Selective Ruthenium-Catalyzed Reductive Alkoxylation and Amination of Cyclic Imides

Article abstract of DOI:10.1002/anie.201508575

Reported herein, for the first time, is the selective ruthenium-catalyzed reductive alkoxylation and amination of phthalimides/succinimides. Notably, this novel methodology avoids hydrogenation of the aromatic ring and allows methoxylation of substituted imides with good to excellent selectivity for one of the carbonyl groups. The reported method opens the door to the development of new processes for the selective synthesis of various functionalized N-heterocyclic compounds. As an example, intramolecular reductive couplings to afford tricyclic compounds are presented for the first time.

Full text of DOI:10.1002/anie.201508575

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201508575
German Edition: DOI: 10.1002/ange.201508575
Reduction Reactions
Selective Ruthenium-Catalyzed Reductive Alkoxylation and
Amination of Cyclic Imides
Jose R. Cabrero-Antonino, Ivµn Sorribes, Kathrin Junge, and Matthias Beller*
Abstract: Reported herein, for the first time, is the selective
ruthenium-catalyzed reductive alkoxylation and amination of
phthalimides/succinimides. Notably, this novel methodology
avoids hydrogenation of the aromatic ring and allows methox-
ylation of substituted imides with good to excellent selectivity
for one of the carbonyl groups. The reported method opens the
door to the development of new processes for the selective
synthesis of various functionalized N-heterocyclic compounds.
As an example, intramolecular reductive couplings to afford
tricyclic compounds are presented for the first time.
I
soindolinones and their derivatives constitute attractive
building blocks for organic synthesis and represent valuable
scaffolds in pharmaceuticals and agrochemicals with diverse
biological activities.[1] Because of the continuing interest in
this class of heterocyclic compounds, in the last years several
improved procedures for their synthesis have been devel-
oped.[2] Among them, the selective monoreduction of easily
available phthalimides represents a most convenient and
straightforward approach. Unfortunately, in general, stoi-
chiometric amounts of either zinc or tin in the presence of
acid, or the use of inorganic metal hydrides have to be
employed in these transformations, and thus limits functional-
group compatibility and generates significant amounts of
waste-products.[3] In addition, reductions in the presence of
different heterogeneous catalysts have been disclosed under
harsher reaction conditions.[4] So far only a small number of
defined organometallic complexes have been developed for
the hydrogenation and hydrosilylation of cyclic imides
(Scheme 1). Originally, Patton and Drago reported the
hydrogenation of N-methylsuccinimide in low yields by
using a ruthenium catalyst.[5] More recently, Bruneau and
co-workers reported an elegant ruthenium-catalyzed hydro-
genation of cyclic imides[6] with concomitant hydrogenation of
the aromatic ring. Later on, Ikariya and co-workers presented
the dihydrogenation of cyclic imides to the corresponding
ring-opened alcohol-amide products.[7] Notably, the group of
Bergens reported a ruthenium/base-catalyzed monohydroge-
nation of phthalimides to give hydroxy lactams, albeit in low
yields with limited substrate scope.[8] In 2011, our group
reported the first selective monoreduction of phthalimides
Scheme 1. Different reported examples of homogeneous catalytic
reduction of phthalimides using hydrogen or silanes. TBAF=tetra-n-
butylammonium fluoride.
under mild reaction conditions using hydrosilanes as reducing
agents.[9] García et al. reported the nickel-catalyzed reduction
of phthalimide to benzamide and the carbonyl monohydro-
genation of phthalimide without reduction of the aromatic
ring but no general substrate scope was presented.[10]
Most recently, Agbossou-Niedetcom et al. reported the
rhodium/molybdenum-catalyzed full reduction of cyclic
imides (Scheme 1).[11] Finally, this year Xie et al. reported
the zinc-catalyzed reduction of cyclic imides with hydro-
silanes.[12] In any case, selective reduction of one of the
carbonyl groups was not achieved for aryl ring-substituted
phthalimides.
In recent years, the so-called ruthenium/Triphos catalyst
system
[Triphos = 1,1,1-tris(diphenylphosphinomethyl)-
ethane] showed unique activity for methylation of amines
with carbon dioxide[13] and hydrogenation of carboxylic acid
derivatives.[4b, 14] Inspired by this work, the hydrogenation of
N-methylphthalimide (1a) in the presence of [Ru(acac)3],
Triphos, and an organic acid [methanesulfonic acid (MSA)] as
co-catalyst was selected as a starting point of the present
investigation.[15] Firstly, the hydrogenation of this benchmark
substrate was conducted at 50 bar of H2, 1308C, and using
[*] Dr. J. R. Cabrero-Antonino, Dr. I. Sorribes, Dr. K. Junge,
Prof. Dr. M. Beller
Leibniz-Institut für Katalyse e.V.
Albert-Einstein-Str. 29a, 18059 Rostock (Germany)
E-mail: matthias.beller@catalysis.de
Supporting information and ORCID(s) from the author(s) for this
article are available on the WWW under http://dx.doi.org/10.1002/
anie.201508575.
