A Facile Direct Route to N-(Un)substituted Lactams by Cycloamination of Oxocarboxylic Acids without External Hydrogen

Article abstract of DOI:10.1002/cssc.201901780

Lactams are privileged in bioactive natural products and pharmaceutical agents and widely featured in functional materials. This study presents a novel versatile approach to the direct synthesis of lactams from oxocarboxylic acids without catalyst or external hydrogen. The method involves the in situ release of formic acid from formamides induced by water to facilitate efficient cycloamination. Water also suppresses the formation of byproducts. This unconventional pathway is elucidated by a combination of model experiments and density functional theory calculations, whereby cyclic imines (5-methyl-3,4-dihydro-2-pyrrolone and its tautomeric structures) are found to be favorable intermediates toward lactam formation, in contrast to the conventional approach encompassing cascade reductive amination and cyclization. This sustainable and simple protocol is broadly applicable for the efficient production of various N-unsubstituted and N-substituted lactams.

Full text of DOI:10.1002/cssc.201901780

Accepted Article
Title: A facile direct route to N-(un)substituted lactams by
cycloamination of oxocarboxylic acids without external hydrogen
Authors: Hu Li, Hongguo Wu, Heng Zhang, Yaqiong Su, Song Yang,
and Emiel Hensen
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To be cited as: ChemSusChem 10.1002/cssc.201901780
Link to VoR: http://dx.doi.org/10.1002/cssc.201901780
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10.1002/cssc.201901780
ChemSusChem
Communication
A facile direct route to N-(un)substituted lactams by
cycloamination of oxocarboxylic acids without external hydrogen
Hu Li,[a],ǂ Hongguo Wu,[a],ǂ Heng Zhang,[a] Yaqiong Su,[b]* Song Yang[a]* and Emiel J. M. Hensen[b]*
Abstract: Lactams are privileged in bioactive natural products and
pharmaceutical agents and widely featured in functional materials.
This study presents a novel versatile approach to the direct
synthesis of lactams from oxocarboxylic acids without catalyst and
external hydrogen. The method involves the in situ release of formic
acid from formamides induced by water to facilitate efficient
cycloamination. Water also suppresses the formation of by-products.
This unconventional pathway is elucidated by a combination of
model experiments and density functional theory calculations, where
cyclic imines (5-methyl-3,4-dihydro-2-pyrrolone and its tautomeric
structures) are found to be favourable intermediates toward the
lactam, different from the conventional approach encompassing
cascade reductive amination and cyclization. This sustainable and
simple protocol is broadly applicable for the efficient production of
various N-unsubstituted and N-substituted lactams.
low-cost substrates.
Oxocarboxylic acids contain one or more aldehydic or keto
groups in a carboxylic acid and are widely available compounds.
A prime example is levulinic acid (LA), which can be easily
obtained from renewable lignocellulosic biomass.[10] The keto-
acid LA can be converted with primary amines to N-substituted
lactams or pyrrolidones via cascade reductive amination and
cyclization catalyzed by transition metals (Scheme 1).[11] In
connection with this, various strategies have recently been
proposed to design and prepare catalysts with unique
functionalities for simplifying the overall process, such as the
use of low-pressure hydrogen, or hydrogen-donating co-
reactants such as formic acid (HCOOH) and hydrosilanes under
mild conditions.[11-13] Significant progress has been made in the
selective production of N-substituted lactams and pyrrolidones
from LA (Table S1), but in all cases the use of an organic
solvent, an external hydrogen source and/or additives are key to
obtain good results.
Lactams are cyclic amides, which form a class of core
structural motifs privileged in a variety of bioactive natural
products and pharmaceutical agents.[1] These heterocyclic
scaffolds feature amongst others in functional materials and
catalysts.[2] Pyrrolidones are an ubiquitous sub-group of lactams,
which are of great and long-standing interest in the preparation
of those five-membered nitrogen-containing heterocycles.[2a,3]
The regioselective establishment of C-C and C-N bonds is a
powerful strategy to build N-heterocyclic compounds. An
attractive approach to secondary lactams is catalytic cyclization
of primary amides with intramolecular alkenes in the presence of
metal catalysts via aza-Heck or aza-Wacker mechanisms, in
spite of the need to use, respectively, highly electrophilic or
nucleophilic nitrogen species.[4] Lactams can also be obtained in
other ways, such as by combining homoenolates with acid-
activated imines,[5] intramolecular hydrocarbamoylation of allylic
formamides,[6] Michael/proton transfer/enol lactonization of acyl
chlorides with dicarbonyls,[7] intramolecular alkenylation of
acyclic bromoalkenes,[8] and cycloamination of prenyl
carbamates and ureas[9]. All of these approaches require
specific catalysts and/or additives as well as organic solvents in
order to obtain satisfactory yields. Therefore, it would be
desirable to develop a catalyst- and solvent-free protocol for the
construction of valuable lactam skeletons from sustainable and
Scheme 1. Cycloamination strategies for the synthesis of N-(un)substituted
lactams.
