Reactivity of 3-Oxo-β-lactams with Respect to Primary Amines—An Experimental and Computational Approach

Article abstract of DOI:10.1002/chem.201703852

The reactivity of 3-oxo-β-lactams with respect to primary amines was investigated in depth. Depending on the specific azetidin-2-one C4 substituent, this reaction was shown to selectively produce 3-imino-β-lactams (through dehydration), α-aminoamides (thr

Full text of DOI:10.1002/chem.201703852

A Journal of
Accepted Article
Title: Reactivity of 3-oxo-β-lactams with respect to primary amines - an
experimental and computational approach
Authors: Nicola Piens, Hannelore Goossens, Dietmar Hertsen, Sari
Deketelaere, Lieselotte Crul, Lotte Demeurisse, Jelle De
Moor, Elias Van den Broeck, Karen Mollet, Kristof Van Hecke,
Veronique Van Speybroeck, and Matthias D'hooghe
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To be cited as: Chem. Eur. J. 10.1002/chem.201703852
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Supported by

10.1002/chem.201703852
Chemistry - A European Journal
Reactivity of 3-oxo-β-lactams with respect to primary amines
– an experimental and computational approach
Nicola Piens,[a] Hannelore Goossens,[b] Dietmar Hertsen,[b] Sari Deketelaere,[a] Lieselotte
Crul,[a] Lotte Demeurisse,[a] Jelle De Moor,[a,b] Elias Van den Broeck,[a,b] Karen Mollet,[a]
Kristof Van Hecke,[c] Veronique Van Speybroeck,*[b] and Matthias D'hooghe*[a]
[a] Dr. N. Piens, S. Deketelaere, L. Crul, L. Demeurisse, J. De Moor, E. Van den Broeck, Dr. K. Mollet, Prof. Dr.
M. D'hooghe
SynBioC Research Group
Department of Sustainable Organic Chemistry and Technology
Faculty of Bioscience Engineering
Ghent University, Coupure Links 653, 9000 Ghent (Belgium)
E-mail: matthias.dhooghe@UGent.be
[b] Dr. H. Goossens, D. Hertsen, J. De Moor, E. Van den Broeck, Prof. Dr. V. Van Speybroeck
Center for Molecular Modeling
Ghent University, Technologiepark 903, 9052 Zwijnaarde (Belgium)
E-mail: veronique.vanspeybroeck@UGent.be
[c] Prof. Dr. K. Van Hecke
XStruct
Department of Inorganic and Physical Chemistry
Faculty of Sciences
Ghent University, Krijgslaan 281-S3, 9000 Ghent (Belgium)
 Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.xxxxxxxxx.
ABSTRACT
The reactivity of 3-oxo-β-lactams with respect to primary amines was investigated in depth.
Depending on the specific azetidin-2-one C4 substituent, this reaction was shown to
selectively produce 3-imino-β-lactams (through dehydration), α-aminoamides (through CO
elimination) or ethanediamides (through an unprecedented C3-C4 ring opening). In addition to
the experimental results, the mechanisms and factors governing these peculiar transformations
were also examined and elucidated by means of density functional theory calculations.