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Table 1: Ruthenium-catalyzed reductive methoxylation of different sub-
stituted phthalimides.
methanol as a solvent. To our surprise, an unprecedented
reductive methoxylation of one of the carbonyl groups
occurred, thus affording 3-methoxy-2-methylisoindolin-1-
one (2a) in 91% yield (see entry 1 in Table SI1 in the
Supporting Information). When the reaction was carried out
with simple [Ru(acac)3], the aryl ring-hydrogenated product
2-methylhexahydro-1H-isoindole-1,3(2H)-dione (4a) was
afforded in good yield (76%), and traces of 2-methyloctahy-
dro-1H-isoindol-1-one (3a) were formed by the concomitant
ring and carbonyl reduction (see Table SI1, entry 2). Most
likely, ruthenium nanoparticles are formed here. Under
otherwise identical reaction conditions, the use of the [Ru-
(acac)3]/Triphos system in the absence of any cocatalyst
generated 3a in only 22% yield and the lactone isobenzo-
furan-1(3H)-one (5a) as the major product (see Table SI1,
entry 3). A plausible route for the formation of 5a involves
Entry[a]
Phthalimide 1
Product 2
Yield
[%][b]
1
2a (R’=Me)
94
2
3
4
1b
1c
1d
2b (R’=Et)
2c (R’=i-Pr)
2d (R’=n-Bu)
85
92
88
À
C N bond cleavage of the cyclic imide, followed by the
reduction of the aldehyde to the alcohol and cyclization after
release of methylamine. By using a combination of [Ru-
(acac)3]/MSA in the absence of Triphos, only 3a and 4a were
observed (see Table SI1, entry 4).
5
65
86
6[c]
Next, the influence of the amount of acid cocatalyst was
investigated in more detail (see Table SI1, entries 5–7).
Applying 4 mol% of MSA afforded a quantitative yield of
2a. Gratifyingly, the reaction also proceeded well when using
much lower amounts of the catalyst (see Table SI1, entries 9–
13). In addition, the influence of hydrogen pressure and
temperature were studied as critical parameters. To our
delight, 2a was obtained from 1a in excellent yield (> 99%)
at 15 bar of hydrogen (see Table SI1, entry 16). However,
when the reaction was conducted at 1008C, 2a was obtained
in lower yield (49%; see Table SI1, entry 18). By comparing
different ruthenium pre-catalysts and phosphine ligands (see
Tables SI2 and SI3 in the Supporting Information) it was
observed that the initially used [Ru(acac)3]/Triphos sys-
tem[14b,d,g,15,16] was the best, but similar results were also
obtained with [Ru(cod)(2-methylallyl)2] (cod = 1,5-cyclo-
octadiene).
7[d]
88
8
75
96
83
75
83
9
10
11[d]
12[e]
With these findings in hand, we decided to study the
reductive methoxylation of a wide range of N-substituted
phthalimides (Table 1). In the case of N-alkyl-substituted
phthalimides (1a–d), the reaction afforded the compounds
2a–d in up to 92% yield upon isolation (entries 1–4). For
ꢀ
phthalimides with alkyl substituents containing a C C bond
(1e–f), methoxylated products (2e–f) with a reduced triple
bond were obtained in good to excellent yields (entries 5 and
6). Other alkyl-substituted phthalimides containing hetero-
atoms (1g–i) also gave 2-methoxylated products (2g–i) in very
good yields (entries 7–9). It is noteworthy that for 1h the
ketone group was reduced but not methoxylated, whereas for
1i the dimethoxylated compound 2i was obtained. In
addition, N-substituted phthalimides with aryl or benzyl
groups (1j–l) afforded the corresponding products 2j–l in
high yields (entries 10–12). Interestingly, the reaction also
performed well for the tetrafluoro-substituted derivative 1m
to give the compound 2m in good yield (entry 13).
13[c,f]
76
[a] Standard reaction conditions: Phthalimide (0.5 mmol), [Ru(acac)3]
(1 mol%), Triphos (1.2 mol%), MeSO3H (2 mol%), H2 (15 bar), MeOH
(2 mL), 1308C, and 18 h. [b] Yield of isolated product. [c] Run with
[Ru(acac)3] (4 mol%), Triphos (5 mol%), and MeSO3H (8 mol%).
[d] Run for 6 h. [e] Run for 3 h. [f] Run at 50 bar of H2. acac=acetyl-
acetonate.
Next, we studied the reduction of more challenging aryl-
ring-substituted N-methylphthalimides (Scheme 2). To the
best of our knowledge regioselective hydrogenations have not
been achieved yet. Substrates containing electron-donor
groups, such as 4-NH2 (1n) and 4-NMe2 (1o), on the aromatic
ring gave excellent selectivities (> 94%) in the methoxylation
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either under neat conditions or in the presence of an excess of
alcohol using THF as the solvent (Scheme 5; see Table SI4 in
the Supporting Informmation). To our delight, primary and
secondary aliphatic alcohols, as well as phenethyl and
benzylic ones gave the corresponding 2-alkoxylated isoindol-
inones with good to excellent yields (8a–k). It should be
noted that this methodology allows to obtain fluorinated
isoindolinone derivatives in a straightforward manner (8c and
8k).
