Transition-metal-based Lewis acid and base ambiphilic catalysts of iridium hydride complexes: Multicomponent synthesis of glutarimides

Article abstract of DOI:10.1002/anie.200351689

Mutual destruction of reagents in acid-and base-promoted reactions in the same container is now avoidable with the iridium polyhydride complex [IrH₅(PiPr₃)₂] (1), which is an ambiphilic Lewis acid and base catalyst. By using catalyst 1, a three-component reaction of nitriles, olefins, and water proceeds efficiently to give glutarimides, which are pharmacologically important (see scheme).

Full text of DOI:10.1002/anie.200351689

Communications
[
5,9]
Ambiphilic Lewis Acid and Base Catalyst
Michael addition,
and activation of the CꢀN triple bond
[4]
promotes hydration and amidation of nitriles. In this way,
the ambiphilic iridium complex 1 catalyzes the one-pot
reaction of a mixture of nitriles, olefins, and water to give
glutarimides efficiently.
Glutarimides have recently attracted attention as useful
pharmaceuticals with pharmacological effects such as immu-
Transition-Metal-Based Lewis Acid and Base
Ambiphilic Catalysts of Iridium Hydride
Complexes: Multicomponent Synthesis of
Glutarimides**
[
10]
nomodulatory, neuroplegic, and antitumor activity,
and
Hikaru Takaya, Kazunori Yoshida, Katsuhiro Isozaki,
Hiroki Terai, and Shun-Ichi Murahashi*
hence methods for the ready synthesis of these compounds
are needed. A variety of glutarimides can be prepared by the
three-component reaction reported herein. Representative
reactions are listed in Table 1. A range of substituents needed
for pharmacological activity can be easily introduced into the
2- or 3-position of the glutarimide ring. The reaction of a
mixture of a-aryl alkanenitrile, acrylonitrile 2, and water
(1:1:5) gave the corresponding 2-arylglutarimides in a yield of
92% or more (Table 1, entries 1 and 2). The conventional
methods for the synthesis of these glutarimides, with Triton B
and sulfuric acid used in that order, gave less than a 37%
The majority of reactions promoted by Lewis acids or bases
are stoichiometric. Catalysts based on transition metals
instead of conventional Lewis acids and bases might be
useful, because the neutralization of reagents would not be
necessary, and salts would not form. We found that such
[
1–4]
[1,5]
transition-metal-based Lewis acid
and base
catalysts
that have low redox potentials are environmentally benign
and useful for organic synthesis. This concept can be extended
[
6]
[11]
to ambiphilic catalysts based on transition metals. These
catalysts make possible both acid- and base-promoted
reactions in a single container without the mutual destruction
of reagents by neutralization, and multicomponent catalytic
reactions that may be useful for combinatorial chemistry can
be constructed.
yield. The glutarimide 3 thus obtained is an useful sedative
Glutethimide and a precursor of Aminoglutethimide, an
anticancer drug. The reaction of methyl 2-cyanopropanoate
proceeds efficiently to give the corresponding 2-substituted
glutarimide accompanied by removal of the ester group
(Table 1, entry 3). The reaction of methyl 3-(4-chlorophenyl)-
2-cyanopropanoate gave the corresponding glutarimide 4,
We report herein that the iridium polyhydride complex
[
12]
[
IrH (PiPr ) ] 1 is an excellent Lewis acid and base ambiphilic
which may be a useful anticonvulsant (Table 1, entry 4).
5
3 2
catalyst based on a transition metal, and that a novel three-
component reaction of nitriles, olefins, and water occurs in the
presence of catalyst 1 to gave glutarimides, which are highly
versatile intermediates for synthesis of biologically active
The esterolytic reaction is useful for the synthesis of 3-
substituted glutarimides. The treatment of methyl cyanoace-
tate 5 with b-substituted cyanoolefin in the presence of water
gave the corresponding 3-substituted glutarimide 6 (Table 1,
entry 5). a,b-Unsaturated esters also can be used as starting
substrates. In fact, glutarimide 6 was also obtained from
methyl crotonate. Similar three-component reactions of 1,3-
dicarbonyl compounds can be carried out by a-CÀH activa-
[
7]
compounds [Eq. 1]. Iridium complex 1 is important as both
tion of the carbonyl group. In this way, 4-methyl-4,6,7,8-
tetrahydro-1H,3H-quinoline-2,5-dione was obtained from
1
,3-cyclohexanedione, crotononitrile, and water (Table 1,
[
13]
entry 7).
[
8]
a redox base and Lewis acid catalyst. The a-CÀH activation
The efficiency of such reactions is highlighted by the
stereoselective synthesis of glutarimides. The reaction of a
mixture of (benzenesulfonyl)acetonitrile 7, cyanoolefin 8a,
of nitriles occurs to give a carbanion equivalent species for
1
and water gave 9a (R = Me) selectively in a 64% yield
+
[
*] Prof. Dr. S.-I. Murahashi, Dr. H. Takaya, K. Yoshida, K. Isozaki,
[14]
(9a:10a = 96:4) [Eq. 2].
It is noteworthy that a diaster-
H. Terai
Department of Chemistry
Graduate School of Engineering Science
Osaka University
1–3, Machikaneyama, Toyonaka, Osaka 560-8531 (Japan)
E-mail: murahashi@high.ous.ac.jp
+
[
] Present address: Department of Chemistry
Faculty of Engineering
Okayama University of Science
1–1, Ridaicho, Okayama 700-0005 (Japan)
Fax: (+81)86-256-9513
[
**] This work was supported by the “Research for the Future Program”,
The Japan Society for the Promotion of Science, and a Grant-in-Aid
for Scientific Research, the Ministry of Education, Culture, Sports,
Science, and Technology, Japan.
1
[14]
eomer 9b (R = Ph) was obtained exclusively in 52% yield
from the reaction of a mixture of 7, 8b, and water. The
reaction of a mixture of 7 (Z)-2-phenyl-2-hexenenitrile, and
Supporting information for this article is available on the WWW
under http://www.angewandte.org or fromthe author.
3
302
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200351689
Angew. Chem. Int. Ed. 2003, 42, 3302 – 3304

