Synthesis of Cyclic Imides by Acceptorless Dehydrogenative Coupling of Diols and Amines Catalyzed by a Manganese Pincer Complex

Article abstract of DOI:10.1021/jacs.7b08341

The first example of base-metal-catalyzed dehydrogenative coupling of diols and amines to form cyclic imides is reported. The reaction is catalyzed by a pincer complex of the earth abundant manganese and forms hydrogen gas as the sole byproduct, making the overall process atom economical and environmentally benign.

Full text of DOI:10.1021/jacs.7b08341

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Communication
Synthesis of Cyclic Imides by Acceptorless Dehydrogenative Coupling
of Diols and Amines Catalyzed by a Manganese Pincer Complex
Noel Angel Espinosa-Jalapa, Amit Kumar, Gregory Leitus, Yael Diskin-Posner, and David Milstein
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b08341 • Publication Date (Web): 10 Aug 2017
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Synthesis of Cyclic Imides by Acceptorless Dehydrogenative Cou-
pling of Diols and Amines Catalyzed by a Manganese
Pincer Complex.
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Noel Angel Espinosa-Jalapa,† Amit Kumar,† Gregory Leitus,§ Yael Diskin-Posner§ and David Mil-
stein.†,*
Department of †Organic Chemistry and §Chemical Research Support, The Weizmann Institute of Science, Rehovot
76100, Israel.
Supporting Information Placeholder
diols and amines are inexpensive and readily available, and
the reaction generates valuable dihydrogen as the only by-
ABSTRACT: The first example of base-metal-catalyzed dehy-
drogenative coupling of diols and amines to form cyclic imides is
product. This makes the overall process atom economical
and environmentally benign.
reported. The reaction is catalyzed by a pincer complex of the
earth abundant manganese and forms hydrogen gas as the sole by-
product, making the overall process atom economical and envi-
ronmentally benign.
Hydrogenation and dehydrogenation reactions cata-
lyzed by Mn pincer complexes became a hot area of research,
after our initial report on Mn catalyzed dehydrogenative
coupling of alcohols and amines to form imines.17 We have
recently reported the synthesis and reactivity of the Mn(I)
complex 1 bearing a pyridine-based PNNH pincer ligand.17d
In the presence of a base, complex 1 showed high catalytic
activity for a broad-scope hydrogenation of non-activated
esters under mild conditions. The active catalyst was charac-
terized as the amido complex 2, which was prepared by the
deprotonation of 1 and also generated in situ (Scheme 1). H2
activation takes place by metal-ligand cooperation (MLC),18
in which the manganese metal center and the PNNH-pincer
ligand participate synergistically. We now report that the
manganese complex 1, in the presence of a catalytic amount
of KH, catalyzes the atom-economical and environmentally
benign synthesis of cyclic imides from diols and amines
(Scheme 1).
Cyclic imides are an important class of organic com-
pounds, valuable for synthetic, biological and polymer chem-
istry.1 They are also used for a variety of pharmacological
purposes such as sedatives, hypnotics, anticonvulscants,
hypotensive agents, antitubercular agents and carcinostat-
ics.1a,2 Several drugs containing the cyclic imide group, such
as thalidomide,3 phensuximide,4 buspirone5 and luracidone6
are on the market and many derivatives are potential drug
candidates.7 Due to such high industrial value, an atom eco-
nomic, sustainable and environmentally benign synthetic
route to cyclic imides from cheap starting materials is highly
desirable. However, the conventional method for the synthe-
sis of cyclic imides involves harsh thermal conditions and
generates stoichiometric amounts of waste.1a,8 Recent devel-
opments towards efficient transition metal catalyzed synthe-
sis of cyclic imides include iridium catalyzed three compo-
nent reaction of nitriles, olefins and water to produce glu-
tarimides;9 palladium catalyzed carbonylative cyclization of
o-halobenzoates and primary amines to form isoindole-1,3-
diones;10 ruthenium catalyzed carbonylation of aromatic
amides to form phthalimides,11 and rhodium catalyzed conju-
gate addition of phenyl boronic acids to unprotected malei-
mides.12 Asymmetric cyclic imides have also been synthesized
using rhodium catalysts.13 Drawbacks of these methods in-
clude expensive and toxic noble-metal based systems, limited
availability of appropriate starting materials, and, in some
cases, waste generation. Fe3(CO)12 catalyzed carbonylation of
alkynes using excess ammonia and CO pressure to form
succinimides has also been reported.14
Scheme 1. Dehydrogenative coupling of alcohols and
amines to form cyclic imides and the pyridine-based
pincer complexes used in this study.
