Highly efficient synthesis of aldenamines from carboxamides by iridium-catalyzed silane-reduction/dehydration under mild conditions

Article abstract of DOI:10.1039/b821317h

The combination of IrCl(CO)(PPh₃)₂ with 1,1,3,3-tetramethyldisiloxane or poly(methylhydrosiloxane) (PMHS) is found to be an efficient catalyst system for the preparation of aldenamines from carboxamides; in particular, facile removal of silicone and iridium residues from the product can be achieved by the use of PMHS.

Full text of DOI:10.1039/b821317h

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Highly efficient synthesis of aldenamines from carboxamides by
iridium-catalyzed silane-reduction/dehydration under mild conditionsw
Yukihiro Motoyama,a Masaharu Aoki,b Naoki Takaoka,b Ryuta Aotob
and Hideo Nagashima*a
Received (in Cambridge, UK) 27th November 2008, Accepted 8th January 2009
First published as an Advance Article on the web 2nd February 2009
DOI: 10.1039/b821317h
The combination of IrCl(CO)(PPh3)2 with 1,1,3,3-tetramethyl-
disiloxane or poly(methylhydrosiloxane) (PMHS) is found to be
an efficient catalyst system for the preparation of aldenamines
from carboxamides; in particular, facile removal of silicone and
iridium residues from the product can be achieved by the use
of PMHS.
of the product from the insoluble silicone resin that is formed,
which contains most of the iridium residues. This new reaction
is apparently more useful than the previously reported process
of Corriu et al.,6 in which preparation of PhCHQCHNEt2
(54% yield) is achieved by RhCl(PPh3)3-catalyzed reaction of
PhCH2CONEt2 with 1,2-bis(dimethylsilyl)ethane at 90 1C
for 12 h.7
As reported previously, (m3,Z2,Z3,Z5-ACE)Ru3(CO)7
(ACE = acenaphthylene) and several platinum compounds
are good catalysts for the conversion of tertiary amides to
amines with hydrosilanes.5 In the cases with low cata-
lyst loadings (r0.1 mol%), aldenamine is formed as the
by-product. Table 1 shows the results of the reaction of
PhCH2CONEt2 (1a) with TMDS in the presence of several
transition metal catalysts. As shown in entries 1–3, the
ruthenium- and platinum-catalyzed reactions proceed at room
temperature to form a mixture of enamine (2a) and amine (3)
in moderate yields. Similar reactions with other trialkylsilanes
also gave a mixture of 2a and 3. The COD complexes of Rh
and Ir also catalyzed the reaction with TMDS to form a
mixture of 2a and 3 (entries 4 and 5). The reaction catalyzed
by RhCl(PPh3)3 was slow under these conditions. A dramatic
increase in the reaction rate was discovered when a combina-
tion of IrCl(CO)(PPh3)2 and TMDS was used for the reaction;
amide 1a was completely consumed at 25 1C within 30 min
using 0.05 mol% of the catalyst to result in practically
exclusive formation of (E)-PhCHQCHNEt2 2a in 96% yield.
Only a small amount of 3 was formed as the by-product
Enamines are of great utility in organic synthesis because they
act as isolable nucleophiles equivalent to enolates.1 Enamines
are generally synthesized by acid assisted condensation of
secondary amines and carbonyl compounds.2 Although cata-
lytic dehydrogenation of amines, cross-coupling between
amines and alkenyl halides, and hydroamination of alkynes
are also effective methods,3 these require long reaction times at
high temperatures. Recently, Belanger et al. have reported the
´
4 A molecular sieves (MS 4A)-promoted condensation of
aldehydes and amines.4 The reaction proceeds even at 0 1C
within a few hours, however, this method requires large
amounts of MS 4A (1.16 g mmolꢀ1 of carbonyl compound).
Furthermore, in most of the above methods, distillation or
chromatography is necessary for removing the residual mate-
rials, which results in the lowering of the yield of enamine.
Thus, the development of a new catalyst system, which shows
high catalytic activity under mild conditions and realizes a
facile isolation of labile enamines, is an important target in
organic synthesis.
We have recently reported the transition metal-catalyzed
silane-reduction of carboxamides to amines.5 During the
course of these studies, we became aware that aldenamines
were sometimes formed as a by-product by way of addition of
an R3Si–H bond to the CQO bond of the amide followed by
elimination of R3SiOH. Our efforts to achieve the synthesis of
enamines as the major product resulted in the discovery that
the combination of IrCl(CO)(PPh3)2 and 1,1,3,3-tetramethyl-
disiloxane (TMDS) provides an efficient synthetic process
for aldenamines from carboxamides under mild condi-
tions in high catalyst turnover numbers. Furthermore, use of
poly(methylhydrosiloxane) (PMHS) leads to facile separation
Table 1 Selected results of the reaction of 1a and TMDS with various
transition metal catalystsa
Yield (%)b
2a
3
Entry
Catalyst (mol%)
Time/h
1
2
3
4
5
6
7
8
(ACE)Ru3(CO)7 (0.1)
PtCl2(cod) (0.1)
Karstedt’s cat. (0.1)
[RhCl(cod)]2 (0.05)
[IrCl(cod)]2 (0.05)
RhCl(PPh3)3 (0.1)
IrCl(CO)(PPh3)2 (0.05)
IrCl(CO)(PPh3)2 (0.01)
4
4
4
4
4
4
0.5
0.5
13
43
41
11
15
3
4
8
7
a Institute for Materials Chemistry and Engineering,
Kyushu University, Kasuga, Fukuoka 816-8580, Japan.
