Synthesis of cyclic imides from nitriles and diols using hydrogen transfer as a substrate-activating strategy

Article abstract of DOI:10.1021/ol501835t

An atom-economical and versatile method for the synthesis of cyclic imides from nitriles and diols was developed. The method utilizes a Ru-catalyzed transfer-hydrogenation reaction in which the substrates, diols, and nitriles are simultaneously activated into lactones and amines in a redox-neutral manner to afford the corresponding cyclic imides with evolution of H₂ gas as the sole byproduct. This operationally simple and catalytic synthetic method provides a sustainable and easily accessible route to cyclic imides.

Full text of DOI:10.1021/ol501835t

Letter
pubs.acs.org/OrgLett
Synthesis of Cyclic Imides from Nitriles and Diols Using Hydrogen
Transfer as a Substrate-Activating Strategy
Jaewoon Kim and Soon Hyeok Hong*
Department of Chemistry, College of Natural Sciences, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul 151-747,
Republic of Korea
S
* Supporting Information
ABSTRACT: An atom-economical and versatile method for the
synthesis of cyclic imides from nitriles and diols was developed. The
method utilizes a Ru-catalyzed transfer-hydrogenation reaction in
which the substrates, diols, and nitriles are simultaneously activated
into lactones and amines in a redox-neutral manner to afford the
corresponding cyclic imides with evolution of H2 gas as the sole
byproduct. This operationally simple and catalytic synthetic method provides a sustainable and easily accessible route to cyclic
imides.
yclic imide is a key functional group in synthetic,
biological, medicinal, and polymer chemistry.1 In
Scheme 1. Synthesis of Imides from Nitriles
C
particular, the cyclic imide group is found in several drugs
such as thalidomide,2 phensuximide,3 buspirone,4 and lurasi-
done,5 and several derivatives have been recently evaluated as
attractive new drug candidates with high bioactivities.6 Despite
their utility, the conventional methods for the preparation of
cyclic imides have many limitations such as harsh thermal
reaction conditions and harmful waste generation from the
activating reagents used.1,7 Although some newer methods
involving transition metal catalysis or skeleton rearrangement
have been developed to overcome poor atom-economy and low
efficiency, limited access to starting materials has restricted the
utility of these methods.8 To address the challenge, we
previously reported an efficient synthetic strategy for cyclic
imides from diols and amines.9
Nitrile is a useful and versatile functional group to
incorporate a nitrogen atom into a chemical skeleton. Several
studies have focused on the synthesis of imides from nitriles.
Murahashi and co-workers developed a three-component
reaction involving nitriles, vinylnitriles, and water to afford
the corresponding glutarimides, using the carbons of the nitriles
as the carbonyl source by the hydration of the nitrile groups
(Scheme 1A).8a In other examples, the imide moiety is
generated by the addition of a nitrile to an electrophilic
carbonyl carbon followed by the hydration of the nitrile
(Scheme 1B−D).10
Inspired by our recently developed catalytic amide synthesis
from nitriles and alcohols,11 we developed a novel atom-
economical and catalytic synthetic method for cyclic imides
from versatile nitriles and alcohols (Scheme 1). This is a
distinct method for imide synthesis directly from nitriles,
compared to the other methods using nitrile carbon as the
carbonyl source (Scheme 1A−D). Initially, we hypothesized
that first a direct amide bond formation would occur between
one of the alcohol groups of diol and nitrile in the same manner
as described in the previous study.11 However, we observed
that the nitrile was fully reduced to an amine using the
hydrogen atoms of the diol along with the generation of a
lactone (Scheme 1). Notably, this reaction adopts redox-neutral
Received: June 25, 2014
© XXXX American Chemical Society
A
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Letter
a
,b
hydrogen transfer as the substrate-activating strategy to
generate both the reactive nucleophile and electrophile in the
reaction mixture.
