry 3).
Therefore, we propose that 1a was reduced first to produce 4 by benzylamine acting as hydrogen
source, and subsequently the condensation of 4 was carried out to yield the saturated imine 7.
Table 3. Monitoring Saturated Products Formation: Effect of the Time Reaction a
Yield (%) b
Conv 1a
Entry
Time (h)
(%)
3
4
5
6
7
1
2
24
36
48
97
15
37
19
5
21
100
100
ꢀ
ꢀ
45
14
26
ꢀ
12
6
17
80
3c
a
Reaction Conditions: 1a (0.15 mmol), Benzylamine (0.77 mmol), 2 (1 mg, 1.55*10ꢀ3 mmol), ethanol
b
c
(3 mL), 180 ºC. All yields were measured by GCꢀMS. Mercuryꢀdrop test using the same reaction
conditions resulted in no inhibition.
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With the optimized conditions at hand, we next assessed the use of other substituted α,βꢀenones
having a variety of different substituents. α,β−Enones were prepared by the reported
procedures1aꢀ1e and selected NMR and GCꢀMS for each substrate are available in the SI Section.
The reactivity shown by these substrates in the transfer hydrogenation is summarized in Table 4.
All of them achieve total conversion but with different selectivity. For instance, oꢀsubstituted
derivatives exhibit a better yield in the transfer hydrogenation and condensation tandem
processes to yield the saturated imine 7 with moderate to good yields (62 % ꢀ 91 %) (entries 1, 3,
5ꢀ8, Table 4). The products derived only from a transfer hydrogenation process to yield the
saturated ketones were particularly favored having enones bearing the electroꢀdonating group (1i
and 1j) CH3 and OCH3 at the para position (Entries 9ꢀ10). Note that the reaction of DBA (1h)
with benzylamine and catalytic amounts of [(dippe)Ni(ꢀꢀH)]2 yield the corresponding saturated
imine 7 in high yield 91 %.
Table 4. Substrate Scope for the Transfer Hydrogenation and Condensation of Enones a
Yield (%) b
Conv 1 c
(%)
Entry
Substrate
R1
4
7
1
2
3
oꢀCF3
pꢀF
100
100
100
14
80
1a
1b
1c
36
32
40
68
oꢀF
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4
5
pꢀCF3
oꢀCH3
oꢀOCH3
oꢀBr
100
100
100
100
100
100
100
25
38
36
21
8
36
62
64
78
91
48
10
1d
1e
1f
6
7
1g
1h
1i
8
H
9
pꢀCH3
pꢀOCH3
51
90
10
1j
a
Reaction Conditions: 1a (0.15 mmol), Benzylamine (0.77 mmol), 2 (1 mg, 1.55*10ꢀ3
b
c
mmol), ethanol (3 mL), 180 ºC, 48 h. All yields were measured by GCꢀMS. Complete
conversion of 1(a-j) is calculated by summing 4, 7 and additional product 5 (α,βꢀ
unsaturated imine).
The effect of the ancillary ligand in the activity and selectivity of this tandem process was
assessed (see Table 5). In general, the use of bidentated σꢀdonor ligands allowed to
selectively producing 7 (entries 1ꢀ4); however, the steric hindrance of the terbutyl and
cyclohexyl groups does not compete in terms of selectivity with isopropyl groups.
Interestingly, when the reaction was carried out without a catalytic precursor, the product 7
was produced in very poor yield and with low conversion of the starting material (entry 7).
Thus, a tandem hydrogenation and condensation of α,βꢀenone 1h with benzylamine was
successfully achieved with [(dippe)Ni(ꢀꢀH)]2.
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Table 5. Ancillary Ligand Screening a
Ligand
(P-P)
Conv 1h c
(%)
Yield (%) b
7
Entry
Catalytic Precursor
4
1
2
3
4
5
6
7
None
None
None
None
dppe
100
100
100
100
100
100
51
9
91
55
63
65
51
11
20
[(dippe)Ni(ꢀꢀH)]2
[(dcype)Ni(ꢀꢀH)]2
[(dtbpe)Ni(ꢀꢀH)]2
[(dippe)NiCl2]
Ni (COD)2
45
27
35
34
19
ꢀ
Ni (COD)2
dippe
None
None
a
Reaction Conditions: 1a (0.15 mmol) , Benzylamine (0.77 mmol), Cat. Prec. (1 mol %), Ligand (3
mol %), ethanol (3 mL), 180 ºC, 48 h. b All yields were measured by GCꢀMS. c Complete conversion of
1h is calculated by summing 4, 7 and additional product 5 (α,βꢀunsaturated imine).
