Synthesis of cyclic imides from simple diols

Article abstract of DOI:10.1002/anie.201002136

There's something imide so strong: Cyclic imides were synthesized from simple diols with primary amines in a single step using an in-situ-generated ruthenium catalytic system. The atom-economical and operatively simple syntheses of succinimides, phthalimides, and glutarimides, which are important building blocks in natural products and drugs, was also demonstrated. Copyright

Full text of DOI:10.1002/anie.201002136

Angewandte
Chemie
DOI: 10.1002/anie.201002136
Cyclic Imides
Synthesis of Cyclic Imides from Simple Diols**
Jian Zhang, Muthaiah Senthilkumar, Subhash Chandra Ghosh, and Soon Hyeok Hong*
Imide derivatives are widely used organic compounds that
have numerous applications in biological, medicinal, syn-
thetic, and polymer chemistry.[1] In particular, cyclic imides
are important building blocks for natural products and drugs,
such as palasimide,[2] salfredins,[3] thalidomide,[4] julocrotine,[5]
lamprolobine,[6] migrastatin,[7] and phensuximide[1] (Figure 1).
boronic acids to maleimides for the synthesis of chiral
3-substituted succinimide derivatives.[15] However, each of
these routes has its own synthetic problems, especially when
applied to syntheses of a range of the cyclic imides, mostly
owing to the limited availability of suitably functionalized
starting materials. Therefore, the atom-economical synthesis
of functionalized imide derivatives from widely used precur-
sors is a challenging goal.
To address this challenge, we postulated that the imides
could be synthesized directly from alcohols with amines or
amides using a similar strategy to the reported oxidative
amide synthesis from alcohols and amines, catalyzed by
ruthenium-,[16,17] rhodium-,[18] and silver-based[19] complexes
(Scheme 1).[20] The strategy for the amide synthesis was to
oxidize the alcohol to the aldehyde first and then further
Figure 1. Examples of bioactive compounds containing a cyclic imide
moiety.
Despite their wide applicability, available routes for the
synthesis of cyclic imides from readily available starting
materials are limited.[1h] The typical methods are the dehy-
drative condensation of an anhydride with an amine at high
temperatures or with help of Lewis acid,[1,8] and the cycliza-
tion of an amic acid in the presence of acidic reagents,[1,9] both
of which are not atom economical, usually generating
stoichiometric amount of by-products.[10] Some recent
approaches include: the iridium-catalyzed multicomponent
synthesis of glutarimides;[11] the ring expansion of 4-formyl-b-
lactams for the synthesis of succinimide derivatives;[12] the
iron-catalyzed carbonylative succinimide synthesis using an
alkyne, CO, or NH3;[13] the ruthenium- or palladium-catalyzed
carbonylation of aromatic compounds leading to phthali-
mides;[14] and the rhodium-catalyzed 1,4-addition of aryl
Scheme 1. Synthesis of amides and cyclic imides from alcohols and
amines.
oxidize a hemiaminal, formed from the aldehyde and the
amine, to an amide, with the evolution of two equivalents of
hydrogen gas. We focused on identifying an active catalytic
system to realize a useful imide synthesis by promoting the
further reaction of the less-nucleophilic nitrogen atom of the
amide with alcohols. Herein, we report the first direct cyclic
imide synthesis from simple diols using an in-situ-generated
ruthenium-hydride-based catalyst.
The reaction between 1,4-butanediol (3a) and benzyl-
amine (4a) to afford N-benzylsuccinimide (5a) was chosen to
screen the catalytic conditions (Table 1). We started our
investigation by employing the reported ruthenium catalytic
systems used previously in amide synthesis by others[16] and
ourselves.[17] [{Ru(benzene)Cl2}2] (1a)[17a] and [{Ru(para-cym-
ene)Cl2}2] (1b)[17a] showed limited activity, even with the help
of an N-heterocyclic carbene (NHC) precursor, 1,3-diisopro-
pylimidazolium bromide (2), under basic conditions (Table 1,
entries 1 and 2). Unfortunately, use of the previously reported
[{Ru(para-cymene)Cl2}2] with a diphenylphosphinobutane
(dppb) ligand did not exhibit any activity for the imide
synthesis (Table 1, entry 3).[16b] Then, we noticed an early
example of the use of [RuH2(PPh3)4] (1c) for the synthesis of
[*] J. Zhang, Dr. M. Senthilkumar, Dr. S. C. Ghosh, Prof. S. H. Hong
Division of Chemistry and Biological Chemistry
Nanyang Technological University
21 Nanyang Link, SPMS-CBC-06-21, Singapore 637371 (Singapore)
Fax: (+65)6791-1961
E-mail: hongsh@ntu.edu.sg
[**] The Singapore National Research Foundation was gratefully
acknowledged for financial support (NRF-RF2008-05). J.Z. thanks
the Nanyang Technological University for a graduate student
scholarship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002136.