Leuckart reductive amination is a well-known reaction for
catalyst-free upgrading of aldehydes and ketones to formamides
using HCOOH as a hydrogen donor, although it is hampered by
a low selectivity and high required reaction temperatures (ca.
180 °C).[14] Efforts to improve the product selectivity and reaction
rate include the use of basic additives (e.g., NEt3) or microwave
heating to activate HCOOH and minimize the negative effect of
its acidity during reductive amination.[15] Herein, we propose a
novel and generic strategy involving in situ controlled-release of
HCOOH from N-formyl species with deionized water for cyclic
diamination of LA and other keto-acids. Our synthesis protocol
provides access to various N-(un)substituted lactams without
catalyst and external hydrogen, and requires no organic solvent
(Scheme 1).
[a]
Dr. H. Li, H. Wu, H. Zhang, Prof. S. Yang
State Key Laboratory Breeding Base of Green Pesticide &
Agricultural Bioengineering, Key Laboratory of Green Pesticide &
Agricultural Bioengineering, Ministry of Education, State-Local Joint
Laboratory for Comprehensive Utilization of Biomass, Center for
R&D of Fine Chemicals
Guizhou University
Guiyang, Guizhou 550025, China
E-mail: jhzx.msm@gmail.com
Dr. Y. Su, Prof. E.J.M. Hensen
Laboratory of Inorganic Materials & Catalysis, Schuit Institute of
Catalysis, Department of Chemical Engineering and Chemistry
Eindhoven University of Technology
We explored the use of formamide (H2NCHO) and HCOOH as
nitrogen and hydrogen sources, respectively, for the
cycloamination of LA (without catalyst and solvent) and obtained
a moderate 5-methyl-2-pyrrolidinone (MPD) yield of 83% after
[b]
P.O. Box 513, 5600 MB Eindhoven, The Netherlands
Email: y-q.su@tue.nl; e.j.m.hensen@tue.nl
ǂ Both authors contributed equally to the work.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/cssc.201901780
ChemSusChem
Communication
reaction for 1.5 h at 160 °C (Table 1, entry 1). From a green
chemistry point of view, the 10-fold excess of HCOOH results in
undesired waste with respect to process mass intensity (PMI =
8.7, entry 1) and E-factor (5.0, Table S2) parameters. Without
HCOOH, the MPD yield decreased to 41% at 160 °C (entry 2),
implying the possibility of in situ release of HCOOH from
H2NCHO or other N-formyl intermediates during the reaction. To
explore this opportunity, several control experiments were
conducted. First, LA can be directly cyclized to angelica lactones
(ALs) by dehydration.[16] Second, H2NCHO can be hydrolyzed in
water with conversions up to ca. 70% after 1.5 h at 160 °C and
were then constant upon prolonged reaction to 4 h. These
findings demonstrate that water obtained by LA dehydration can
in principle promote the hydrolysis of H2NCHO and relevant N-
formyl intermediates to release HCOOH. As expected, the
addition of water (30 equiv.) into the reaction systems with and
without HCOOH (entries 3 & 4) significantly accelerates the
cycloamination reaction, providing comparable MPD yields of 92%
and 94%. It is worth noting that the reaction without HCOOH
exhibits superior green chemistry metrics including a high
reaction mass efficiency (RME), a low E-factor, and good atom
economy compared to the case with HCOOH (Table S2). The
PMI of the present protocol that avoids the use of HCOOH is 8.5
(entry 4), much lower than values between 20 and 199 for other
approaches reported in the literature (entries 5-11).[11,12d,13c,17]
These features render our novel synthetic protocol highly
promising for the sustainable production of lactams in good yield.