Since benzylamines turned out to be the useful reagents in the transfer hydrogenation (Table 1),
we decided to use a variety of monoꢀsubstituted benzylamines including electronꢀdonating and
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electronꢀwithdrawing groups using the optimized reaction conditions (500 equiv of amine, 100
equiv of 1a, 1 mol % of 2 in ethanol at 180 ºC). The main results are summarized on Table 6. As
expected, benzylamine produced 7 in good yield (80 %, entry 1). Using orthoꢀsubstituted
benzylamines (entries 2ꢀ5), the reaction afforded the desired products 4 and 7 with high yields
(54 % to 86 %). Unfortunately, the use of paraꢀsubstituted benzylamines (entries 6ꢀ8) gave poor
product selectivity. A mechanistic proposal for this process is presented in the SI section.
Table 6. Scope of Amines in Transfer Hydrogenation and Condensation of 1a a
Yield (%) b
Conv 1a c
(%)
Entry
R2
4
7
1
2
3
4
5
C6H5
100
100
100
100
100
14
80
oꢀOCH3ꢀC6H4
oꢀCH3ꢀC6H4
oꢀCF3ꢀC6H4
oꢀFꢀC6H4
24
45
13
43
76
54
86
57
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6
7
8
pꢀCH3ꢀC6H4
pꢀFꢀC6H4
100
100
100
13
55
10
14
19
7
pꢀCF3ꢀC6H4
a
Reaction Conditions: 1a (0.15 mmol), Benzylamines (0.77 mmol), 2 (1 mg, 1.55*10ꢀ3 mmol),
b
c
ethanol (3 mL), 180 ºC, 48 h. All yields were measured by GCꢀMS. Complete conversion of
1a is calculated by summing 4, 7 and additional product 5 (the corresponding α,βꢀunsaturated
imine).
2.3. Catalytic Proposal.
A mechanistic proposal for this tandem process is illustrated in Scheme 3, to explain the initial
transfer hydrogenation of α,βꢀEnones to the corresponding saturated ketones and subsequent
condensation with primary benzylamines we propose an initial step reacting the corresponding
dienones 1(a-j) with 2 to yield the complex A. Dinuclear complex A can be converted to active
catalyst B by heating via the sequence showed in Scheme 2, followed by the oxidative addition
of benzylamines (a-g) and hydride transfer to nickel complex B to give intermediate C. Then a
hydride addition to the βꢀposition produce species D.
nickel
D undergo βꢀ
hydride elimination to produce imine formation (I) and enolization to produce E. It is known
that, an amine, once oxidized to the imine by hydrogen transfer, reacts with another equivalent of
the substrate amine obtaining a transamination product with liberation of ammonia.34 In the
mechanism, one equivalent imine I or II. The resulting Niꢀenolate E underwent hydride addition
to αꢀposition in α,βꢀunsaturated ketones and followed by a reductive elimination to give the
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corresponding nickelꢀenone complex F. The secondary transfer hydrogenation occurs in the
same way to initial steps C to E followed by a reductive elimination to give saturated ketone.
The 1,2ꢀaddition of benzylamines to saturated ketones gave the corresponding saturated imines.
Scheme 3. Proposed Catalytic Cycle
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3. CONCLUSION
We have demonstrated that [(dippe)Ni(ꢀꢀH)]2 (2) was an effective catalytic precursor for the
transfer hydrogenation of α,βꢀunsaturated ketones using benzylꢀ amines as hydrogen donors to
afford saturated ketones in low to moderate yields. Furthermore, the 1,2ꢀaddition of
benzylamines to the produced saturated ketones allowed the formation of saturated imines in
good to excellent yields in a tandem process. These features, along with the tolerance to a variety
of ortho and para substituents in aromatic enones and benzylamines, extends the scope of the
current method to the synthesis of saturated imines.