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Table 1: Catalyst screening.[a]
Table 2: Synthesis of succinimides from 1,4-butanediol.[a]
Entry
Amine
Amide
Yield
[%][b]
1
2
3
4b
4c
4d
5b
5c
5d
81
76
88
Entry
Catalyst
Ligand
Yield [%][b]
1[c]
2[d]
3[e]
4[f]
5[g]
6[h]
7[i]
1a
1b
1b
1c
1c
1d
1e
2, CH3CN
2, pyridine
dppb
14
24
0
–
0
2, CH3CN
2, PCy3
–
70
41
52
[a] Typical reaction conditions: 3a (0.5 mmol, 1.0 equiv), 4a (0.55 mmol,
1.1 equiv), a solvent (0.8 mL), reflux, 24 h. [b] Yields are of the isolated
product, and represent the average of at least two runs. [c] 1a
(2.5 mol%), 2 (5 mol%), NaH (15 mol%), CH3CN (5 mol%), tolue-
ne.[17a] [d] 1b (2.5 mol%), 2 (5 mol%), NaH (15 mol%), pyridine
(5 mol%), toluene.[17a] [e] 1b (2.5 mol%), dppb (5 mol%), 3-methyl-2-
butanone (2.5 equiv), Cs2CO3 (10 mol%), tBuOH.[16b] [f] 1c (5 mol%), 1-
4
4e
5e
87
hexyne (2.5 equiv), DME.[16a] [g] 1c (5 mol%),
2 (5 mol%), NaH
5
6
7
4 f
4g
4h
5 f
5g
5h
61
44
73
(20 mol%), CH3CN (5 mol%), toluene.[17c] [h] 1d (5 mol%),
2
(5 mol%), PCy3 (5 mol%), KOtBu (20 mol%), toluene.[16c] [i] 1e
(5 mol%), toluene.[16d] DME=1,2-dimethoxyethane.
cyclic lactams from a,w-aminoalcohols by Naota and Mur-
ahashi (Figure 2).[16a] Although their original conditions, using
a hydrogen acceptor, afforded no 5a product (Table 1,
entry 4), [RuH2(PPh3)4] showed good activity (70%) with
8
4i
4j
5i
5j
59
73
68
57
36
9
Figure 2. Ruthenium catalysts.
10
11
12
4k
4l
5k
5l
the help of NHC precursor 2 (Table 1, entry 5).[21] The NHC-
promoted [RuH2(PPh3)4]-based catalyst was recently
reported to be active for the synthesis of amides from either
alcohols or aldehydes with amines.[17c] Other catalytic systems
based on 1d[16c] and 1e[16d] exhibited lower activities in the
cyclic-imide synthesis (Table 1, entries 6 and 7).
4m
5m
Having identified our active catalytic system, we tested
various amines with 1,4-butandiol to afford N-substituted
succinimide derivatives (Table 2). Excellent activities were
observed with alkyl and benzyl amines (Table 2, entries 1–5).
Noticeably, more-electron-rich benzyl amines favored the
cyclization reaction than electron-poor ones (Table 2,
entries 4–5; cf. Table 1, entry 5). Pyridine and ether groups
were tolerant in this reaction (Table 2, entries 6–9). While
2-aminomethylpyridine (4g) exhibited a lower yield, presum-
ably owing to interference of ruthenium binding to 3a, the
reactions of 3-aminomethylpyridine (4h) and 4-aminome-
thylpyridine (4i) proceeded smoothly (Table 2, entries 6–8).
Moderately hindered amines proceeded well to generate their
[a] Reaction conditions: 3a (0.5 mmol, 1.0 equiv), amine (1.1 equiv), 1c
(5 mol%), 2 (5 mol%), NaH (20 mol%), CH3CN (5 mol%), toluene
(0.5 mL), reflux, 24 h. [b] Yields are of the isolated product, and represent
the average of at least two runs.
corresponding succinimides, although it was sensitive to steric
hindrance, as reported in the previous amide syntheses
(Table 2, entries 10–12).[16–17] In the case of less-basic aryl
amines, such as aniline, the reaction did not proceed as well as
observed in the analogous amide synthesis.[16c,17] g-Butyrolac-
tone was observed, especially with low yielding substrates
(e.g. 5% with 4g, and 13% with 4m), along with other
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unidentified messy by-products, presumably from possible
inter- and intra-molecular amidation and esterification reac-
tions.[22,23]
moderate yields (Table 3, entries 8–9). However, the synthesis
of a seven-membered cyclic imide from 1,6-hexanediol was
not successful. An anticonvulsant drug, phensuximide (5w)
was synthesized from the corresponding diol 3n with methyl-
amine in 63% yield (Table 3, entry 10).