1
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INTRODUCTION
Through the development of the ‘β-lactam synthon method’ by Ojima in the 1980s and
1990s,1 azetidin-2-ones have acquired a prominent position in organic chemistry as building
blocks for further elaboration. Indeed, by exploiting the inherent reactivity associated with
this strained four-membered ring system, several β-lactam classes have been deployed as
important intermediates in the synthesis of a wide variety of acyclic and heterocyclic nitrogen
compounds by selective bond-cleavage and ring-rearrangement protocols.2
One of those classes, the highly reactive 3-oxo-β-lactams, have a long tradition as key
scaffolds in the stereocontrolled synthesis of a broad diversity of functionalized azetidin-2-
ones and other scaffolds of pharmaceutical interest.3 Already in 1972, Sheehan has reported
the preparation of benzyl 6-oxopenicillanate as a source of new antibacterials, e.g. by means
of its further transformation to oxygen and carbon analogs of penicillin V.4 Interesting
examples concerning the use of monocyclic 3-oxo-β-lactams en route to biological
applications comprise the total synthesis of the antifungal lipopeptide Echinocandin B,5
serotonin reuptake inhibitor Dapoxetine6 and potent anticancer agent Haouamine B.7
Furthermore, azetidin-2,3-diones have proven to be useful precursors for α-hydroxy-β-amino
acids such as N-benzoyl-(2R,3S)-phenylisoserine methyl ester, the renowned side chain of the
antitumor agent Taxol.8 In the framework of our interest in the use of functionalized β-lactams
as building blocks in heterocyclic chemistry,2g, 2j we pursued the strategy to treat 3-oxo-β-
lactams with primary alkylamines as a possible entry to the synthetically useful class of 3-
alkylimino-β-lactams. Subsequent imine reduction could then afford the corresponding 3-
amino-β-lactams, which represent important structural entities present in many β-lactam
antibiotics and β-lactamase inhibitors.9
Although transformation of azetidin-2,3-diones into 3-iminoazetidin-2-ones seems easy to
achieve at first sight by applying (standard) imination conditions, only one single example
using free amines has been described in the literature so far. In 1996, Cainelli and coworkers
have treated 1-(4-methoxyphenyl)-4-phenylazetidine-2,3-dione (1a) with benzhydrylamine in
dichloromethane in the presence of magnesium sulphate as a drying agent, affording
3-benzhydrylimino-1-(4-methoxyphenyl)-4-phenylazetidin-2-one (2a) in 76% isolated yield
after trituration with pentane (Scheme 1, A).10 Other literature examples concerning the
imination of 3-oxo-β-lactams fall outside the scope of this comparison because they all
employ hydroxylamine hydrochloride or methoxyamine hydrochloride instead of a primary
alkylamine.11
2
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In 2000, Alcaide and coworkers have described the unexpected formation of α-aminoamides
3a-p in 42-77% yield when treating azetidine-2,3-diones 1a-e with a selection of primary
amines in tetrahydrofuran, with or without the addition of magnesium sulphate (Scheme 1,
B).12 Mechanistically, this transformation was explained by the nucleophilic addition of the
amine across the 3-oxo group, followed by C2-C3 ring opening and carbon monoxide
elimination.12b However, when applying similar reaction conditions on azetidine-2,3-dione 1f
in a preliminary experiment, we observed the formation of the novel ethanediamide 4a
(Scheme 1, C) via an unprecedented C3-C4 ring opening (vide infra). This remarkable new
reactivity persuaded us to perform a thorough and comprehensive study, both experimentally
and computationally, on the different factors governing the reactivity of 3-oxo-β-lactams with
respect to primary alkylamines.
Scheme 1: Treatment of 3-oxo-β-lactams 1 with primary amines: literature information and
preliminary in-house results
3
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RESULTS AND DISCUSSION
The synthesis of the starting 3-oxo-β-lactams 1 was performed by means of four consecutive
steps (Scheme 2, Table 1) with respect to literature precedents (see supporting information).