Angewandte
Chemie
[
a]
Table 1: Iridium-catalyzed three-component reaction.
addition of 13 to olefin followed by isomer-
ization would give cyanocarbanion intermedi-
[
b]
Entry
Pronucleophile
Olefin
Product
Yield (%)
[
17,18]
ate 14.
Isomerization of 14 to a keten-
[
19]
imino iridium intermediate followed by the
nucleophilic addition of water and proton
1
94
[
13]
transfer would give amide complex 15. The
amide intermediate was detected at the earlier
stage of the reaction; however, the Michael
adduct could not be detected during the
reaction. Iridium-promoted intramolecular
addition of the amide moiety of 15 to the
coordinated nitrile and subsequent hydroly-
c
2
3
2
2
92
98
90
[
4,20]
sis
would afford glutarimide, ammonia,
and (L Ir) to complete the catalytic cycle. The
n
4
2
stereoselective formation of glutarimides can
be ascribed to the isomerization of 15 by
[
21]
a-CÀH activations of the amide and nitrile.
In the three-component reaction, the iridium
catalyst acts as a base to generate the carbon
nucleophile by a-CÀH activation and also acts
5
6
7
91
69
68
as a Lewis acid to activate and hydrolyze the
5
6
CꢀN triple bonds of nitriles.
We have found that RuH (PPh ) is an
2
3 4
efficient transition-metal-based-base catalyst
and can be used for selective four-component
condensation reactions in combinatorial
[
22]
chemistry. Such reactions can lead to the
combinatorial synthesis of glutarimides. A
polymer-supported iridium catalyst would be
an excellent catalyst for the one-pot, three-
component synthesis of glutarimides. In the
[
(
a] A mixture of nitriles (1.0 mmol), olefins (1.1 mmol), H O (5.0 mmol), and IrH (PiPr )
1) (0.10 mmol) in THF (0.25 mL) was stirred in a sealed glass tube at 1508C for 20 h under
2
5
3
2
an argon atmosphere. [b] Yield of isolated product based on starting pronucleophiles.
c] 2.0 mmol of 2 was added and the reaction was carried out at 1808C for 30 h.
[
presence
of
polystyrene-supported
1
[
15]
water gave only one diastereomer 11 (yield 30%) among
the four possible diastereomers.
(10 mol%), the three-component reaction of 5, 8a, and
water gave 3-methylglutarimide (6) in 69% yield [Eq. 3].
This reaction might be explained in terms of the mech-
anism shown in Scheme 1. The catalytically active species
seems to be the coordinatively unsaturated iridium species
(
L Ir), formed by the dissociation of molecular hydrogen. The
n
coordination of nitrile to L Ir and a-CÀH activation of nitriles
n
would give the C-bound a-cyanocarbanion complex of
iridium 12. Isomerization of 12 to the corresponding N-
[
5b,16]
bound cyanocarbanion complex 13
would occur, and the
Received: April 17, 2003 [Z51689]
Keywords: ambiphilic catalyst · C-H activation · glutarimide ·
.
iridium · multicomponent reactions
[
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Angew. Chem. Int. Ed. 2003, 42, 3302 – 3304
www.angewandte.org
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3303

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[
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[
[
[
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À1
spectra of the complexes show n˜ (CN) at 2140 cm and their
1
3
120, 4244.
C NMR chemical shifts shifted to extremely lower magnetic
9] C-H activations by iridium complexes see also, a) B. A. Ander-
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1
995, 28, 154, and references therein; b) H. Chen, S. Schlecht,
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3
304
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 3302 – 3304