Several years ago, we reported the dehydrogenative
coupling of alcohols and amines to form amides, involving
metal-ligand cooperation, catalyzed by a Ru-PNN* (the aster-
isk denotes the dearomatized ligand) complex 4,19 which can
be obtained by treatment of the hydrido chloride complex 3
by a base. We have now synthesized the analogous Mn-PNN
complexes 5 and 6. Complex 5 was prepared by the reaction
of Mn(CO)5Br with the PNN ligand in THF. It was isolated in
Hong reported the synthesis of cyclic imides from diols
and amines using a ruthenium catalyst,15 and recently the
coupling of nitriles and diols to form cyclic imides catalyzed
by RuH2(PPh3)4.16 Both these synthetic methods use rutheni-
um (5 mol%) and base (20 mol%). Herein we report the first
base-metal (manganese) catalyst for the dehydrogenative
coupling of diols with amines (Scheme 1). Both the substrate
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88% yield and characterized by NMR and IR spectroscopy
and single crystal X-ray diffraction. Upon addition of 1.2
equivalents of KOtBu to a suspension of 5 in pentane the
solution became dark green, yielding the dearomatized Mn-
PNN* complex 6 which was isolated in 79% yield (See SI for
the synthesis and characterization of complexes 5 and 6).
The new complex 6 was first tested for the synthesis of cyclic
imides. However, no reaction was observed upon refluxing a
toluene solution (2 mL) of 1,4-butanediol (1 mmol) and 4-
methyl-benzylamine (1 mmol) for 40 hrs in presence of 6 (5
mol%) or in the presence of 5 (5 mol%) and KH (10 mol%,
See SI, Table S4). On the other hand, using catalyst 1 (5
mol%) and KH (5 mol%) under the same reaction conditions,
87% conversion of the amine was observed after 40 hrs to
give the correspondig succinimide in 72% isolated yield (En-
try 5). Increasing the amount of base to 10 mol% resulted in
the quantitative conversion of the amine and the product
succinimide was isolated in 92% yield (Table 1, 7a). Under
these catalytic conditions, aromatic amines were converted
to succinimide derivatives in good to excellent isolated yields
(7a–j). In the case of hexylamine, quantitative conversion of
the amine was observed under analogous catalytic condi-
tions, but the respective succinimide was isolated in only
29% yield, along with unidentified products. However, per-
forming the reactions at lower concentration (0.25 M of diols
and amines) improved the yield of the N-alkyl substituted
imides. The low isolated yields (42-67%) in the case of ali-
phatic amines are a result of formation of some uncharacter-
ized by-products (7k–p). In the case of tert-butylamine and
4-methylaniline, formation of cyclic imides was not observed
showed formation of H2. Using a gas-burette, 56 mL of gas
were collected (see SI for details), and H NMR spectroscopy
showed the formation of 63% yield of 7a (in an open system
7a was obtained quantitatively). Thus, 3.7 equivalents of
hydrogen gas were collected per one equivalent of cyclic
imide.
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The catalytic activity of the PNNH complex 1 was also
compared with that of the ruthenium PNN complex 3. Reac-
tion of 1,4-butanediol with benzylamine in presence of 3 (5
mol%) and KH (10 mol%) resulted in the formation of 7b in
59% yield after 24 hrs. Under the same condition, when
complex 1 (5 mol%) and KH (10 mol%) were used, 48% of the
cyclic imide was obtained after 24 hrs exhibiting comparable
catalytic activity relative to ruthenium. On the other hand,
the Mn PNN complex 5, analogous to the Ru complex 3, is
not catalytically active.