Finally, instead of alcohols we envisioned the possibility of
using amines for a selective reductive amination of phthal-
imides. As shown in Scheme 6, 1a and 1b can be directly
Scheme 2. Ruthenium-catalyzed selective reductive methoxylation of
different partially aryl-ring-substituted N-methylphtalimides. [a] Com-
bined yield of the two isolated regioisomers. [b] Yield of the isolated
major regioisomer. [c] Selectivity was determined by 1H NMR analysis
(see the Supporting Information). [d] Selectivity was calculated by GC-
MS.
of one of the carbonyl groups, thus affording 2n’ (94%) and
2o’ (96%), respectively. When the phthalimide aromatic ring
contains an electron-withdrawing group, such as Br, or an aryl
substituent (1p–t),[17] good to excellent yields of the corre-
sponding products were achieved (76–98%) with good
regioselectivities (65–76%).
Interestingly, the reaction can also be carried out in
intramolecular fashion (Scheme 3). Using phthalimide deriv-
atives 1u and 1v, the tricyclic compound 2u was obtained in
excellent yield in both cases. Remarkably, this protocol can
also be applied for the selective methoxylation of N-
substituted succinimides (6a–c), thus affording the corre-
sponding 2-methoxysuccinimides 7a–c in up to 84% yield
(Scheme 4).
Scheme 5. Ruthenium-catalyzed selective reductive alkoxylation of 1a
with alcohols. Yields of the isolated product are given. [a] Reaction
conditions: 1a (0.5 mmol), [Ru(acac)3] (1 mol%), Triphos (1.2 mol%),
MeSO3H (2 mol%), H2 (15 bar), alcohol (2 mL), 1308C and 18 h.
[b] Run with [Ru(acac)3] (4 mol%), Triphos (8 mol%), MeSO3H
(8 mol%), alcohol (7.5 mmol, 15 equiv), H2 (50 bar), THF (1 mL), and
150 8C. [c] Run with [Ru(acac)3] (2 mol%), Triphos (4 mol%), MeSO3H
(4 mol%), alcohol (7.5 mmol, 15 equiv), H2 (50 bar), and THF (1 mL).
THF=tetrahydrofuran.
The generality of this reductive alkoxylation protocol was
further investigated by reaction of 1a with different alcohols
Scheme 3. One-pot ruthenium-catalyzed intramolecular reductive cycli-
zation of 1u and 1v to give the compound 2u. Yields of the isolated
product are given. [a] Run with [Ru(acac)3] (4 mol%), Triphos
(8 mol%), MeSO3H (8 mol%).
Scheme 6. Ruthenium-catalyzed selective reductive amination of 1a
and 1b with amines. Yields of the isolated product are given.[a] Run
with amine (7.5 mmol, 15 equiv) and THF (1 mL). [b] Run with amine
(2 mL) as solvent.
Scheme 4. Ruthenium-catalyzed selective reductive methoxylation of
N-substituted succinimides. Yields of the isolated product are given.
[a] Run for 18 h.
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aminated, thus affording the corresponding 2-aminated iso-
indolinones (9a–e) in moderate yields. Other types of amines
could be used for this transformation.
In conclusion, we demonstrate the first reductive alkox-
ylation and amination of substituted phthalimides using
hydrogen as a reducing agent. By using a [Ru/Triphos]-
based catalyst system in combination with an organic acid, N-
substituted phthalimides react with a wide range of alcohols
and amines, thus affording the corresponding 2-substituted
isoindolinones in good to excellent yields. For aryl-ring-
substituted phthalimides an excellent selectivity for the
reduction of one of the carbonyl groups has been also
achieved for the first time. In addition, the reaction also
proceeds successfully in an intramolecular fashion to give
tricyclic compounds in high yields. It is shown that N-
substituted succinimides can also undergo this transformation
successfully.
Experimental Section
General procedure for the reductive alkoxylation or amination of
cyclic imides: A 4 mL glass vial containing a stirring bar was
sequentially charged with cyclic imide (0.5 mmol), [Ru(acac)3],
Triphos, alcohol or amine (15 equiv), and a freshly prepared 0.2m
MeOH or THF solution of the cocatalyst MeSO3H. Afterwards, the
reaction vial was capped with a septum equipped with a syringe and
set in the alloy plate, which was then placed into a 300 mL autoclave.
Once sealed, the autoclave was purged three times with 30 bar of
hydrogen, then pressurized to 15–50 bar and placed into an aluminum
block, which was preheated at 130–1508C. After 3–18 h, the autoclave
was cooled in an ice bath, and the remaining gas was carefully
released. Finally, reaction mixture was purified by silica gel column
chromatography (n-heptane/ethyl acetate mixtures).
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Keywords: homogeneous catalysis · heterocycles ·
reduction reactions · ruthenium · synthetic methods
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Received: September 25, 2015
Published online: November 11, 2015
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