E-mail: nagasima@cm.kyushu-u.ac.jp; Fax: +81-92-583-7819;
Tel: +81-92-583-7819
o2
3
o1
o1
o1
b Graduate School of Engineering Sciences, Kyushu University,
Kasuga, Fukuoka 816-8580, Japan
96
82
a
w Electronic supplementary information (ESI) available: Detailed
experimental procedures and results; characterization data and copies
of NMR spectra of the products. See DOI: 10.1039/b821317h
All reactions were carried out with 1a (1 mmol), TMDS (2 mmol),
b
and catalyst (0.01–1 mol%) at 25 1C. Determined by GLC analysis.
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Table 2 Reaction of various amides 1a–i with TMDSa
treatment of the crude sample with KOH–MeOH. Attempted
purification of the crude enamine by column chromatography
also gave a significant amount of aldehyde as a by-product
(entry 4). It is difficult to remove the silicone waste by
distillation.
Entry
1
Amide 1
Yield (%)b
1a
1b
2a: 96c (85)d
2
3
2b: 498 (86)d
2c: 498 (82)d
Problematic isolation of the enamines is solved by using
PMHS as the hydrosilane. As reported previously, facile
isolation of amine products from the reaction mixture is
achieved in the Ru- and Pt-catalyzed deoxygenative reduction
of carboxamides with PMHS; the reduction is accompanied
with O-crosslinking of the PMHS to produce an insoluble
siloxane resin, into which all of the metal species is soaked
up.5c,d,8 This automatic removal of the catalyst9 and silicone
waste can also be achieved with the present Ir-catalyzed
enamine synthesis.
1c
1d
4
5
2d: 498 (23)e
2e: 498
1e
6
7
1f
2f: 97
2g: 98
1g
Treatment of amides with PMHS [n = 25.6 (average),
Si–H = 4 equiv. to amide] gave the corresponding enamines
and insoluble silicone resin containing iridium (Ir@Si). Thus,
both the catalyst and silicone wastes were easily separable from
the enamine by simple filtration, and there was no detectable Ir
species in the enamine by ICP-MS analysis (o30 ppb). It is
noteworthy that the Ir–PMHS system shows higher catalytic
activity than the Ir–TMDS system; the reaction proceeded
smoothly with only 0.01 mol% of catalyst and TOF exceeded
20000 [mol (amide)/mol (Ir)ꢂh]. As shown in Table 3, the
8
1h
1i
2h: 498
9
2i: 96 (86)d
a
All reactions were carried out with carboxamide 1 (1 mmol), TMDS
(2 mmol), and catalyst (0.05 mol%) in toluene (0.5 mL) at 25 1C for
30 min. Determined by 1H NMR spectroscopy. Determined
b
c
d
e
by GLC. After treatment with KOH–MeOH. After silica gel
chromatography. 70% of the aldehyde was also obtained.
Table 3 Reaction of various amides with PMHSa
(o0.5% by GLC analysis) (entry 7). The reaction with
0.01 mol% of Ir catalyst proceeded smoothly to afford 2a in
82% yield; turnover frequency (TOF) of the Ir–TMDS system
exceeded 16 000 [mol (1a)/mol (Ir)ꢂh] (entry 8). Interestingly,
the present Ir-catalyzed enamine formation from the carbox-
amide only proceeded with TMDS, and no reaction took place
with other hydrosilanes such as EtMe2SiH, Et3SiH, Ph2SiH2,
1,2-bis(dimethylsilyl)ethane and o-bis(dimethylsilyl)benzene.
In Table 2 are summarized the reactions of various carbox-
amides with TMDS under 0.05 mol% IrCl(CO)(PPh3)2 cata-
lysis in toluene at 25 1C for 30 min. All carboxamides (1a–i)
listed were completely converted to the corresponding
E-enamines (2a–i) without formation of the Z-isomer or the
amine product. The reaction is not dependent on the sub-
stituents on the nitrogen atom; the amides derived from
diethylamine, N-methylaniline or morpholine afforded the
corresponding (E)-enamines in high yields (entries 1–3). As
shown in entries 5–9, the reaction can be applied to the
synthesis of enamines containing other functional groups such
as halogens, esters, ketones, and alkenes, which are potentially
reducible under the catalytic conditions. Application of the
present reaction to a b,g-unsaturated amide 1i resulted in
formation of a conjugated dienamine, (E,E)-2i, as a single
product (entry 9). In this Ir–TMDS system, the crude enamine
that is obtained after removal of the solvent contains silicones
and catalyst residue. Treatment of the crude samples of
enamines stabilized by p-conjugation (2a–c and 2i) with
KOH in MeOH followed by extraction with ether gave the
enamine not containing silicone and Ir in good yields
(entries 1–3 and 9) (details are described in the ESIw). In contrast,
enamines without p-conjugation 2d–h are unstable, and some
amount of aldehyde was obtained as a by-product during the
Entry
1
Amide
Enamine
Yield (%)
1a
2a
2b
2c
92b (3: 7b)
2
3
1b
1c
95
95
4
5
1d
1e
2d
2e
90
50c
6
7
1f
2f
86
—
1g
2g
8
1h
1i
2h
2i
96
9
98
98
10d
a
All reactions were carried out with carboxamide 1 (1 mmol), PMHS
(Si–H = 4 mmol), and catalyst (0.01 mol%) in toluene (0.5 mL) at
25 1C for 30 min. Determined by GLC. Determined by 1H NMR
spectroscopy. 3.00 g (13.3 mmol) of 1i was used.