Table 1. Catalytic cycloamination of LA to lactams using different systems
Hydrogen Additive/ Temp. Time
Yield
(%)
83
41
92
Entry
Catalyst
Nitrogen source
Lactam
PMI[c]
Rate[d]
Ref.
source
Solvent
(°C)
160
160
160
160
(h)
1.5
4
1[a]
2[a]
3[b]
4[b]
-
-
-
-
H2NHCO
H2NHCO
H2NHCO
H2NHCO
HCOOH
-
8.7
6.2
13.7
8.5
1107
205
1227
470
-
-
This
work
HCOOH
H2O
H2O
1.5
4
-
94
Benzyl
amine
5
6
7
8
-
HCOOH
3 bar H2
HCOOH
PhSiH3
NEt3 / DMSO
100
100
120
120
12
87
99
199
73
13c
12d
17
n-Octyl
amine
Pt-MoOx/TiO2
-
20
66
50
Ru-P
complex
Benzyl
amine
-
12
95
90
79
In(OAc)3
R-NH2
Toluene
1-24
49-97
>20
180
11b
9
Pt/P-TiO2
Pt/P-TiO2
Aqueous NH3
5 bar
NH3 gas
1 bar H2
15 bar H2
HCOOH
MeOH
MeOH
H2O
25
25
72
72
16
85
87
85
32
38
45
12
12
53
11a
11a
11c
10
11
Au/ZrO2-VS
Aqueous NH3
130
[a] Molar ratio of LA/H2NHCO/HCOOH/H2O 1:3:10:30
[b] Molar ratio of LA/H2NHCO/H2O 1:6:30
[c] Process mass intensity (PMI) is defined as (Mass of raw materials input) / (Mass of desired output)
[d] Reaction rate defined as mole of product / time (μmol h-1)
formamidopentanamide (FPAM) intermediates.[11b,12d,18] These
findings suggest that the reducing and C-N coupling
functionalities of the reaction system are responsible for the
product distribution, which lies between typical catalyst-mediated
reductive amination and our novel approach free from catalyst
and external hydrogen.
Table 1 shows that systems depending on metal catalysts
require much longer reaction times (up to 72 h) to achieve
moderate yields of either substituted or unsubstituted lactams
(entries 8-11), despite relatively low reaction temperatures (25-
130 °C).[11] Our protocol shows superior performance in terms of
the reaction rate with and without HCOOH (1227 and 470 μmol
h-1, entries 3 & 4), while affording good lactam yield comparable
to previously reported results (entries 3-11). The significant
higher MPD formation rate with HCOOH indicates that hydrogen
transfer may be the rate-determining step. Therefore, we
hypothesized that optimizing the reaction conditions towards
faster in situ release of HCOOH from H2NCHO and involved N-
formyl species assisted by water can improve the reaction
performance without HCOOH. The use of 6 eqv. H2NCHO and
30 eqv. water results in a satisfactory yield of ca. 90% MPD from
LA at 160 °C after 2 h (Figures S1 & S2). The reaction
temperature and time strongly impact the MPD formation rate
and product distribution (Figure S3). Specifically, unreduced 5-
methyl-3,4-dihydro-2-pyrrolone (MDPY) and nitrogen-free γ-
valerolactone (GVL) were observed as by-products in the novel
reaction system (Figures S4 & S5), besides previously reported
As follows from Table 1, the thermal reaction system of LA
and H2NCHO with HCOOH (1107 μmol h-1) instead of water
(470 μmol h-1) results in a superior MPD formation rate (entry 1
vs 4), highlighting the significance of hydrogen transfer in the
overall cycloamination reaction. Although both types of reactions
proceed via the key intermediates FPAC and FPAM, the
reaction with excess HCOOH affords another cyclic compound
N-formyl 5-methyl-2-pyrrolidinone (FMP) as a main by-product
(Figure 1). We also observe that the presence of HCOOH
substantially decreases the time to completely convert LA (20
min), in comparison with the water-assisted system (120 min).
Notably, the formation of the relatively stable FMP results in a
low MPD yield (Figure 1). Water suppresses the formation of
FMP by hydrolysis, thus improving the MPD yield (Table 1, entry
1 vs 3). Thus, we can infer that water is not only favorable for in
situ release of HCOOH by hydrolysis of H2NCHO and N-formyl
intermediates, but also avoids the formation of undesired
4-formamidopentanoic
acid
(FPAC)
and
4-
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10.1002/cssc.201901780
ChemSusChem
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species like FMP that are chemically stable under anhydrous
conditions.
allowed us to depict the reaction pathways for LA cycloamination
with H2NCHO and water in Figure 2A. Initially, H2NCHO is
reversibly hydrolyzed to NH3 and HCOOH under hydrothermal
conditions with a reported free energy of activation (ca. 146
kJ/mol),[21] while LA is able to undergo either C-N coupling with
H2NCHO to afford 4-(formylimino)pentanoic acid (IM-1) via IM-0
or intramolecular dehydration to give ALs with tautomeric
structures, respectively, due to lack of enough HCOOH derived
from H2NCHO hydrolysis in the early stage. With the assistance
of the in situ formed HCOOH, a limited amount of ALs is
hydrogenated to GVL (Figure 2A). As the dominant reaction
pathway, IM-1 is more prone to release HCOOH and undergo
intramolecular cyclization, giving a favorable precursor MDPY
with relevant tautomeric structures that are gradually
transformed into MPD by hydrogen transfer during prolonged
reaction. In parallel, IM-1 may undergo cascade transfer
hydrogenation (FPAC), amidation (FPAM), and cyclization to
afford the MPD product, despite the low rates of these reactions.