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Following the facile synthesis of succinimide derivatives
from 1,4-butanediol, we explored the possibility of the syn-
thesis of N-substituted glutarimides from 1,5-pentanediol
and various amines (See SI, Table S6). Preliminary studies of
the reaction of 1,5-pentenediol under conditions established
for the synthesis of N-benzyl succinimides afforded the de-
sired N-benzyl glutarimide in only 12% yield, along with
other unidentified products. Using a higher catalyst loading
(10 mol%) and lower substrate concentration (0.125 M) glu-
tarimide derivatives were isolated in good to moderate yields
(49-72%). Reaction of the more challenging 1,3-propanediol
and 4-methylbenzylamine under conditions described in
Table 1 (same as that of 7a) did not result in any consump-
tion of amine after 40 hrs and no formation of lactone or
amide was observed by 1H NMR spectroscopy and GC-MS.
1
and H NMR spectroscopy showed only formation of lactone
Investigating the mechanism of cyclic imide formation,
we first studied the catalytic dehydrogenation of diols. When
Table 1. Synthesis of N-substituted succinimide deriva-
tives.a,b
a
toluene solution containing 1 mmol of 1,2-benzene-
dimethanol, complex 1 (1 mol%) and KH (2 mol%) was re-
fluxed under argon atmosphere for 18 hrs, quantitative con-
version of the diol was observed to give phthalide in 99%
yield. The aliphatic 1,4-butanediol and 1,5-pentanediol were
also successfully dehydrogenated, yielding γ-butyrolactone
and δ-valerolactone respectively (See SI, Table S3). The de-
hydrogenative cyclization of diols to lactones was mainly
reported with noble metals such as ruthenium, iridium and
palladium.20 Beller recently reported the synthesis of lactones
from diols catalyzed by an iron(II) pincer complex with a
wide substrate scope.21 The catalytic activity of the Mn com-
plex 1 reported here is similar to that of the iron complex.
Very recently, dehydrogenative coupling of alcohols to form
esters catalyzed by a Mn pincer complex was reported by
Gauvin.17e
The facile dehydrogenation of diols to form lactones
suggests that a lactone might be an intermediate in the for-
mation of imides from diols. In fact, the reaction of γ-
butyrolactone with 4-methylbenzylamine catalyzed by 1 (5
mol%) and KH (10 mol%) resulted in 68% conversion of the
amine with 65% yield of the corresponding cyclic imide,
along with unreacted γ-butyrolactone (20%) after 28 hrs
(Scheme 2, n = 1). The reaction of δ-valerolactone with 4-
methylbenzylamine rendered quantitative conversion of the
amine after 28 hrs with 78% isolated yield of the correspond-
ing cyclic imide (Scheme 2, n = 2). When the reaction of γ-
butyrolactone with 4-methylbenzylamine was conducted in
the absence of catalyst, 50% consumption of 4-
1
(a) Conversions based on consumption of the amine, determined by H NMR
and GC-MS with mesitylene as internal standard. All reactions were performed
in open Schlenk tube under argon (b) Yields of isolated product in brackets.
(c) Reaction conditions: [Mn] = 1 (5 mol%), KH (10 mol%), toluene (2 mL), 1,4-
butanediol (1.0 mmol), amine (1.0 mmol), internal standard (mesitylene, 1
mmol), reflux, 40 hrs. (d) 1,4-butanediol (0.5 mmol), amine (0.5 mmol), inter-
nal standard (mesitylene, 0.5 mmol). (e) 1,4-butanediol (0.5 mmol), amine
(0.25 mmol), and internal standard (mesitylene, 0.5 mmol).