First, aldehydes 5a-g were condensed with different primary amines in dichloromethane in the
presence of magnesium sulphate, and the resulting imines 6a-j were used as such in the
Staudinger synthesis of 3-acetoxy-β-lactams 7a-j. To that end, imines 6a-j were treated with
acetoxyacetyl chloride in dichloromethane in the presence of triethylamine to afford the
corresponding azetidin-2-ones 7a-j in 39-87% isolated yield and with varying
diastereoselectivities. This relative cis or trans stereochemistry could be easily deduced from
the 1H NMR spectra (CDCl3) of β-lactams 7, because the vicinal coupling constants between
the 3H and 4H protons on the β-lactam ring varied between 4.4 and 5.6 Hz for the obtained
cis isomers and had a value of 1.6 Hz for the trans isomers, which corresponds well with
reported literature values.13 Subsequently, the latter azetidin-2-ones 7a-j were converted into
the corresponding 3-hydroxy-β-lactams 8a-j via a potassium carbonate-mediated acetate
hydrolysis in methanol or in a methanol/water (1/1) mixture. No attempts were made toward
the separation of cis/trans isomers for compounds 7 and 8, as this is not relevant with respect
to the synthesis of the target structures 1. It should be noted that the low isolated yields of β-
lactams 7i,j and 8h can be explained by the formation of the corresponding N-acyl enamines
during the Staudinger synthesis, which appeared to be difficult to avoid when using N-
(alkylidene)amines as substrates.14 Finally, an Albright-Onodera oxidation protocol using
phosphorus pentoxide as dimethyl sulfoxide activator was applied on azetidin-2-ones 8a-j,
affording the premised azetidine-2,3-diones 1a,b,f-m in 51-91% yield after purification by
column chromatography on silica gel. For azetidine-2,3-diones 1, representatives 1f-m (as
well as β-lactam precursors 7c-j and 8c-j) have not been reported before.
Scheme 2: Synthesis of 3-oxo-β-lactams 1
4
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Table 1: Synthesis of imines 6, 3-acetoxy-β-lactams 7, 3-hydroxy-β-lactams 8 and 3-oxo-β-lactams 1
Compound 7
(yield [%])a
cis/transb
Compound 6
(yield [%])
Compound 8 Compound 1
Entry
R1
R2
(yield [%])
8a (98)
8b (85)a
8c (92)
(yield [%])d
1a (91)
1b (72)
1f (91)
7a (87)
1
2
PMP
PMP
iPr
Ph
6a (99)
6b (99)
6c (98)
6d (96)
6e (97)
6f (97)
6g (93)
6h (99)
6i (99)
6j (96)
21/79
7b (70)
100/0
7c (83)
3
Ph
4-MeC6H4
4-ClC6H4
PMP
Ph
100/0
7d (87)
4
iBu
8d (97)
8e (95)
1g (86)
1h (51)
1i (67)
100/0
7e (81)
5
iPr
100/0
7f (69)
6
nPr
8f (63)a
8g (73)a
8h (40)d
8i (78)a
8j (61)a
100/0
7g (67)
7
4-FC6H4
iPr
1j (58)a
1k (51)
1l (73)
11/89
7hc
8
nPr
100/0
7i (44)d
9
PMP
4-FC6H4
iPr
100/0
7j (39)d
10
iPr
1m (84)
100/0
a After purification by recrystallization from absolute EtOH or EtOAc/hexane (30/1), unless stated otherwise.
b Based on 1H NMR (CDCl3) analysis of the crude reaction mixture.
c Separation of β-lactam 7h and the corresponding N-acyl enamine proved to be impossible at this stage.
d After purification by column chromatography (SiO2).
In the next stage, the reactivity of 3-oxo-β-lactams 1 with respect to primary alkylamines was
investigated as a potential entry into the synthetically useful and virtually unexplored class of
3-alkylimino-β-lactams. To that end, 1-isopropyl-4-phenylazetidine-2,3-dione (1f) was
dissolved in anhydrous dichloromethane and treated with one equiv. of n-propylamine at
room temperature for two hours (Scheme 1, C). Surprisingly, while the formation of either the
corresponding 3-imino-β-lactam10 or α-aminoamide12 was expected, spectroscopic analysis
revealed the molecular structure of the obtained product to be exclusively N1-benzyl-N1-
isopropyl-N2-propylethanediamide (4a). Additional experiments were carried out with an
excess of the volatile amine (10 equiv.), tetrahydrofuran as the solvent, the presence of
5
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magnesium sulphate or titanium tetrachloride (in diethyl ether) as drying agents and
temperatures varying from -78 °C to reflux, all affording a full and selective substrate
conversion toward the same product 4a (Scheme 1, C).