4. EXPERIMENTAL SECTION
Unless otherwise noted, all manipulations were performed using standard Schlenk techniques in
an inertꢀgas/vacuum double manifold or under an argon atmosphere (Praxair 99.998) in an
MBraun glovebox (<1 ppm H2O and O2). All liquid reagents were purchased as reagent grade
and were degassed before use. The α,βꢀUnsaturated ketones 1h-1j were purchased from Aldrich
and were stored in a glovebox for their further use. Compounds 1a-1g were prepared by an aldol
condensation, following the method of Masuda et al.1a The nickel (I) complexes, [(PꢀP)Ni(ꢀꢀH)]2
(PꢀP = chelating phosphine ligand), were prepared from a nꢀhexane slurry of [(PꢀP)NiCl2]36a
using SuperꢀHydride (LiHBEt3), according to the reported procedure. 36b The solvents were dried
using standard techniques and stored in the glovebox before use. Deuterated solvents were
purchased from Cambridge Isotope Laboratories and were stored under 4 Å molecular sieves for
24 h before use. NMR spectra were recorded at room temperature on a 300 MHz Varian Unity
spectrometer unless otherwise noted. 1H NMR spectra (δ parts per million) are reported relative
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to the residual protioꢀsolvent. 13C{1H} spectra give the characteristic carbon signal of each
solvent. 31P{1H} NMR chemical shifts (δ parts per million) are reported relatively to external
85% H3PO4. 19F NMR chemical shifts (δ parts per million) are reported relatively to external
trifluoroacetic acid. Coupling constants (J values) are given in Hz. GCꢀMS determinations were
performed using an Agilent Technologies G3171A equipped with a column: 5 %
1
phenylmethylsilicone, 30 m * .25 mm * .25 ꢀm. H and 13C{1H} NMR spectra of the reduction
products were obtained in CDCl3. An Oxford Diffraction Gemini “A” diffractometer with CCD
area detector (λMo Kα = 0.71073 Å) was used for Xꢀray structure determinations. Catalytic
experiments were carried out in a 100 mL stainless steel Parr, T315SS reactor. Elemental
analyses (EAs) were also performed by USAIꢀUNAM using a PerkinElmer microanalizer 2400.
EAs of pure compounds showed variable inconsistencies due to their high oxygen sensitivity and
were not reported; however, all of them display satisfactory MSꢀEI+. Mass spectrometry
determinations (MSꢀEI+) of pure compounds were performed by USAIꢀUNAM using a Thermoꢀ
Electron DFS.
4.1. Preparation [{(dippe)Ni}2(η2-C
α,Cβ-C19H12F6O)] (2a): The reaction of C19H12F6O = 1,5ꢀ
bis(2ꢀ(trifluoromethyl)phenyl)pentaꢀ1,4ꢀdienꢀ3ꢀone 1a (0.081 mmol, 0.030 g) with [(dippe)Ni(ꢀꢀ
H)]2 2 (0.081 mmol, 0.0521 g) in THFꢀd8 (1mL) yielded dinuclear Ni(0) complex
[{(dippe)Ni}2(η2ꢀC
α,CβꢀC19H12F6O)] (2a). Immediate effervescence due to reductive elimination
of H2 was observed during mixing. The resulting solution was analyzed by NMR spectroscopy:
1H NMR (300 MHz, THFꢀd8, r.t.): δ = 7.36 (d, J HꢀH = 9 Hz, H(f), H(f’), aromatic), 7.22 (d, J HꢀH
= 9 Hz, H(c), H(c’), aromatic), 7.12 (t, J HꢀH = 9 Hz, H(d), H(d’), aromatic), 6.87 (t, J HꢀH = 9 Hz,
H(e), H(e’), aromatic), 4.44 (m, J HꢀP = 6 Hz, H(b), H(b’), CHꢀolefinic), 4.31 (m, J HꢀP = 6 Hz,
H(a), H(a’), CHꢀolefinic), 2.5ꢀ0.5 (m, iPr CH, CH2, CH3). 31P{1H} NMR (121.32 MHz, THFꢀd8,
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r.t.): δ = 74.0 (dd, J PꢀP = 51 Hz, J CꢀP = 7.27 Hz), 69.0 (dd, J PꢀP = 51 Hz, J CꢀP = 7.27 Hz).