The formation of GVL (Figures 1B & S3), which can be
obtained from ALs via hydrogenation with HCOOH,[19] suggests
that ALs can be the intermediates leading to the nitrogen-
containing cyclics (i.e., MDPY and MPD). To explore this
possibility, α-AL was thermally treated with H2NCHO in water or
neat conditions, wherein respectively 44% and <6% MPD yields
together with MDPY in ca. 8% and <1% yields were obtained
after heating at 160 °C for 1 h. We can explain these differences
by the reversibility of the reaction between LA and ALs,[16] with
the presence of water shifting the equilibrium to the LA side. LA
is the species that reacts to form MPD and MDPY. A kinetic
study of the conversion of LA to MPD with normal and
deuterated water reveals a secondary hydrogen isotope effect
with kH/kD = 0.94 (Figure S6). The equilibrium deuterium isotope
effect suggests reversible processes in the overall reaction of LA
to MPD,[20] especially those participated with water.
Figure 1. Product distribution in cycloamination of LA with H2NCHO assisted
by HCOOH (A) or water (B) heated at 160 °C for variable times.
Figure 2. Cycloamination of LA with H2NCHO and water: (A) Reaction
pathways, and (B) Computed free energy profiles.
IM: intermediate; TS: transition state; Values in parentheses are free energies
and enthalpies (kJ/mol).
Considering the possible activation role of acidic carboxyl
group (-COOH) of LA in the synthesis of MPD via
cycloamination, ethyl levulinate (EL) was used as a substrate
instead of LA, yielding ca. 90% MPD (Figure S7). A kinetic study
showed comparable reaction rate constant (kLA/kEL = 1.05) for
cycloamination of LA (0.0519 min-1) and EL (0.0493 min-1; Figure
S8), demonstrating that the acidity of the substrate has a minor
effect on the reaction outcome. We also investigated the order of
amination and amidation steps in the LA-to-MPD conversion by
examining the reactivity of 2-pentanone and pentanoic acid
under otherwise similar conditions (Figure S9). The results
clearly show that amination is much faster than amidation
independent of the presence of HCOOH. Another salient detail
of this experiment was that the conversion of 2-pentanone and
pentanoic acid were both lowered in water in comparison with
the HCOOH-mediated reaction (Figure S9), further revealing
that the rate-determining step in the cycloamination without
external hydrogen source is likely the in situ release of HCOOH
from H2NCHO and involved N-formyl species assisted by water.
The hydrogen transfer process and the presence of ALs and
MDPY tautomeric structures are illustrated by deuterium-labeled
experiments (Figures S10-S12). The large body of reaction data
To examine whether LA-to-MPD conversion proceeding
through MDPY is kinetically and thermodynamically favorable,
density functional theory (DFT) calculations were performed at
the B3LYP/6-311+G(2s,2p) level in conjunction with polarizable
continuum model (PCM) to simulate the solvent effect (Figures 2
& S13). LA can react with H2NCHO to obtain intermediate IM-0
by overcoming an activation free energy barrier (Ga) of 171
kJ/mol, followed by conversion to IM-1 through releasing one
water molecule (Ga = 90 kJ/mol). From IM-1 to the product MPD
via the precursor MDPY involving the release of HCOOH, the
highest activation energy barrier is calculated to be 177 kJ/mol,
in good agreement with the experimental activation energy of
162 kJ mol-1 (Figure S14). In contrast, the pathway via the
precursor FPAC and FPAM toward MPD, respectively, requires
a 32 kJ/mol and 63 kJ/mol higher activation energy, clearly
demonstrating that the pathway involving MDPY is preferred.
Notably, the FPAM formation requires a comparable activation
energy of 180 kJ mol-1, indicative of the possibility of resulting
FPAM from IM-1 via FPAC, as identified by GC-MS (Figure S4),
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Communication
which is also consistent with the experimental results (Figures 1
In order to evaluate the potential of practical implementation of
our new protocol, the efficiency of the catalyst- and external
hydrogen-free system in the cycloamination of LA with H2NCHO
and water was examined in a continuous-flow microreactor.