Subsequently, also azetidine-2,3-diones 1a,f-j were smoothly converted into novel
ethanediamides 4b-l using similar reaction conditions in 76–95% yield (Scheme 3). For the
specific substitution pattern of substrates 1, see Table 1. These ethanediamides 4 were present
as 1/1 (4a-g,k) or 9/1 (4h-j,l) mixtures of two rotamers, which can be explained by a hindered
rotation about the amide bond. It should be noted that for compounds 4h-j,l (R1 = aryl), the
crude reaction mixture was contaminated with several unidentified side products, although in
a combined yield of maximum 10%, making an additional purification step by preparative
TLC necessary to obtain analytical purity. The application of aniline as primary amine (cf.
aromatic amines, R3 = Ar) in these experiments led to complex reaction mixtures. In addition
to their main application as substitutes for urea in fertilizers,15 ethanediamides (also known as
oxamides) represent important structural motifs showing diverse bioactivities,16 which
explains the interest in new and better strategies for their construction.
From a mechanistic point of view, the formation of the latter ethanediamides 4 can be
rationalized considering the initial nucleophilic addition of the primary amine across the
3-oxo group of azetidin-2,3-diones 1, followed by a C3-C4 ring opening of the intermediate
hemiaminals 9 (Scheme 3). This unprecedented C3-C4 ring opening of 3-oxo-β-lactams is
clearly provoked by the presence of an aromatic C4 substituent (R2 = Ph, 4-MeC6H4,
4-ClC6H4, PMP). Indeed, the availability of a benzylic position at the β-lactam C4 facilitates a
C3-C4 bond fission through benzylic stabilization of the forming carbanion.
Scheme 3: Synthesis of ethanediamides 4
6
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As can be seen in scheme 3, the introduction of an electron-donating aromatic C4 substituent
(such as R2 = PMP), which could destabilize the developing carbanion to a certain extent,
proved to be ineffective to switch the reactivity of 3-oxo-β-lactam 1i toward the formation of
the corresponding 3-imino-β-lactam, supporting the importance of the proposed benzylic
stabilization hypothesis. This line of reasoning was further corroborated by the transformation
of 3-oxo-β-lactam 1j into ethanediamide 4l, in which an electron-withdrawing aromatic N1
substituent (R1 = 4-FC6H4) could not induce the formation of the corresponding
α-aminoamide by carbon monoxide elimination through additional stabilization of the
developing nitrogen anion.
In order to further investigate the role of the specific β-lactam substituents on the reactivity of
3-oxo-β-lactams with respect to primary alkylamines, azetidin-2,3-dione 1k, bearing an alkyl
group at both positions N1 and C4 (R1 = iPr, R2 = nPr), was subjected to standard imination
conditions. The absence of a benzylic position at the β-lactam C4 might prevent C3-C4 ring
opening in favor of the formation of the desired 3-imino-β-lactam. Indeed, treatment of
1-isopropyl-4-propylazetidine-2,3-dione (1k) with one equiv. of n-propylamine in anhydrous
dichloromethane in the presence of two equiv. of magnesium sulphate at room temperature
for two hours afforded 1-isopropyl-4-propyl-3-(propylimino)azetidin-2-one (2b) in 91% yield
1
and with a E/Z ratio (based on H NMR in CDCl3) of 7/93 or vice versa (Scheme 4). Also 4-
isopropylazetidine-2,3-diones 1l,m, bearing aromatic N1 substituents (R1 = PMP, 4-FC6H4),
could be selectively converted toward the corresponding new 3-imino-β-lactams 2c,d under
microwave irradiation, pointing to the suitability of 4-alkylazetidine-2,3-diones as eligible
substrates for the preparation of 3-(alkylimino)azetidin-2-ones. Imines 2c-d proved to be both
base and acid stable upon washing with 1 M sodium hydroxide and column chromatography
on silica gel, respectively.