13C{1H} NMR (75.36 MHz, THFꢀd8, r.t.): δ = 193.4 (s, C(a), C=O), 150.4 (s, C(d), C(d’), Cꢀ
aromatic), 132.5 (s, C(f), C(f’), CHꢀaromatic), 132.2 (s, C(g), C(g’), CHꢀaromatic), 131.3 (s,
C(e), C(e’), CHꢀaromatic), 120.8 (t, J CꢀF = 30.89 Hz, C(i), C(i’), Cꢀaromatic), 150.4 (quadruplet,
J CꢀF = 5.27 Hz, C(h), C(h’), CHꢀaromatic), 115.76 (t, J CꢀF = 274.3 Hz, C(j), C(j’), CF3ꢀ
aromatic), 62.4 (d, J CꢀP = 15 Hz, C(c), C(c’), CHꢀolefinic), 44.6 (d, J CꢀP = 15 Hz, C(b), C(b’),
CHꢀolefinic), 30.0 – 17.0 (m, iPr, CH, CH2, CH3). 19F NMR (282 MHz, THFꢀd8, r.t.): δ = ꢀ60.2
(s, F(a), CF3ꢀaromatic) [MSꢀEI+, m/z (%) 1011 (15%)]. Suitable crystals for singleꢀcrystal Xꢀray
studies for compound 2a were grown from a concentrate solution in THFꢀd8 at ꢀ30 ºC.
4.2. Preparation [{(dippe)Ni}2(η2-C
α,Cβ-C17H12F2O)] (2b): Similar to the preparation of
compound 2a (vide supra), the reaction between C17H12F2O = 1,5ꢀbis(4ꢀfluorophenyl)pentaꢀ1,4ꢀ
dienꢀ3ꢀone 1b (0.199 mmol, 0.054 g) and [(dippe)Ni(ꢀꢀH)]2 2 (0.199 mmol, 0.0128 g) in THFꢀd8
(1mL) yielded dinuclear Ni(0) complex [{(dippe)Ni}2(η2ꢀC
α,CβꢀC17H12F2O)] (2b). Immediate
effervescence due to reductive elimination of H2 was observed during mixing. The resulting
solution was analyzed by NMR spectroscopy: (300 MHz, THFꢀd8, r.t.): δ = 7.10 (t, J HꢀH = 6 Hz,
H(c), H(c’), aromatic), 6.75 (t, J HꢀH = 9 Hz, H(d), H(d’), aromatic), 4.41 (d, J HꢀP = 12 Hz, H(b),
H(b’), CHꢀolefinic), 4.30 (d, J HꢀP = 15 Hz, H(a), H(a’), CHꢀolefinic), 2.4ꢀ0.1 (m, iPr CH, CH2,
CH3). 31P{1H} NMR (121.32 MHz, THFꢀd8, r.t.): δ = 72.6 (dd, J PꢀP = 57 Hz, J CꢀP = 8.49 Hz),
71.2 (dd, J PꢀP = 57 Hz, J CꢀP = 8.49 Hz). 13C{1H} NMR (75.36 MHz, THFꢀd8, r.t.): δ = 190.56 (s,
C(a), 13C=O), 146.46 (s, C(g), Cꢀaromatic), 130.88 (s, C(d), C(d’), CHꢀaromatic), 126.22 (s,
C(e), C(e’), CHꢀaromatic), 115.53 (s, C(f), C(f’), CHꢀaromatic), 60.66 (d, J CꢀP = 12.8 Hz, C(c),
C(c’), CHꢀolefinic), 49.18 (d, J CꢀP = 20.34 Hz, C(b), C(b’), CHꢀolefinic), 30.0 – 15.0 (m, iPr,
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CH, CH2, CH3). 19F NMR (282 MHz, THFꢀd8, r.t.): δ = ꢀ124.28 (s, F(a), Fꢀaromatic) [MSꢀEI+,
m/z (%) 911 (10%)]. Slow evaporation of THFꢀd8 at ꢀ26 ºC in the drybox allowed the
crystallization of the pure product.