Scheme 2. Cyclic Imides from Diols and Nitriles
The reaction of 1,4-butanediol (1a) with benzonitrile (2a)
was selected as the model system to optimize the reaction
conditions (Table 1). RuH2(PPh3)4 was selected as the
a
Table 1. Optimization of Reaction Conditions
b
entry
1
ligand
solvent
concn (M)
yield (%)
4
4
4
4
4
5
6
7
8
4
4
4
4
4
4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
benzene
benzene
anisole
anisole
xylene
0.8
0.8
0.4
1.3
1.7
0.8
0.8
0.8
0.8
0.8
0.4
0.8
0.8
0.8
0.8
61
48
66
63
59
22
24
39
47
71
77
61
44
53
0
c
2
3
4
5
6
7
8
9
d
10
d
11
12
e
13
14
15
DMF
a
Reaction conditions: 1a (0.55 mmol, 1.1 equiv), 2a (0.50 mmol, 1.0
equiv), RuH2(PPh3)4 (5 mol %), ligand (5 mol %), NaH (20 mol %),
solvent (0.6 mL for 0.8 M), 110 °C in an open system under argon
b
c
atmosphere for 24 h unless otherwise noted. Determined by GC. In
a closed system. 80 °C. 140 °C.
d
e
precatalyst for the reaction after screening various ruthenium
complexes and their analogs known as the catalysts for
dehydrogenative amide synthesis.12 When the reaction was
performed in a closed system, the yield of the product
decreased (entry 2). Because the reaction generates hydrogen
gas, liberating hydrogen in an open system facilitated the
reaction. The reaction proceeded better with lower concen-
trations (entries 3−5 and 10−11). Among the N-heterocyclic
carbene (NHC) precursors investigated, 4 resulted in the
highest yield (entries 6−9). Among the various solvents
investigated, benzene produced the highest yield (77%) under
reflux conditions (entries 10−15).
With the optimized conditions in hand, the reactions of
various nitriles with diols were investigated, affording the
corresponding cyclic imides (Scheme 2). Various aliphatic
nitriles afforded the corresponding succinimides in good yields,
including secondary cyanides which were moderately hindered
(3b−3f and 3j). The reactions of benzonitrile derivatives also
proceeded well, affording 3g−3i in good yields. Noticeably,
electron-poor benzonitriles exhibited relatively lower activity
(3h and 3i). When an aliphatic nitrile bearing an olefin group,
5-hexenenitrile, was applied, the corresponding amide 3j was
obtained in a moderate yield with the reduction of the olefin
group. We also investigated the reactions with various diols
a
Reaction conditions: diol (0.55 mmol, 1.1 equiv), nitrile (0.50 mmol,
1.0 equiv), RuH2(PPh3)4 (5 mol %), 4 (5 mol %), NaH (20 mol %),
benzene (1.2 mL, 0.4 M), 80 °C in an open system under an argon
b
atmosphere for 18 h. Isolated yield.
(3k−3s). Sterically favored cis-1,2-cyclohexanedimethanol
afforded bicyclic succinimide derivatives in very good yields
(3k−3n). Phthalimide derivatives were synthesized from 1,2-
benzenedimethanol in good yields (3o−3q). Moreover, the
reaction with 2-phenylbutanediol afforded the corresponding
cyclic imide in a fair yield (3r). In the case of 1,5-pantanediol,
six-membered glutarimide (3s) was obtained in 43% yield with
unidentified messy byproducts. Heterocyclic nitriles such as
pyridinecarbonitriles and thiophenecarbonitriles did not work
well under our reaction conditions presumably due to their
coordination to catalytically active Ru species.
Inspired by the results, the synthesis of a linear imide was
attempted with 2 equiv of alcohol (9) and nitrile (2b) (Scheme
B
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3). However, we could obtain only amide (10) without any
formation of the target linear imide (11). When the reaction
involvement of lactone and amine as the intermediates in the
reaction.
Additional experiments were performed to verify that 13 and
14 were involved in the major reaction pathway (Scheme 4). In
Scheme 3. Attempts To Synthesize Imides
Scheme 4. Cyclic Imide from Lactone and Amine
was performed with hydroxyamide (12), which is a possible
intermediate for the cyclic imide formation, the reaction
proceeded well in 67% yield (Scheme 3). This suggests that the
formation of the second C−N bond to afford cyclic imide
requires a kinetic favor of intramolecular ring formation after
the formation of the first intermolecular amide bond.
To investigate a possible reaction mechanism, a kinetic study
was conducted by monitoring the progress of the reaction of 1a
with 2a (Figure 1). Interestingly, γ-butyrolactone (13) and
the presence of a catalytic amount of both a diol (1a) and
nitrile (2a), the reaction of 13 with 14 proceeded smoothly to
afford 3a in 76% yield. This result also supports that hydrogen
transfer from the diol to the nitrile affording a lactone and an
amine is a key step in the mechanism of cyclic imide formation.