Scheme 4: Synthesis of 3-imino-β-lactams 2
7
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Taking the above-described results into account, it can be concluded that the presence of an
aromatic C4 substituent is the main prerequisite for the formation of ethanediamides upon
treatment of azetidine-2,3-diones with primary amines. This unprecedented reactivity of
3-oxo-β-lactams stands in sharp contrast with the previously described formation of
3-benzhydrylimino-1-(4-methoxyphenyl)-4-phenylazetidin-2-one (2a)10 (Scheme 1, A) or
2-[(4-methoxyphenyl)amino]-2-phenylacetamides 3a-d12 (Scheme 1, B) from 1-(4-
methoxyphenyl)-4-phenylazetidine-2,3-dione (1a) under similar reaction conditions. In order
to scrutinize this discrepancy, we decided to repeat these literature procedures with full respect
to reaction scale and dilution. Unfortunately, all our attempts to reproduce the experimental
result described by Cainelli10 led to complex reaction mixtures, in which no significant
amounts of either 3-imino-β-lactams, α-aminoamides or ethanediamides were detected.
In addition, when conscientiously repeating the procedures described by Alcaide,12 N1-benzyl-
N1-(4-methoxyphenyl)ethanediamides 4j,m,n were isolated as major compounds instead of
the in the literature obtained 2-[(4-methoxyphenyl)amino]-2-phenylacetamides 3a-c (Scheme
5). This result confirms our benzylic stabilization hypothesis. It should be stressed that for
compounds 4j,m,n, the crude reaction mixtures were contaminated with multiple unidentified
side products, although in a combined yield of maximum 15%, in which the occurrence of α-
1
aminoamides 3a-c (<5%) was confirmed by H NMR (CDCl3). Furthermore, a detailed
13
spectroscopic analysis revealed that the C NMR (CDCl3) spectral data of the in our hands
obtained ethanediamide 4m were identical to the reported data for compound 3b (except for
an extra carbonyl signal around 160 ppm), which could point to an incorrect assignment of
compound 3b in the literature. To ensure that ethanediamides 4 cannot be transformed into the
corresponding
α-aminoamides
3
via
CO
elimination,
N1,N2-dibenzyl-N1-(4-
methoxyphenyl)ethanediamide (4j) was heated under reflux in tetrahydrofuran for several
days (with or without the addition of benzylamine), resulting in full recuperation of the
starting compound 4j. It should be noted that when comparing the synthesis of ethanediamide
4j in schemes 3 and 5, it seems that both CH2Cl2 and THF are suitable as solvent for the
transformation of azetidin-2,3-diones 1 into ethanediamides 4.
8
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Scheme 5: Treatment of 1-(4-methoxyphenyl)-4-phenylazetidine-2,3-dione (1a) with primary amines:
comparison of our results with literature data
Finally, also (S)-4-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-1-(4-methoxyphenyl)azetidine-2,3-
dione (1b) was treated with a few primary amines to verify the claimed formation of
α-aminoamides 3 (Scheme 1, B).12 To that end, azetidin-2,3-dione 1b was dissolved in
tetrahydrofuran, after which a solution of benzylamine, allylamine or isopropylamine in THF
was added. After stirring for 2-24 hours at room temperature, a selective conversion of 15-
50%
toward
the
corresponding
(S)-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-[(4-
methoxyphenyl)amino]acetamides 3e,f,q was observed. This reaction could be driven to
completion by stirring for 72 hours at 40 °C, giving rise to α-aminoamides 3e,f,q in 53-69%
yield after purification by preparative TLC (Scheme 6). Mechanistically, this transformation
was explained by the nucleophilic addition of the amine across the 3-oxo group of azetidine-
2,3-dione 1b, followed by C2-C3 ring opening and carbon monoxide elimination.12b
Irrefutable proof for the formation of α-aminoamides 3 was eventually established by single
crystal X-ray analysis of (S)-N-benzyl-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-[(4-
methoxyphenyl)amino]acetamide (3e) (Figure 1). In other words, (S)-4-((S)-2,2-dimethyl-1,3-
dioxolan-4-yl)-1-(4-methoxyphenyl)azetidine-2,3-dione (1b) was confirmed to be an eligible
substrate for the selective synthesis of α-aminoamides 3 upon treatment with primary amines
as reported,12 pointing to the peculiar effect of the C4 dioxolane substituent on the overall
reactivity.