4.3. Preparation [(dippe)Ni(η2-C
α,Cβ-C19H12F6O)] (3a): The reaction of C19H12F6O = 1,5ꢀ
bis(2ꢀ(trifluoromethyl)phenyl)pentaꢀ1,4ꢀdienꢀ3ꢀone 1a (0.081 mmol, 0.030 g) with [(dippe)Ni(ꢀꢀ
H)]2 2 (0.0405 mmol, 0.0261 g) in THFꢀd8 (1mL) yielded mononuclear Ni(0) complex
[{(dippe)Ni}(η2ꢀC
α,CβꢀC19H12F6O)] (2b). Immediate effervescence due to reductive elimination
of H2 was observed during mixing. The resulting solution was analyzed by NMR spectroscopy:
(300 MHz, THFꢀd8, r.t.): δ = 7.65 (d, J HꢀH = 6 Hz, H(f), H(f’), aromatic), 7.57 (d, J HꢀH = 6 Hz,
H(c), H(c’), aromatic), 7.42 (t, J HꢀH = 9 Hz, H(d), H(d’), aromatic), 7.26 (t, J HꢀH = 9 Hz, H(e),
H(e’), aromatic), 6.13 (d, J HꢀP = 15 Hz, H(b), H(b’), CHꢀolefinic), 5.71 (d, J HꢀP = 12 Hz, H(a),
H(a’), CHꢀolefinic), 2.5ꢀ0.1 (m, iPr CH, CH2, CH3). 31P{1H} NMR (121.32 MHz, Tolꢀd8, r.t.): δ
= 75.0 (d, J PꢀP = 39 Hz), 73.5 (d, J PꢀP = 39 Hz). [MSꢀEI+, m/z (%) 690 (10%)]. Crystals of 3a
were obtained from Tolꢀd8 at ꢀ26 ºC in the drybox and allowed the crystallization of the pure
product.
4.4. Preparation [(dippe)Ni(η2-C
α,Cβ-C17H12F2O)] (3b). Similar to the preparation of
compound 2b (vide supra), the reaction between C17H12F2O = 1,5ꢀbis(4ꢀfluorophenyl)pentaꢀ1,4ꢀ
dienꢀ3ꢀone 1b (0.199 mmol, 0.054 g) and [(dippe)Ni(ꢀꢀH)]2 2 (0.199 mmol, 0.0128 g) in THFꢀd8
(1mL) yielded mononuclear Ni(0) complex [(dippe)Ni(η2ꢀC
α,CβꢀC17H12F2O)] (3b). Immediate
effervescence due to reductive elimination of H2 was observed during mixing. The resulting
solution was analyzed by NMR spectroscopy: (300 MHz, THFꢀd8, r.t.): δ = 7.41 (t, J HꢀH = 6 Hz,
H(c), H(c’), aromatic), 6.96 (t, J HꢀH = 9 Hz, H(d), H(d’), aromatic), 5.91 (d, J HꢀP = 12 Hz, H(b),
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H(b’), CHꢀolefinic), 5.70 (d, J HꢀP = 15 Hz, H(a), H(a’), CHꢀolefinic), 2.3ꢀ0.1 (m, iPr CH, CH2,
CH3). 31P{1H} NMR (121.32 MHz, THFꢀd8, r.t.): δ = 76.2 (d, J PꢀP = 41 Hz), 73.5 (d, J PꢀP = 41
Hz). [MSꢀEI+, m/z (%) 591 (40%)].
4.5. Preparation 1,5-bis(2-(trifluoromethyl)pentan-3-one. The reaction of C19H12F6O = 1,5ꢀ
bis(2ꢀ(trifluoromethyl)phenyl)pentaꢀ1,4ꢀdienꢀ3ꢀone 1a (0.15 mmol, 0.057 g), C7H9N =
benzylamine (0.77 mmol, 0.0 g) and [(dippe)Ni(ꢀꢀH)]2 (0.0015 mmol, 0.001 g) in ethanol, (0.3
mL), was prepared in the drybox. The resulting mixture (yellow solution) was stirred at 180 ºC
for 2 days (Entry 5, Table 2). The product (yellow oil) was purified in silica gel TLC (10%
Hexane in THF) to give 1,5ꢀbis(2ꢀ(trifluoromethyl)pentanꢀ3ꢀone 4. 1H NMR (300 MHz, CDCl3):
δ = 7.51 (d, J HꢀH = 9 Hz, H(f), H(f’), aromatics), 7.36 (t, J HꢀH = 9 Hz, H(d), H(d’), aromatic),
7.20 ꢀ 7.14 (m, J HꢀH = 9 Hz, H(c), H(c’), H(e), H(e’), aromatic), 2.99 (t, J HꢀH = 9 Hz, H(b),
H(b’), CHꢀolefinic), 2.62 (t, J HꢀH = 9 Hz, H(a), H(a’), CHꢀolefinic). 13C{1H} NMR (75.36 MHz,
THFꢀd8, r.t.): δ = 208.1 (s, C(a), 13C=O), 139.98 (s, C(d), Cꢀaromatic), 132.19 (s, C(f), C(f’),
CHꢀaromatic), 131.42 (s, C(e), C(e’), CHꢀaromatic), 128.54 (t, J CꢀF = 29.4 Hz C(i), C(i’), CHꢀ
aromatic), 126.60 (s, C(g), C(g’), CHꢀaromatic), 126.40 (quadruplet, J CꢀF = 5.27 Hz C(h), C(h’),
CHꢀaromatic), 122.98 (t, J CꢀF = 273.5 Hz C(j), C(j’), CF3ꢀaromatic), 44.66 (s, C(b), C(b’), CHꢀ
pentanꢀ3ꢀone), 26.91 (s, C(a), C(a’), CHꢀpentanꢀ3ꢀone). 19F NMR (282 MHz, THFꢀd8, r.t.): δ = ꢀ
59.7 (s, F(a), CF3ꢀaromatic).
