Unexpected selectivity in ruthenium-catalyzed hydrosilylation of primary amides: Synthesis of secondary amines

Article abstract of DOI:10.1039/c3cc39149c

Selective ruthenium-catalyzed reductive coupling of primary amides under hydrosilylation conditions is achieved using an one pot procedure. Using 3 equiv. of phenylsilane and [RuCl₂(mesitylene)]₂ (1-2 mol%) as the catalyst at 100 °C under neat conditions, secondary symmetric amines were obtained in good yields and with high chemoselectivities. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc39149c

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Unexpected selectivity in ruthenium-catalyzed
hydrosilylation of primary amides: synthesis of
secondary amines†
Cite this: Chem. Commun., 2013,
49, 3691
Received 21st December 2012,
Accepted 1st March 2013
Bin Li, Jean-Baptiste Sortais and Christophe Darcel*
DOI: 10.1039/c3cc39149c
www.rsc.org/chemcomm
Selective ruthenium-catalyzed reductive coupling of primary amides
under hydrosilylation conditions is achieved using an one pot procedure.
Using 3 equiv. of phenylsilane and [RuCl2(mesitylene)]2 (1–2 mol%) as
the catalyst at 100 8C under neat conditions, secondary symmetric
amines were obtained in good yields and with high chemoselectivities.
Scheme 1 Comparison of different transition metal catalyzed reductions of
The development of synthetic strategies for amines has been
attracting the continuing interest of chemists because they
constitute a central class of compounds in agrochemical,
natural product, and pharmaceutical areas. Among the numer-
ous synthetic ways to prepare amine derivatives,1 the reduction
of imines or amides, even if it is one of the well documented
strategies using a stoichiometric amount of reactive alkali
hydrides such as lithium aluminium hydride or boron
hydrides,2 is still a challenging task, mainly due to the lack of
functional group tolerance of such reducing reagents. During
the last few decades, transition metal catalyzed reductions to
obtain amines have been widely developed and have offered
efficient and versatile strategies.3,4 Usually, among the amides,
the reduction of primary amides is the most difficult to per-
form. In transition metal-catalyzed hydrogenation, harsh reac-
tion conditions such as high temperature and pressure are
commonly employed.5 Hydrosilanes have emerged as competi-
tive alternative hydride sources to the classical metallic hydride
sources and hydrogen, and have been widely employed for the
reduction of carbonyl and carboxylic derivatives.6 Indeed, the
reduction of tertiary and secondary amides into, respectively,
tertiary and secondary amines was described using hydro-
silanes catalyzed by classical transition metal based catalysts7
including iron8 and ruthenium.9 In contrast, only scarce
reports deal with the more challenging reduction of primary
amides using hydrosilanes as hydride sources. Using ruthe-
nium clusters,10 an iron based system11 or a fluoride ammo-
nium salt12 as the catalyst, under hydrosilylation conditions,
primary amides.
primary amides were selectively dehydrated leading to the
corresponding nitriles (Scheme 1a). Notably, Beller et al. have
shown that the use of two different iron catalysts allowed the
selective reduction of primary amides into the expected corres-
ponding primary amines.13 Using Ti(OiPr)4 as a catalyst in the
presence of PMHS, Lemaire et al. also succeeded in obtaining
selectively primary amines.14
Following our continuous efforts to perform selective
reduction via hydrosilylation,15,16 we report herein the first
reduction of primary amides leading specifically to secondary
amines under hydrosilylation conditions using simple com-
mercially available stable ruthenium(II) catalysts (Scheme 1b).
Initial studies focussed on the reduction of benzamide 1 with
several ruthenium catalyst precursors and phenylsilane (3 equiv.)
as the hydride donor (Table 1). Preliminary tests on the catalytic
activity of the CpRuCl(PPh3)2 complex led to no or low conversions
(Table 1, entry 1). In contrast, RuCl3ÁxH2O led to a full conversion
of the benzamide but with moderate selectivity as 68% of
dibenzylamine 4 was obtained with 28% of the benzylbenzylidene
intermediate 3 and a trace amount (3%) of benzonitrile 2, the
dehydrated compound (entry 2). Using [Ru(OAc)2(p-cymene)]
(10 mol%), even if a full conversion was observed, only moderate
selectivities were obtained, with aldimine 3 as the major product
(entry 3). Among the [RuCl2(arene)]2 complexes tested (5 mol%),
there were two good candidates for selective transformation of
benzamide 1 into dibenzylamine 4: [RuCl2(mesitylene)]2 and
[RuCl2(p-cymene)]2 led to a full conversion, with 94% and 93%
of dibenzylamine, respectively (entries 4 and 6). Decreasing the
catalyst amount to 2.5 mol% led to full conversion but to mixtures
of dibenzylamine 4 and imine 3 (entries 7 and 8).