Scheme 6: Synthesis of α-aminoamides 3
9
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Figure 1: Molecular structure of (S)-N-benzyl-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-[(4-
methoxyphenyl)amino]acetamide (3e)
When summarizing all the experimental results obtained in this work, it is clear that the
specific reactivity of 3-oxo-β-lactams 1 with respect to primary amines can be completely
controlled by the choice of the C4 substituent, affording the selective preparation of 3-imino-
β-lactams 2 (dehydration products), α-aminoamides 3 (CO-elimination products) or
unprecedented ethanediamides 4 (C3-C4 ring-opening products). This interesting behavior is
exemplified in Scheme 7, which presents an overview of the reactivity of
1-(4-methoxyphenyl)azetidine-2,3-diones 1a,b,l (only different with respect to their C4 (R2)
substituent) upon treatment with isopropylamine in tetrahydrofuran. The selective formation
of either 3-imino-β-lactams or ethanediamides from 4-alkyl- or 4-aryl-3-oxo-β-lactams,
respectively, is certainly of relevance from a synthetic chemistry point of view, whereas the
production of α-aminoamides from 3-oxo-β-lactams seems to be a peculiarity related to the
presence of a specific C4 substituent (in casu the (S)-2,2-dimethyl-1,3-dioxolan-4-yl group).
In order to further investigate the proposed mechanistic rationalizations governing this
intriguing reactivity profile, density functional theory (DFT) calculations were performed
next, in which the main goal was to support the unprecedented C3-C4 ring opening of 3-oxo-
β-lactams with an aromatic C4 substituent (R2 = Ar) computationally. Because the formation
of α-aminoamides 3 has only been observed in the case of very specific substituents (i.e. R1 =
PMP and R2 = (S)-2,2-dimethyl-1,3-dioxolan-4-yl)), combined with the possible incorrect
assignment of compound 3b in the literature (vide supra), further in-depth experimental
studies are necessary to elucidate the exact reaction parameters inducing CO elimination. For
that reason, the illustrative DFT calculations were primary focused on the difference in
reactivity for 3-oxo-β-lactams with an aromatic C4 substituent (i.e. R2 = Ph cf. Scheme 7)
versus a simple alkyl C4 substituent (i.e. R2 = iPr cf. Scheme 7).
10
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Scheme 7: Treatment of 1-(4-methoxyphenyl)azetidine-2,3-diones 1a,b,l with isopropylamine
THEORETICAL RATIONALIZATION
Computational methodology
The M06-2X functional,17 which accounts for dispersion effects, was used for geometry
optimizations with a 6-31+G(d,p) basis set. This level of theory has proven to yield reliable
results for reactions involving small N-heterocycles.18 Minima (ground states) and first-order
saddle points (transition states) were characterized by normal mode analysis. Reactant and
product complexes were verified by intrinsic reaction coordinate (IRC) calculations,19
followed by full geometry optimizations. A continuum model was used to account for the
solvent environment.20 D3 dispersion corrections were added by calculating the electronic
energies at the B3LYP-D3/6-311+G(d,p) level of theory,21 using the geometries and thermal
free energy corrections obtained with M06-2X/6-31+G(d,p) at 1 atm and 298 K. These
corrections, proposed by Grimme et al., account for the dispersion effects in complex systems
and at long range.22 All computations were carried out with the Gaussian 09 program
package.23
Amination of 3-oxo-β-lactams 1
Initial nucleophilic addition of primary amines across the 3-oxo group of azetidine-2,3-diones 1
leads in a first step to intermediate hemiaminals 9-11 (Scheme 3, 4 and 6). Whereas an
unrealistic Gibbs free activation barrier of 115.4 kJ/mol was found for the reaction of 3-oxo-
β-lactam 1 (R1 = R2 = Me) with MeNH2 (M06-2X/6-31+G(d,p)), assistance of a second amine
molecule substantially lowered this activation barrier to a plausible value of 62.1 kJ/mol
(Figure 2). Thus, during the nucleophilic attack of the amine nitrogen atom across the
11
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carbonyl carbon atom, a proton is transferred from the nitrogen atom to the carbonyl oxygen
atom via a second amine molecule, which acts as a proton bridge.