along with the unreacted amines. For the detection of hydro-
gen gas, a reaction for the synthesis of 7a was performed in a
closed Schlenk tube under the conditions of Table 1 for the
synthesis of 7a. Analysis of the gas phase after 40 hrs by GC
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methylbenzylamine was observed by NMR spectroscopy after
(Scheme 3I) suggests that pathway I also operates. The re-
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40 hrs. Hydroxyamide was isolated in 48% yield along with
the unreacted γ-butyrolactone (50%) and no cyclic imide was
observed after the reaction. This suggests that the manga-
nese catalyst is essential for the formation of cyclic imides as
also previously reported by Hong.15
maining hydroxy group of the hydroxyamide B can then
dehydrogenate to form the aldehyde C which can undergo
intramolecular cyclization to produce the cyclic hemiaminal
intermediate D. Finally, dehydrogenation of D can lead to
the cyclic imide (Scheme 4). Noteworthy, Hong reported a
mechanism for the Ru-catalyzed reaction which excludes
lactone intermediacy.15a
Scheme 2. Reaction of lactones with amines.a
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Scheme 4. Proposed mechanism for the dehydrognea-
tive coupling of diols and amines to form cyclic imides.
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aConditions for (I): [Mn] 1 (5 mol%), KH (10 mol%), toluene (2 mL), reflux 28
hrs, lactone (1 mmol for n=1 and 0.5 mmol for n=2), 4-methylbenzylamine (1
mmol for n=1 and 0.5 mmol for n=2).
We further studied the reaction of 1,5-pentanediol with
4-methyl benzylamine, under identical condition to those
used for the synthesis of glutarimide derivatives (Table S1),
and monitored the reaction by NMR spectroscopy. Interest-
ingly, when the reaction was stopped after 1 hr, a mixture of
hydroxyamide (B) and lactone was obtained in 14% and 22%
yields, respectively, whereas formation of glutarimide was
not observed at this stage (Scheme 3 (I)). Over time, a white
precipitate was observed, presumably due to formation of the
less soluble glutarimide. After 40 hrs, glutarimide and B were
isolated in 57% and 20% yield, respectively (Scheme 3(II)).
Interestingly, when a separate reaction was carried out for 40
hrs and then recharged with the catalyst (5 mol% 1 and 10
mol% KH), B was completely consumed after 12 hrs of re-
charge and the corresponding glutarimide was isolated in
80% yield (Scheme 3(II), see Figure S1 in SI for more details),
suggesting that cyclic imide formation occurs via the hydrox-
yamide intermediate (B).
Exploring the role of the metal complex, we strongly
believe that deprotonation of N-H proton is important for
the formation of active catalyst, as the dearomatized -NEt2
manganese complex 6 is catalytically inactive. In a control
experiment, when the independently prepared amido com-
plex 2 was used as the catalyst under the condition described
in Table 1, 68% of succinimide was obtained starting from
1,4-butanediol and 4-methylbenzylamine, confirming that 2
is an active catalyst. Further, we studied the stoichiometric
reactivity of the deprotonated manganese complex 2 with
diols. Addition of 2 equivalents of 1,4-butanediol to the dark
blue solution of complex 2 in tol-d8 at room temperature
resulted in an immediate color change to dark red and for-
mation of a new complex, characterized as the manganese
alkoxy complex 8. The IR spectrum of 8 exhibits two strong
absorption bands at 1832 (νasym) and 1915 cm-1 (νsym) in 1:1
ratio, in agreement with an approximately 900 angle between
the two CO ligands. A signal at 2937 cm-1 was assigned to
Scheme 3. Reaction of 1,5-pentanediol (0.5 mmol) with 4-
methylbenzylamine (0.5 mmol).a (I) after 1 h. (II) after
40 hrs and then recharged.
1
ν(N-H). In the H NMR spectrum, the OCH2R and NH pro-
3
tons resonate at 3.45 (brs, broad) and 2.97 (brt, JHH = 14.6
Hz), respectively. The 31P NMR spectrum showed a singlet at
116.0 ppm, shifted upfield relative to that of 2 (135.0 ppm).18
Heating a solution of 8 in tol-d8 at 130°C for 30 min in a
sealed NMR tube resulted in appearance of three hydride
1
aConditions: i) [Mn] 1 (10 mol%), KH (20 mol%), toluene (4 mL), reflux. ii) [Mn] 1
(5 mol%), KH (10 mol%), reflux.