Under above-optimized reaction conditions (LA/H2NCHO/H2O
molar ratio 1:6:30, reaction temperature 160 °C), a good MPD
yield of 87% can be obtained with a residence time of 20 min. In
&
S3). In view of gaseous NH3 and HCOOH being
simultaneously formed in a certain amount from the thermal
hydrolysis of H2NCHO, the initial amination of LA with NH3
instead of H2NCHO was also taken into consideration (Figure 2).
The energy barrier for the reaction between LA and NH3 to
afford MDPY successively via IM-2 and IM-3 was calculated to
be 155 kJ/mol, which is slightly lower than the latter (177 kJ/mol). comparison with the established batch procedure (Table 1, entry
It is worth noting that the used reactants LA (b.p. ~245 °C) and
H2NCHO (b.p. ~210 °C) are both in liquid phase during the
reaction process at a temperature of 160 °C. Therefore, we may
expect that amination occurs between these components as well
as between liquid LA and NH3 (gas), considering mass transfer
limitations of gas-liquid phase reactions.[22] In addition, the ALs
formation is disadvantageous by LA dehydration (Figure 2 &
S13), as proved by the poor GVL yield. These results elaborate
that cyclic imines (MDPY with its tautomeric structures) derived
from LA by cycloamination are preferentially converted to the
lactam via subsequent hydrogen transfer, which is totally
different to the typical cascade reductive amination and
cyclization process.
4), the flow reactor shortens the reaction duration, with superior
reaction rate and comparable lactam yield.
Table 2 Production of N-(un)substituted lactams from various oxocarboxylic
acids and formamides
Oxocarboxylic acid
Formamide
R2
Entry
1
Lactams
t(h)
4
Y(%)
94
R1
N
CH3
1
H
Encouraged by the prominent performance of the developed
reaction system, the substrate scope with respect to functional
group tolerance was further examined (Table 2). Apart from
H2NCHO (entry 1), ammonium formate (HCOONH4) was found
to exhibit much higher reactivity (entry 2), leading to shorter
reaction (3 h) and higher MPD yield (97%). In comparison with
H2NCHO, the increasing hydrolysis ability of ammonium formate
can contribute to the superior performance, also proving that the
release of HCOOH from thermal treatment of H2NCHO and
involved N-formyl species is the rate-determining step. However,
LA promoted by the mixture of equivalent HCOOH and NH3 (aq.)
only gave MPD in a low yield of ca. 70% under identical
conditions, while increased amounts of GVL and
formylated/condensed co-products were observed. Even worse,
when primary amines (e.g., propylamine, cyclohexylamine,
aniline, 3-methylaniline, 4-methylaniline, and benzylamine) and
HCOOH were used as substrates for the cascade aqueous
reaction processes, only 10-50% yields of N-substituted lactams
were observed under optimized conditions. These results
indicate that the in situ release of HCOOH from H2NCHO,
HCOONH4 or other N-formyl species assisted by water is more
favorable for suppressing the occurrence of side reactions to
ensure relatively high selectivity toward MPD. When the 4-
substituent of the oxocarboxylic acid substrate is changed from
methyl to phenyl, 4-chlorophenyl, 4-fluorophenyl, and 2-thienyl
groups, corresponding unsubstituted lactams in good yields (81-
93%) are achieved (entries 3-6). All together with those 1,4-
dicarbonyl substrates, a range of 1,5- and 1,6-dicarbonyl
compounds can be also subjected to cycloamination, affording
moderate to good yields (68-92%) of six- and seven-membered
lactams, respectively (entries 7-10). Importantly, unsubstituted
benzolactams (62-80%) can be obtained from o-phenyl
dicarbonyl compounds with H2NCHO assisted by water (entries
11 & 12). In addition to H2NCHO, a series of other formamides
2[a]
CH3
1
HCOONH4
3
97
3
4
5
6
1
1
1
1
H
H
H
H
4
5
6
4
81
86
87
93
7
8
CH3
CH3
2
3
H
H
5
5
92
68
9
2
2
H
H
H
H
4
4
5
5
85
70
80
62
10
11
12
13
14
CH3
CH3
1
1
CH3
4
4
98
94
CH3CH2
15
16
CH3
CH3
1
1
4
4
80
85
that can be simply synthesized by catalyst-free N-formylation of
[23]
amines with CO2
were also employed as both nitrogen and
hydrogen sources, and relevant N-substituted lactams with
satisfactory yields (75-98%) can be attained (entries 13-22).
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10.1002/cssc.201901780
ChemSusChem
Communication
extraction with CH2Cl2 or ethyl acetate for 3 times (5 mL × 3).