Figure 2: Gibbs free energy profile for the amination of 3-oxo-β-lactams 1 into 3-amino-3-hydroxy-
β-lactams 9-11 with assistance of a second amine molecule (PCM (ε = 7.43) M06-2X/6-31+G(d,p),
kJ/mol). PRC denotes pre-reactive complex. Critical distance is given in Å. Energies relative to the separate reactants.
Dehydration, CO elimination and C3-C4 ring opening of 3-amino-3-hydroxy-β-lactams 9-11
These intermediate hemiaminals 9-11 can subsequently undergo dehydration, CO elimination
or C3-C4 ring opening, leading to 3-imino-β-lactams 2, α-aminoamides 3 or ethanediamides
4, respectively. Initially, all three reactions have been thoroughly investigated for R1 = R2 =
R3 = Me, which clearly showed that the barriers for all three reactions without any assisting
molecules are unrealistically high (>200 kJ/mol, M06-2X/6-31+G(d,p)). Therefore, an extra
β-lactam molecule 9-11 was added to assist the reactions under study. Indeed, the amino and
hydroxyl groups of these additional β-lactams 9-11 can act as proton-accepting and/or proton-
donating sites, facilitating the reactions under study. Various possibilities have been
examined: assistance of one or two groups, and stepwise or concerted pathways. Assistance
by an extra β-lactam molecule was shown to lower the reaction barriers tremendously. For the
three reactions under study (i.e. dehydration, C3-C4 ring opening and CO elimination of
β-lactams 9-11 with R1 = R2 = R3 = Me), the reaction barriers for all these possible pathways
were compared (see table S1 of the Supplementary Information).
Subsequently, for the pathways with the lowest reaction barriers and those with a reaction
barrier of less than 20 kJ/mol higher, the methyl group on the β-lactam C4 carbon atom (R2)
was replaced by an isopropyl group and a phenyl group, since these substituents selectively
12
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lead to 3-imino-β-lactams 2 (i.e. dehydration products, Scheme 4) and ethanediamides 4 (i.e.
C3-C4 ring-opening products, Scheme 3), respectively (see table S2 of the Supplementary
Information). The Gibbs free energy profiles for the pathways with the lowest reaction barrier
for the three reactions under study are shown in figures 3 and 4.
For R2 = iPr (Figure 3), the dehydration reaction is shown to be clearly preferred over the CO
elimination reaction and the C3-C4 ring-opening reaction (ΔG‡ = 93.6, 128.8 and 149.2
kJ/mol, respectively), as found experimentally. The dehydration occurs via a stepwise
pathway in which the hydroxyl group of the assisting molecule donates a proton to the
hydroxyl group of the reacting molecule with formation of water. In a second step, the amino
group of the reacting molecule readily donates its proton to the negatively charged oxygen
atom of the assisting molecule by a simple proton transfer.
For R2 = Ph (Figure 4), comparable reaction barriers as for R2 = iPr are found for the
dehydration reaction (ΔG‡ = 93.6 and 99.7 kJ/mol for R2 = iPr and Ph, respectively) and the
CO elimination reaction (ΔG‡ = 128.8 and 133.6 kJ/mol for R2 = iPr and Ph, respectively).