b
c
d
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facile removal of silicone and iridium residues from the
product can be achieved by the use of PMHS; the product
can be isolated from the reaction mixture by simple extraction.
Since the reaction is generally applicable to a variety of
carboxamides containing other functional groups, this paper
should stimulate studies on aldenamines as important
synthetic intermediates. Detailed mechanistic studies on the
present catalyst system are now under way.
Scheme 1 Enamine formation followed by cyclopropanation.
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
Notes and references
z To a 0.02 M solution of IrCl(CO)(PPh3)2 in toluene (0.5 mL;
0.01 mmol of [Ir]) was added the substrate (1 mmol) and PMHS
(266 mg, Si–H = 4.0 mmol) at 25 1C. Immediately, hydrogen gas
evolved and the homogeneous solution turned to a gel after 15 min.
After it was allowed to stand for 15 min, the resultant residue was
washed ten times with ether (30 mL total), and the combined organic
solution was filtered through a pad of Celite and the filtrate was
evaporated under reduced pressure to afford the essentially pure
enamine.
Scheme 2 A plausible reaction mechanism.
procedure can be applicable to the reaction of various
carboxamides, and both p-stabilized and non-p-stabilized
enamines were obtained in good to high yields.z The following
points highlight differences from the results obtained in the
reaction with TMDS: (1) a small amount of amine is formed as
a by-product in the reaction of amides with sterically less bulky
N-substituents such as PhCH2CONEt2 1a (entry 1); (2)
the reaction of bromo-substituted carboxamide 1e gave the
enamine 2e in moderate yield due to formation of unidentified
by-products (entry 5); (3) in the reaction of the amido ketone
1g, no organic compound was detectable in the extracts. This is
presumably due to the concomitant occurrence of the
hydrosilylation of the CQO bond in 1g with PMHS, which
results in immobilization of the product to the silicone resin via
Si–O bonds (entry 7). The present procedure is adaptable to a
large quantity of reaction material; 2.74 g of (E,E)-2i was
obtained from 3.00 g (13.3 mmol) of 1i (entry 10). Finally, we
successfully extended our method to the stereospecific syn-
thesis of the trans-aminocyclopropane. The (E)-2b obtained
in Table 3, entry 2 was subjected to the Simmons–Smith
cyclopropanation to afford trans-N-(2-phenylcyclopropyl)-
N-methylaniline (4) as a single product (Scheme 1).
1 (a) G. Stork, A. Brizzolara, H. Landesman, J. Szmuszkovcz and
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A plausible mechanism is shown in Scheme 2. The hydride-
reduction first proceeds at the CQO bond of the amide and
subsequent elimination of siloxane forms an iminium inter-
mediate. Then deprotonation of an a-proton of the iminium
intermediate with hydride takes place much faster than
the hydride reduction, resulting in the formation of the
aldenamine and H2.
6 R. J. P. Corriu, J. J. E. Moreau and M. Pataud-Sat, J. Organomet.
Chem., 1982, 228, 301.
7 Buchwald and co-workers reported a stoichiometric amount of
(i-PrO)4Ti promoted the formation of aldenamines from carboxamides,
which proceeds under mild conditions and tolerates various functional
groups. The aldenamines formed were hydrolyzed to the corresponding
aldehydes without isolation. S. Bower, K. A. Kreutzer and
S. L. Buchwald, Angew. Chem., Int. Ed. Engl., 1996, 35, 1515.
8 Y. Motoyama, K. Mitsui, T. Ishida and H. Nagashima, J. Am.
Chem. Soc., 2005, 127, 13150.
In summary, we have developed an efficient catalyst system
for the preparation of enamines by IrCl(CO)(PPh3)2-catalyzed
silane-reduction/dehydration of carboxamides. The reaction
proceeds under mild conditions in high turnover frequency
with other functional groups remaining intact. Furthermore,
9 Dioumaev and Bullock reported the pioneering work on the
‘‘catalyst self-separation’’, see: V. K. Dioumaev and
R. M. Bullock, Nature, 2003, 424, 530.
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1576 | Chem. Commun., 2009, 1574–1576