The resulting combined extractant was evaporated under
reduced pressure to give the product lactam.
17
18
CH3
CH3
1
1
4
4
83
84
Regarding the continuous-flow reactions, a Labtrix®Start
microreactor system (Chemtrix BV, NL) with a glass micro
reactor (type 3227, volume: 19.5 μL) was utilized. Initially, LA,
H2NCHO, and deionized water in a molar ratio of 1:6:30 was
evenly mixed and added into a flask. The resulting solution was
pumped into the micro reactor (rate: 25 μL/min) under cooling
until the reactor is full. Upon the reactor temperature was raised
to 160 °C, the solution flow rate was set at 1.5 μL/min. After
running for 1.5 h, sampling at timed intervals was conducted for
GC analysis.
19
20
CH3
CH3
1
1
5
5
75
78
21
22
CH3
CH3
1
1
4
4
89
88
Computational methods
Reaction conditions: 2 mmol oxocarboxylic acids, 6 equiv. formamides, 30
equiv. water, 160 °C.
[a] HCOONH4 instead of H2NCHO was used as used nitrogen source.
All DFT calculations were carried using the hybrid functional
[24]
[25]
B3LYP
as implemented in Gaussian 09 D.01 software
.
The all-electron 6-311+G(d,p) basis set was used for all atoms.
In summary, a facile versatile approach to directly synthesize
both N-unsubstituted and N-substituted lactams under catalyst-
and external hydrogen-free conditions has been developed
involving in situ release of HCOOH from formamides promoted
by water for efficient cycloamination. Experimental and
computational results show that cyclic imines are the key
species toward the lactam by undergoing subsequent hydrogen
transfer. This route is completely different to typical catalyzed
reaction pathways, involving reductive amination followed by
cyclization. The novel benign and versatile protocol exhibits
good universality and applicability in lactam synthesis. We
envision it to find broader application by giving access to various
nitrogen-containing compounds, especially high-value N-
heterocycles.
[26]
The polarized continuum model (PCM)
with standard
parameters for water solvent (ε = 78.3) was used to account for
bulk solvent effects during geometry optimization and searching
of transition states. Frequency analysis was performed to ensure
that each transition state has only one imaginary frequency in
the direction of the reaction coordinate. All relative energies
discussed in this paper are referred to Gibbs free energies
considered the zero point energy (ZPE) correction at 453 K.
Acknowledgements
This work is financially supported by the National Natural
Science Foundation of China (21576059, 21666008), Fok Ying-
Tong Education Foundation (161030), Key Technologies R&D
Program of China (2014BAD23B01), and Guizhou Science &
Technology Foundation ([2018]1037, [2017]5788). Y.S. and
E.J.M.H. acknowledge financial support for the research from
The Netherlands Organization for Scientific Research (NWO)
through a Vici grant and Nuffic funding and the European
Union’s Horizon 2020 research and innovation programme
under grant No 686086 (Partial-PGMs).
Experimental
Reaction procedures
All the experiments were carried out in a Teflon-lined
stainless steel autoclave (inner volume 15 mL), placed in an oil-
bath that was preheated to the desired reaction temperature
(120-180 °C). In a typical reaction procedure, 2 mmol LA or keto
acid, 12 mmol H2NCHO or formamides (6 equiv.), and 60 mmol
deionized water (30 equiv.) were added into the autoclave, and
the reaction duration was recorded as the autoclave was placed
into the oil-bath. After a specific reaction time, the autoclave was
taken out of the oil bath and immediately cooled-down to
ambient temperature with tap-water. Upon completion, the
autoclave was opened and deionized water (or methanol) was
added to the reacted mixture, which was subsequently analyzed
by HPLC (or GC). Each experiment was separately conducted
and repeated for 2-3 times. The obtained conversions and yields
are average data of 2-3 individual experiments, with standard
deviation (σ) in the range of 0.5-4.6%. Structures were
Keywords: cycloamination • hydrogen-free reduction • lactams •
water • DFT
[1]
For selected reviews on lactams, see: a) C. Kammerer, G. Prestat, D.
Madec, G. Poli, Acc. Chem. Res. 2014, 47, 3439-3447; b) C. R. Pitts, T.
Lectka, Chem. Rev. 2014, 114, 7930-7953; c) C. Moreno-Marrodan, F.
Liguori, P. Barbaro, Mol. Catal. 2019, 466, 60-69; d) T. D. Tan, L. W.
Ye, Nat. Catal. 2019, 2, 182-183; e) M. Börjesson, A. Tortajada, R.