´
UMR 6226 CNRS-Universite Rennes1 ‘‘Institut des Sciences Chimiques de Rennes’’ –
Centre of Catalysis and Green Chemistry – ‘‘Organometallics: Materials and
Catalysis’’, 35042 Rennes cedex, France. E-mail: christophe.darcel@univ-rennes1.fr
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc39149c
c
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Table 1 Optimization of the conditions for the reduction of primary amides
with silanea
Table 2 Selective hydrosilylation of primary amides into secondary amines with
PhSiH3 using [RuCl2(mesitylene)]2 as the catalysta
Entry
Conditionsa
1 mol%, 5 h
Yieldb [%]
84
Product
Convb Ratiob
1
2
3
4
5
6
7
8
4a, RQH
Entry [Ru] (mol%)
Silane
Solvent (%)
2/3/4
4b, RQp-Br
4c, RQp-Cl
4d, RQo-Cl
4e, RQp-Me
4f, RQm-Me
4g, RQo-Me
2 mol%, 16 h 88
2 mol%, 5 h
2 mol%, 5 h
2 mol%, 5 h
1 mol%, 5 h
1 mol%, 5 h
82
75
75
75
87
1
2
3
CpRuCl(PPh3)2 (10)
RuCl3ÁxH2O (10)
PhSiH3 Toluene 10
PhSiH3 Toluene >99
[Ru(OAc)2(p-cymene)] (10) PhSiH3 Toluene >99
1/2/7
3/28/68
14/72/13
2/3/94
1/18/80
2/4/93
4
5
[RuCl2(mesitylene)]2 (5)
[RuCl2(hmb)]2 (5)
PhSiH3 Toluene >99
PhSiH3 Toluene >99
PhSiH3 Toluene >99
4h, RQp-OMe 2 mol%, 5 hc 72
6
[RuCl2(p-cymene)]2 (5)
7
8
9
[RuCl2(p-cymene)]2 (2.5) PhSiH3 Toluene >99
[RuCl2(mesitylene)]2 (2.5) PhSiH3 Toluene >99
1/62/37
3/53/43
47/0/0
6/2/4
2/4/93
2/0/25
28/0/1
19/2/24
7/15/77
1/2/96(63)
2/3/94
1/25/73
1/6/92(84)
9
4j
4i
2 mol%, 8 hc 84
[RuCl2(p-cymene)]2 (5)
[RuCl2(p-cymene)]2 (5)
[RuCl2(p-cymene)]2 (5)
[RuCl2(p-cymene)]2 (5)
[RuCl2(p-cymene)]2 (5)
[RuCl2(p-cymene)]2 (5)
[RuCl2(p-cymene)]2 (5)
[RuCl2(p-cymene)]2 (5)
Ph3SiH Toluene 47
Ph2SiH2 Toluene 12
PhSiH3 Toluene >99
PMHS Toluene 27
10
11
12
13
14
15
16
17
18
19
10
11
1 mol%, 5 h
65
TMDS
Toluene 29
PhSiH3 THFc
PhSiH3 DMCd
PhSiH3 Neat
45
>99
>99
>99
>99
>99
4k
2 mol%, 16 h 53
12
13
4l, RQPh
4m, RQC5H11 2 mol%, 5 h
2 mol%, 5 h
78
75
[RuCl2(p-cymene)]2 (2.5) PhSiH3 Neat
[RuCl2(p-cymene)]2 (1)
[RuCl2(mesitylene)]2 (1)
PhSiH3 Neat
PhSiH3 Neat
a
RCONH2 (0.5 mmol), phenylsilane (3 equiv.), [RuCl2(mesitylene)]2
b
c
a
(1–2 mol%), solvent-free conditions at 100 1C. Isolated yields. 0.2 mL
RCONH2 (0.5 mmol), silane (3 equiv.), ruthenium complex (1–10 mol%),
b
c
of toluene was added in order to obtain a homogeneous solution.
solvent (2 mL) for 5 h at 100 1C. Determined by GC. Reaction
performed at 50 1C. 8 h. hmb: hexamethylbenzene.
d
The reaction proceeded well also with heteroaromatic
Among the variety of silanes tested in toluene at 100 1C for primary amide derivatives such as thiophenamide leading to
5 h in the presence of 5 mol% of [RuCl2(p-cymene)]2, optimal bis-(thiophenylmethyl)amine with 84% isolated yield after 8 h
conversions toward the formation of dibenzylamine 4 were at 100 1C, adding 0.2 mL of toluene for complete solubilization
obtained using PhSiH3 (3 equiv.) (Table 1, entry 11). Notably, (entry 9). Finally, aliphatic amides can also successfully lead to
Ph3SiH and TMDS (1,1,3,3-tetramethyldisiloxane), even if the the corresponding amines but with lower yields (65 and 53%)
conversion is moderate, seem to favour the formation of the than in the cases of benzamide derivatives (entries 10 and 11).