Excited by the facile synthesis of succinimide derivatives
from 3a, various diols were screened to synthesize cyclic
imides (Table 3). 2-aryl- or alkyl-functionalized 1,4-butane-
diols generated their corresponding succinimides in good
yields (Table 3, entries 1 and 2). A bicyclic succinimide
derivative 5p was also smoothly synthesized from cis-1,2-
cyclohexanedimethanol (3p; Table 3, entry 3). Phthalimide
derivatives were obtained from 1,2-benzenedimethanol (3q)
in good yields (Table 3, entries 4–7). At a lower concentration
(0.3m), phthalide (61%) was observed as the major product
along with 5q (21%). The effective phthalide synthesis from
3q was previously reported with Cp*/ruthenium(II)-catalyst
systems.[22f] Six-membered glutarimides were also formed in
The synthesis of linear imides from the intermolecular
reaction of amides or amines with alcohols was attempted
next (Scheme 2). However, whether the reaction was run
from an amide 6 with 1-pentanol (7) or an amine 4e with two
equivalents of 7, none of the corresponding linear imide 8
product was detected. Only amide 9 was observed in the
reaction of 4e and two equivalents of 7. In the intramolecular
reaction of 10, the reaction proceeded well with 70% yield
suggesting that the cyclic imide formation may proceed via a
stepwise mechanism with a favored intramolecular 5- or 6-
membered ring formation.
On the basis of the observa-
tions in Scheme 2 and the reason-
able previously suggested mecha-
Table 3: Synthesis of cyclic imides from diols.[a]
Entry
Diol
Amine
Cyclic imide
Yield
[%][b]
nisms for amide formation from
alcohols and amines,[16,17] we pro-
posed a mechanism involving the
formation of an amide intermedi-
ate and further cyclization to the
imide product by an intramolecu-
lar reaction of the amide inter-
mediate (Scheme 3). The observa-
tion of lactones, either in low
yielding reactions or in lower con-
centrations, can be explained by an
intramolecular reaction of an alde-
hyde intermediate as reported.[22]
1
2
3
4
5
3n
3o
3p
3q
3q
4e
4e
4e
4e
4d
5n
5o
5p
5q
5r
78
55
80
74
67
The involvement of
a lactone
intermediate in the formation of
a cyclic imide was ruled out from
the reaction of g-butyrolactone
with 4e, as
a trace amount
(< 5%) of the corresponding suc-
cinimide 5e was observed. The
nature of the exact catalyst struc-
ture is under investigation to fully
understand the mechanism and
expand the reaction scope to the
synthesis of linear imides, espe-
cially in regards of the role of a
strong base and possible chelation
effect from the intermediates; it
has been suggested that a strong
base is required to activate preca-
talysts by reaction with an alkox-
ide, formed from an alcohol sub-
strate, and the strong base, as well
as the generation of an NHC from
its precursor.[17]
6
7
8
9
3q
3q
3u
3u
4s
4h
4e
4a
5s
5t
61
51
51
48
5u
5v
10
3n
CH3NH2
4w
5w
63
In conclusion, we have demon-
strated that cyclic imides can be
synthesized directly from simple
diols using an in-situ-generated
ruthenium catalytic system. This
[a] Reaction conditions: Diol (0.5 mmol, 1 equiv, 1.0m), amine (1.1 equiv), 1c (5 mol%), 2 (5 mol%),
NaH (20 mol%), CH3CN (5 mol%), toluene (0.5 mL), reflux, 24 h. [b] Yields are of the isolated product,
and represent the average of at least two runs.
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Keywords: diols · homogeneous catalysis · imides ·
.
N-heterocyclic carbenes · ruthenium
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Experimental Section
1c (28 mg, 0.025 mmol), 2 (5.8 mg, 0.025 mmol), NaH (2.4 mg,
0.10 mmol), and CH3CN (1.2 mL, 0.025 mmol) were placed in an
oven-dried Schlenk tube inside the glove box before toluene (0.5 mL)
was added to the mixture. The Schlenk tube was taken out of the
glove box and heated to reflux in an oil bath under an argon
atmosphere. The flask was removed from the oil bath after 20 min and
a diol (0.50 mmol) and an amine (0.55 mmol) were added. The
reaction mixture was heated to reflux under a flow of argon to
facilitate the removal of hydrogen for 24 h before being cooled down
to room temperature. All the volatiles were removed under vacuum.
Purification of the crude product was performed by column chroma-
tography on silica gel.
Received: April 12, 2010
Revised: May 12, 2010
Published online: July 26, 2010
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