Martin, Chem 2019, 5, 254-256; f) H. Wu, W. Dai, S. Saravanamurugan,
H. Li, S. Yang, ACS Sustainable Chem. Eng. 2019, 7, 10207-10213.
a) L. W. Ye, C. Shu, F. Gagosz, Org. Biomol. Chem. 2014, 12, 1833-
1845; b) C. I. Jette, I. Geibel, S. Bachman, M. Hayashi, S. Sakurai, H.
Shimizu, J. B. Morgan, B. M. Stoltz, Angew. Chem. Int. Ed. 2019, 58,
4297-4301; c) Y. Park, S. Chang, Nat. Catal. 2019, 2, 219-227; d) W. Li,
C. Liu, H. Zhang, K. Ye, G. Zhang, W. Zhang, Z. Duan, S. You, A. Lei,
Angew. Chem. Int. Ed. 2014, 53, 2443-2446; e) N. Wang, Q. S. Gu, Z.
L. Li, Z. Li, Y. L. Guo, Z. Guo, X. Y. Liu, Angew. Chem. Int. Ed. 2018,
57, 14225-14229.
[2]
1
confirmed by H, 13C NMR (JEOL-ECX 500 NMR spectrometer,
CDCl3), GC-MS, and HRMS.
For the product separation from the reaction mixture,
CH2Cl2 or ethyl acetate can be used as an effective extractant.
Typically, 3-5 mL deionized water was added into the mixture
after the reaction, while the product lactam could be isolated by
[3]
[4]
F. Rivas, T. Ling, Org. Prep. Proced. Int. 2016, 48, 254-295.
a) S. A. Shuler, G. Yin, S. B. Krause, C. M. Vesper, D. A. Watson, J. Am.
Chem. Soc. 2016, 138, 13830-13833; b) G. Yang, C. Shen, W. Zhang,
This article is protected by copyright. All rights reserved.

10.1002/cssc.201901780
ChemSusChem
Communication
Angew. Chem. Int. Ed. 2012, 51, 9141-9145; c) R. I. McDonald, G. Liu,
S. S. Stahl, Chem. Rev., 2011, 111, 2981-3019.
Moore, J. Org. Chem. 1944, 9, 529-536; c) F. Chubb, A. S. Hay, R. B.
Sandin, J. Am. Chem. Soc. 1953, 75, 6042-6044.
[5]
X. Zhao, D. A. DiRocco, T. Rovis, J. Am. Chem. Soc. 2011, 133, 12466-
12469.
N. Armanino, E. M. Carreira, J. Am. Chem. Soc. 2013, 135, 6814-6817.
S. Vellalath, K. N. Van, D. Romo, Angew. Chem. Int. Ed. 2013, 52,
13688-13693.
[15] a) R. Carlson, T. Lejon, T. Lundstedt, E. Le Clouerec, Acta Chem. Scand.
1993, 47, 1046-1046; b) A. Loupy, D. Monteux, A. Petit, J. M. Aizpurua,
E. Domínguez, C. Palomo, Tetrahedron Lett. 1996, 37, 8177-8180; c) H.
Li, H. Guo, Y. Su, Y. Hiraga, Z. Fang, E. J. M. Hensen, M. Watanabe, R.
L. Smith, Nat. Commun. 2019, 10, 699.
[6]
[7]
[8]
[9]
P. M. Holstein, D. Dailler, J. Vantourout, J. Shaya, A. Millet, O. Baudoin,
Angew. Chem. Int. Ed. 2016, 55, 2805-2809.
R. Abrams, Q. Lefebvre, J. Clayden, Angew. Chem. Int. Ed. 2018, 57,
13587-13591.
[16] D. Sun, Y. Takahashi, Y. Yamada, S. Sato, Appl. Catal. A: Gen. 2016,
526, 62-69.
[17]
Y. B. Huang, J. J. Dai, X. J. Deng, Y. C. Qu, Q. X. Guo, Y. Fu,
ChemSusChem 2011, 4, 1578-1581.
[10] a) R. Weingarten, W. C. Conner, G. W. Huber, Energy Environ. Sci.
2012, 5, 7559-7574; b) V. Choudhary, S. H. Mushrif, C. Ho, A. Anderko,
V. Nikolakis, N. S. Marinkovic, A. I. Frenkel, S. I. Sandler, D. G.
Vlachos, J. Am. Chem. Soc. 2013, 135, 3997-4006; c) S. Kang, J. Fu,
G. Zhang, Renew. Sustain. Energy Rev. 2018, 94, 340-362.
[11] For selected examples on lactams synthesis, see: a) C. Xie, J. Song, H.