signals in the H NMR spectrum, a doublet centered at -1.41
ppm (JHP = 55.3 Hz), attributed to complex 8,18 and two un-
characterized doublets at -4.62 (JHP = 53.8 Hz) and -7.78 ppm
(JHP = 31.6 Hz). γ-Butyrolactone was observed as the main
organic product. Attempts to isolate the hydride intermedi-
ates were not successful. In line with these observations we
propose a catalytic cycle for the formation of cyclic imides as
shown in Scheme 5. The first step is the reaction of the diol
with the amido-complex 2 to form the intermediate 8, which
can undergo β-hydride elimination of the bound alkoxy
group, possibly via amine “arm” opening, to form a hydride
intermediate such as 9.22 9 can then react with the amine to
form the hydroxyamide B and complex 10. Another possibil-
ity is an outer sphere mechanism: the dissociation of alkox-
ide moiety from 8 followed by hydride and proton extraction
On the basis of the above experiments we propose that
the dehydrogenative coupling of diols and amines proceeds
first through diol dehydrogenation to form a hydroxyalde-
hyde intermediate A (Scheme 4). A then reacts with the
amine to form the observed hydroxyamide intermediate B
(pathway I). Alternatively, A can also cyclize to form a lac-
tone which can further react with the amine to form the
hydroxyamide B (pathway II). Observation of the lactone
after 1 hr of catalysis (Scheme 3I) and the formation of cyclic
imides upon reaction of lactones with amines, as discussed
above (Scheme 3II), supports pathway II. However, the ob-
servation of hydroxyamide after 1 h of the catalytic reaction
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to give complex 9 and the free hydroxyaldehyde.23 Liberation
of hydrogen gas from 10 can regenerate the active catalyst 2
as recently reported by us.18 A similar cycle involving B can
lead to the amido aldehyde, which can cyclize to the ob-
served imide.
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Scheme 5. Proposed catalytic cycle for the formation of
cyclic imides.
9
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In conclusion, we have developed the first base-metal
catalyzed synthesis of cyclic imides from the readily available
diols and amines. This reaction, catalyzed by a manganese
pincer complex, liberates hydrogen as the only by-product
and is environmentally benign.
ASSOCIATED CONTENT
Supporting Information
Experimental and spectroscopic details of the catalytic reactions.
The Supporting Information is available free of charge on the ACS
Publications website.
AUTHOR INFORMATION
Corresponding Author
* david.milstein@weizmann.ac.il
(16) Kim, J.; Hong, S. H. Org. Lett. 2014, 16, 4404.
(17) (a) Mukherjee, A., Nerush, A., Leitus, G., L. Shimon, J. W., Ben-
David, Y., E.-Jalapa N. A., Milstein D. J. Am. Chem. Soc. 2016, 138,
4298. (b) Elangovan, S.; Topf, C.; Fischer, S.; Jiao, H.; Spannenberg,
A.; Baumann, W.; Ludwig, R.; Junge, K.; Beller, M. J. Am. Chem. Soc.
2016, 138, 8809. (c) Elangovan, S.; Neumann, J.; Sortais, J.-B.; Junge,
K.; Darcel, C.; Beller, M. Nat. Commun. 2016, 12641. (d) E.-Jalapa, N.
A.; Nerush, A.; Shimon, L. J. W.; Leitus, G.; Avram, L.; David, Y. B.;
Milstein, D. Chem. Eur. J., 2017, 23, 5934. (e) Nguyen, D. H.; Trivelli,
X.; Capet, F.; Paul, J.; Dumeignil, F.; Gauvin, R. M., ACS Catal. 2017,
7, 2022. (f) Mastalir, M.; Glatz, M.; Pittenauer, E.; Allmaier, G.;
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Irrgang, T.; Dietel, T.; Kempe, R. Angew. Chem. Int. Ed. 2016, 55,
11806.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This research was supported by the European Research Council (ERC
AdG 692775). D. M. holds the Israel Matz Professorial Chair of Or-
ganic Chemistry. N. A. E.-J. thanks Mr. Armando Jinich for a post-
doctoral fellowship. A.K. is thankful to the Israel Planning and Budg-
eting Commission (PBC) for a fellowship.
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