4.6. Catalytic Transfer Hydrogenation. All reactions were made in a 150 mL Schlenk flask
fitted with a Rotaflo valve, typically charged with [(dippe)Ni(ꢀꢀH)]2 (1 mg, 1.55*10ꢀ3 mmol),
and the corresponding α,βꢀunsaturated ketone: C19H12F6O = 1,5ꢀbis(2ꢀ(trifluoromethyl)phenyl)ꢀ
pentaꢀ1,4ꢀdienꢀ3ꢀone 1a (57.35 mg, 0.155 mmol), Benzylamine (a) (82.5 mg, 0.77 mmol),
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dissolved in ethanol (3 mL). The resulting mixtures were heated with vigorous stirring at 180 ºC
and durations indicated in the Table 3. After that duration, the Schlenk flask was opened in a
wellꢀvented hood prior to workup. Orange or yellow colored solutions were formed. These were
filtered over Celite and then analyzed by CGꢀMS.
4.7. Mercury Drop Test. Following the procedure described in section 2.2, Table 3, entry 3, the
same reaction was prepared, and one drop of elemental Hg was added to the reaction mixture. At
the end of each run, the corresponding solution was filtered over Celite and analyzed by CGꢀMS.
4.8. X-ray Structure Determination. The crystals for compounds 2a-2b and 3a were first
cryoprotected using ParatoneꢀN and mounted on glass fibers; then, the crystals were immediately
cooled at 130 K using Cryojet cryostream (Oxford Cryosystems device). Diffraction data were
collected on an Oxford Diffraction Gemini diffractometer with a CCDꢀAtlas area detector using
a radiation source graphite monochromator, λMo
Kα = 0.71073 Å. CrysAlisPro and CrysAlis
RED software packages37a were used for data collection and data integration. The double pass
method of scanning was used to exclude any noise. The collected frames were integrated by
using an orientation matrix determined by using analytical numeric absorption correction37b
using a multifaceted crystal model based on expressions upon the Laue symmetry using
equivalent reflections.
Structure solution and refinement were carried out with the program(s) SHELXSꢀ2013 and
SHELXLꢀ201337c; for molecular graphics, the program ORTEPꢀ3 for Windows37d was used, and
to prepare material for publication, the software WinGX was used. [35e] Fullꢀmatrix leastꢀsquares
2
refinement was carried out by minimizing (Fo – Fc2)2. All nonꢀhydrogen atoms were refined
anisotropically. H positions were refined as riding on their parent atoms with CꢀH = 0.95ꢀ1.00 Å
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and Uiso (H) = 1.2Ueq (C) for aromatic, methylene and methyne groups, and 1.5Ueq (C) for
methyl group. Crystal data and experimental details of the structure determination are listed in
the Supporting Information (see Table S1 to Table S9 at SI section).
The crystallographic data for the structures reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication no. CCDCꢀ1407778ꢀ
1407780. Copies of the data can be obtained free of charge on application to CCDC, 12 Union
Road, Cambridge, CB2 1EZ, UK (fax: (+44) 1223ꢀ336ꢀ033, eꢀmail: deposit@ccdc.cam.ac.uk).
ASSOCIATED CONTENT
Supporting Information available. Includes complete experimental procedures, ORTEP
drawings, NMR spectra, GCꢀMS determinations of all products and a mechanistic proposal.
AUTHOR INFORMATION
Corresponding Author
Eꢀmail: juvent@unam.mx
ACKNOWLEDGMENTS
We thank CONACyT (0178265) and PAPIITꢀDGAPAꢀUNAM (INꢀ201010) for their financial
support to this work. N.C.ꢀB. thanks CONACyT for a graduate studies grant. Also, we thank Dr.
Alma Arévalo for her technical support.
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