Wu, Y. Hu, H. Liu, Z. Zhang, P. Zhang, B. Chen, B. Han, J. Am. Chem.
Soc. 2019, 141, 4002-4009; b) Y. Ogiwara, T. Uchiyama, N. Sakai,
Angew. Chem. Int. Ed. 2016, 55, 1864-1867; c) X. L. Du, L. He, S.
Zhao, Y. M. Liu, Y. Cao, H. Y. He, K. N. Fan, Angew. Chem. Int. Ed.
2011, 50, 7815-7819.
[12] a) M. Muzzio, C. Yu, H. Lin, T. Yom, D. A. Boga, Z. Xi, N. Li, Z. Yin, J. Li,
J. A. Dunn, S. Sun, Green Chem. 2019, DOI: 10.1039/c9gc00396g; b)
C. Wu, X. Luo, H. Zhang, X. Liu, G. Ji, Z. Liu, Z. Liu, Green Chem.
2017, 19, 3525-3529; c) A. Ledoux, L. S. Kuigwa, E. Framery, B.
Andrioletti, Green Chem. 2015, 17, 3251-3254; d) A. S. Touchy, S. M.
A. H. Siddiki, K. Kon, K. Shimizu, ACS Catal. 2014, 4, 3045-3050.
[13] a) C. Wu, H. Zhang, B. Yu, Y. Chen, Z. Ke, S. Guo, Z. Liu, ACS Catal.
2017, 7, 7772-7776; b) Z. Sun, J. Chen, T. Tu, Green Chem. 2017, 19,
789-794; c) Y. Wei, C. Wang, X. Jiang, D. Xue, Z. T. Liu, J. Xiao, Green
Chem. 2014, 16, 1093-1096.
[18] G. Gao, P. Sun, Y. Li, F. Wang, Z. Zhao, Y. Qin, F. Li, ACS Catal. 2017,
7, 4927-4935.
[19] C. G. S. Lima, J. L. Monteiro, T. de Melo Lima, M. Weber Paixão, A. G.
Corrêa, ChemSusChem 2018, 11, 25-47.
[20] a) W. W. Cleland, J. Biol. Chem. 2003, 278, 51975-51984; b) H. Simon,
D. Palm, Angew. Chem. Int. Ed. 1966, 5, 920-933.
[21]
L. Gorb, A. Asensio, I. Tuñón, M. F. Ruiz-López, Chem. Eur. J. 2005,
11, 6743-6753.
[22] a) A. Olivo, E. Ghedini, M. Signoretto, M. Compagnoni, I. Rossetti,
Energies, 2017, 10, 1394; b) A. Hoschek, B. Bghler, A. Schmid, Angew.
Chem. Int. Ed. 2017, 56, 15146-15149; c) F. Chu, Y. Liu, L. Yang, X.
Du, Y. Yang, Appl. Energ. 2017, 205, 1596-1604.
[23] a) H. Lv, Q. Xing, C. Yue, Z. Lei, F. Li, Chem. Commun. 2016, 52, 6545-
6548; b) J. Song, B. Zhou, H. Liu, C. Xie, Q. Meng, Z. Zhang, B. Han,
Green Chem. 2016, 18, 3956-3961.
[24]
A. D. Becke, J. Chem. Phys. 1993, 98, 5648-5652.
[25] M. Frisch, G. Trucks, H. Schlegel, G. Scuseria, M. Robb, J. Cheeseman,
G. Scalmani, V. Barone, B. Mennucci, G. Petersson, Inc., Wallingford,
CT 2010, 6492.
[26] M. Cossi, V. Barone, B. Mennucci, J. Tomasi, Chem. Phys. Lett. 1998,
286, 253-260.
[14]
For selected examples on Leuckart reaction, see: a) R. Leuckart, Ber.
Dtsch. Chem. Ges. 1885, 18, 2341-2344; b) F. S. Crossley, M. L.
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Communication
Entry for the Table of Contents
COMMUNICATION
Free to lactams: An external
hydrogen and catalyst-free approach
is developed to simply synthesize
various N-(un)substituted lactams
from bio-based levulinic acid and
relevant keto acids by direct
cycloamination with formamides,
enabled by the co-added water to in
situ release formic acid. An
H. Li, H. Wu, H. Zhang, Y. Su,* S.
Yang,* E. J. M. Hensen*
Page No. – Page No.
A facile direct route to N-
(un)substituted lactams by
cycloamination of oxocarboxylic
acids without external hydrogen
unconventional pathway
encompassing cyclic imines as the
key species toward the lactams is
elaborated.
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