Notably, the reaction failed in the absence of 1a or 2a (Scheme
4, entries 1−3). This result indicates that both the nitrile and
diol are necessary for the catalysis. We assume that the nitrile
not only works as a substrate but also works as a ligand, and the
diol works as a hydrogen source for the generation of an active
Ru-hydride catalytic intermediate.
Based on the experimental observation, we propose the
following reaction mechanism (Scheme 5). First, the hydrogen
Scheme 5. Proposed Mechanism
Figure 1. Reaction profiles showing the relative amounts of substrates
and products. 1a (0.55 mmol, 1.1 equiv), 2a (0.50 mmol, 1.0 equiv),
[RuH2(PPh3)4] (5 mol %), 4 (5 mol %), NaH (20 mol %), benzene
(0.6 mL), 80 °C in an open system under an argon atmosphere. The
progress of the reaction was monitored by GC analysis using dodecane
as the internal standard.
benzylamine (14) were observed as the major intermediates.
We found that 13 and 14 were quickly generated along with the
rapid consumption of 1a and 2a, while the formation of 12 was
slow. The concentrations of 12, 13, and 14 slowly decreased
while that of a cyclic imide (3a) gradually increased. This
reaction profile is different than our previously reported
amidation of a nitrile.11 In the presence of a monoalcohol
and nitrile, an imine was detected without any amine indicating
an inner-sphere-type mechanism.11 In contrast, the diol and
nitrile substrates generated an equivalent amount of lactone
(13) and amine (14) constantly. This strongly suggests the
transfer from the diol to the nitrile affords the corresponding
lactone and amine. Then, the reaction of the lactone with the
amine affords the corresponding hydroxyamide. The remaining
alcohol group is then dehydrogenated by the Ru catalyst to
generate hydrogen gas and aldehyde, which further reacts with
the nitrogen atom of the amide group to afford a hemiaminal
intermediate. Finally, the dehydrogenation of the hemiaminal
provides the cyclic imide product. Although the hydroxyamide
can be formed directly from the nitrile and alcohol without the
involvement of the lactone and amine, this would be less likely
because we observed the rapid generation of the lactone and
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amine as the major intermediates at the initial stage of the
reaction (Figure 1).
In conclusion, we developed an atom-economical and
versatile protocol for the synthesis of cyclic imides from nitriles
and diols, readily available starting materials. The reaction
involves a Ru-catalyzed transfer-hydrogenation reaction to
simultaneously activate the two substrates, a diol and nitrile,
into the corresponding lactone and amine in a redox-neutral
manner. This operationally simple protocol provides an
efficient route to diverse cyclic imides.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and compound characterization data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
(9) (a) Zhang, J.; Senthilkumar, M.; Ghosh, S. C.; Hong, S. H. Angew.
Chem., Int. Ed. 2010, 49, 6391. (b) Muthaiah, S.; Hong, S. H. Synlett
2011, 1481.
*E-mail: soonhong@snu.ac.kr.
(10) (a) Kikukawa, K.; Kono, K.; Wada, F.; Matsuda, T. Bull. Chem.
Soc. Jpn. 1982, 55, 3671. (b) Kopylovich, M. N.; Pombeiro, A. J. L.;
Fischer, A.; Kloo, L.; Kukushkin, V. Y. Inorg. Chem. 2003, 42, 7239.
(c) Habibi, Z.; Salehi, P.; Zolfigol, M. A.; Yousefi, M. Synlett 2007, 812.
(11) Kang, B.; Fu, Z.; Hong, S. H. J. Am. Chem. Soc. 2013, 135,
11704.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank B. Kang in our group for helpful discussions. This
work was supported by the Basic Science Research Program
(NRF-2012R1A1A1004077) and the Science Research Center
Program (NRF-2014R1A1A5A1011165, Center for New
Directions in Organic Synthesis) through the National
Research Foundation of Korea. We also thank the National
Center for Inter-University Research Facilities of Seoul
National University (NCIRF) for HR-MS analysis.
(12) See Supporting Infromation for details.
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