dehydrated benzonitrile 2 (entries 9 and 13). Such reaction can When using p-nitrobenzamide, under similar conditions, no
also be conducted in a greener solvent such as DMC (dimethyl- conversion was observed, whereas cinnamylamide led to a
carbonate) leading selectively to dibenzylamine 4 in 77% yield mixture of compounds resulting in the partial reduction of
(entry 15). Most importantly, the reaction can also be the CQC bond.
conducted under solvent-free conditions with 1 mol% of
[RuCl2(mesitylene)]2 as the catalyst yielding dibenzylamine 4 reaction, different combinations of benzamide with additional
in 84% isolated yield (entry 19). reducible compounds were evaluated under similar conditions
On the other hand, to evaluate the group tolerance of this
The scope and limitations of this first selective ruthenium- (100 1C, 5 h). Very good chemoselectivities were observed for
catalyzed reduction with PhSiH3 were then explored using the reduction of benzamide in the presence of p-bromostyrene
[RuCl2(mesitylene)]2 as the catalyst (1–2 mol%) at 100 1C under and p-bromoacetophenone as only trace amounts of p-bromo-
neat conditions (Table 2). We have found that the electronic ethylbenzene (7%) and 1-(p-bromobenzyl)ethanol (4%) were,
effects at the aromatic ring on benzamide derivatives were very respectively, detected besides full conversion of the amide.
limited, and the corresponding secondary amines were
Interestingly, when the reaction of 1.5 equiv. of dodecan-
obtained in full conversions and good isolated yields (72–88%) amide is performed in the presence of 1 equiv. of p-methoxy-
(entries 2–8). Of notable interest, no dehalogenation occurred aniline, 2 mol% [RuCl2(mesitylene)]2 and 5 equiv. of phenylsilane
during the reduction process (entries 2–4). When the reaction at 100 1C for 16 h, 67% conversion of the aniline derivative was
was carried out with benzamides bearing substituents in the observed and a mixture of the corresponding p-methoxy-
para-, meta- and ortho-position, a full conversion and good phenyldodecanylamine 6 (40% isolated yield) and the symme-
isolated yields were observed, which shows that the ortho trical bis(dodecyl)amine 4k was obtained in a ratio of 1 : 1.5.
substituent did not hamper the reaction (entries 3, 4 and 5–7). This result showed that the cross-reaction between an amide
Moreover, with a-branched amides such as 2-phenylpropan- and an amine can proceed under such hydrosilylation condi-
amide and 2-methyl-heptanamide, the reduction led to the tions, but in competition with the self-coupling one (Scheme 2).
corresponding amines 4l–m with 78% and 75% isolated yields,
From a mechanistic point of view, first of all, when mixing
respectively (entries 12 and 13).
[RuCl2(p-cymene)]2 with 1 equiv. of triphenylsilane at 100 1C for
c
3692 Chem. Commun., 2013, 49, 3691--3693
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Scheme 2 Dissymmetric secondary amine preparation.
¨
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5 h, a ruthenium hydride species was detected in 1H-NMR at d =
À10.2 ppm, which seems to result from an oxidative addition of
the hydrosilane.17 Another important observation is the very
small amount of nitrile derivative 2 observed under the opti-
mized standard conditions (1–3 mol%) using [RuCl2(arene)]2
catalysts and PhSiH3 as the silane. A proposed mechanism for
this transformation is shown in Scheme 3. The dehydration of
primary amides 1 leading to nitriles 2, already described using
ruthenium catalysts under hydrosilylation conditions,10 seems
to proceed easily under our conditions. The obtained nitrile
compounds 2 should react fast with silane to lead to the
N-silylimines A,18 which can be fully reduced into the disilylated
primary amines B.19 The important step in the observed selectivity
of the described reaction seems to be the in situ formation of the
aldimine 3 from the N-silylimine A and the disilylated primary
amine B. It has already been shown that the hydrosilylation of
aldimines into amines using [RuCl2(p-cymene)]2 catalysts (1 mol%)
proceeded at room temperature in 2 h.16a
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¨
´
´
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´
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´
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primary amides into secondary amines with a cheap and simple
stable ruthenium complex, [RuCl2(mesitylene)]2, as an efficient
catalyst under hydrosilylation and solvent-free conditions.
We are grateful to CNRS, University of Rennes 1, and
´
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`
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Ministere de l’Enseignement Superieur et de la Recherche for
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c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 3691--3693 3693