However, a remarkably lower reaction barrier is found for the C3-C4 ring-opening reaction
(ΔG‡ = 149.2 and 67.8 kJ/mol for R2 = iPr and Ph, respectively), leading to a clear preference
for C3-C4 ring opening. The C3-C4 ring opening occurs via a concerted pathway in which the
amino group of the assisting molecule accepts a proton from the hydroxyl group of the
reacting molecule and the hydroxyl group of the assisting molecule donates a proton to the C4
atom of the reacting molecule. The stabilization of the transition state for C3-C4 ring opening
can be explained by stabilization of the carbanion in the transition state by the phenyl group
(atomic charge, calculated with natural population analysis (NPA),24 of the C4 atom is
-0.397).
13
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Figure 3: Gibbs free energy profiles for the dehydration, CO elimination and C3-C4 ring opening of
β-lactams 9-11 (R2 = iPr) with assistance of a second β-lactam molecule (PCM (ε = 7.43) B3LYP-
D3/6-311+G(d,p)//PCM (ε = 7.43) M06-2X/6-31+G(d,p), kJ/mol). OH denotes assistance by the hydroxyl
group of the assisting molecule, step denotes stepwise, conc denotes concerted. Some critical distances are given in Å.
Energies relative to the separate reactants.
14
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Chemistry - A European Journal
Figure 4: Gibbs free energy profiles for the dehydration, CO elimination and C3-C4 ring opening of
β-lactams 9-11 (R2 = Ph) with assistance of a second β-lactam molecule (PCM (ε = 7.43) B3LYP-
D3/6-311+G(d,p)//PCM (ε = 7.43) M06-2X/6-31+G(d,p), kJ/mol). OH denotes assistance by the hydroxyl
group of the assisting molecule, NH denotes assistance by the amino group of the assisting molecule, step denotes stepwise,
conc denotes concerted. Some critical distances are given in Å. Energies relative to the separate reactants.
15
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CONCLUSIONS
In summary, the reactivity profile of azetidine-2,3-diones with regard to primary amines was
explored in depth, both experimentally and computationally. It was shown that by changing
the specific β-lactam C4 substituent, the selective preparation of either 3-imino-β-lactams
(dehydration products), α-aminoamides (CO-elimination products) or ethanediamides (C3-C4
ring-opening products) can be achieved, thus revisiting preceding literature reports. This work
also comprises the first report on the direct transformation of β-lactam scaffolds into
biologically interesting oxamides (ethanediamides) through an unprecedented C3-C4 ring-
opening pathway. Computationally, a clear preference was found for the dehydration reaction
(imination) when R2 = iPr and for the C3-C4 ring-opening reaction when R2 = Ph, which is in
full correspondence with the experimental results.
ACKNOWLEDGEMENTS
The authors are indebted to Ghent University – Belgium (BOF) for financial support. The
Research Board of Ghent University is acknowledged for financial support. KVH thanks the
Hercules Foundation (project AUGE/11/029 “3D-SPACE: 3D Structural Platform Aiming for
Chemical Excellence”) and the Research Foundation – Flanders (FWO) for funding. DH and
VVS acknowledge the Belgian Science Policy Office Interuniversity Attraction Poles (IAP)
programme for financial support. Computational resources and services used in this work
were provided by Ghent University (Stevin Supercomputer Infrastructure).
KEYWORDS
3-oxo-β-lactams; ring opening; 3-iminoazetidin-2-ones; α-aminoamides; ethanediamides;
DFT calculations
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GRAPHICAL ABSTRACT
Reactivity profile unraveled:
3-Oxo-β-lactams were shown
to selectively produce 3-
imino-β-lactams (dehydration
products), α-aminoamides (CO
elimination
products)
or
unprecedented ethanediamides
(C3-C4 ring-opening products) upon reaction with primary amines. In particular, the specific
β-lactam C4 substituent is responsible for this intriguing reactivity, an observation that was
supported by density functional theory calculations.
20
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