Formation of Fluorinated Amido Esters through Unexpected C3?C4 Bond Fission in 4-Trifluoromethyl-3-oxo-β-lactams

Article abstract of DOI:10.1002/asia.201701636

4-Trifluoromethyl-3-oxo-β-lactams were unexpectedly transformed into 2-[(2,2-difluorovinyl)amino]-2-oxoacetates as major products, accompanied by minor amounts of 2-oxo-2-[(2,2,2-trifluoroethyl)amino]acetates, upon treatment with alkyl halides and triethylamine in DMSO. This peculiar C3?C4 bond fission reactivity was investigated in-depth, from both an experimental and a computational point of view, in order to shed light on the underlying reaction mechanism.

Full text of DOI:10.1002/asia.201701636

CHEMISTRY
AN ASIAN JOURNAL
www.chemasianj.org
Accepted Article
Title: Formation of fluorinated amido esters through unexpected C3-C4
bond fission in 4-trifluoromethyl-3-oxo-β-lactams
Authors: Hang Dao Thi, Hannelore Goossens, Dietmar Hertsen,
Valerie Otte, Tuyen Van Nguyen, Veronique Van Speybroeck,
and Matthias D'hooghe
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Chemistry - An Asian Journal
Formation of fluorinated amido esters through unexpected C3-C4 bond fission
in 4-trifluoromethyl-3-oxo-β-lactams
Hang Dao Thi,[a,b] Hannelore Goossens,[c] Dietmar Hertsen,[c] Valerie Otte,[a,c] Tuyen Van Nguyen,*[b]
Veronique Van Speybroeck*[c] and Matthias D’hooghe*[a]
[a]
H. Dao Thi, V. Otte, Prof. Dr. M. D’hooghe
SynBioC Research Group, Department of Green Chemistry and Technology, Faculty of Bioscience
Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium. E-mail:
matthias.dhooghe@UGent.be
[b]
[c]
H. Dao Thi, Prof. Dr. T. Van Nguyen
Institute of Chemistry, Vietnam Academy of Science and Technology, 18-Hoang Quoc Viet, CauGiay,
Hanoi, Vietnam. E-mail: ngvtuyen@hotmail.com
Dr. H. Goossens, Dr. D. Hertsen, V. Otte, Prof. Dr. V. Van Speybroeck
Center for Molecular Modeling, Ghent University, Technologiepark 903, 9052 Zwijnaarde (Belgium). E-
mail: veronique.vanspeybroeck@UGent.be
Abstract: 4-Trifluoromethyl-3-oxo-β-lactams were unexpectedly transformed into 2-[(2,2-difluorovinyl)amino]-
2-oxoacetates as major products, accompanied by minor amounts of 2-oxo-2-[(2,2,2-
trifluoroethyl)amino]acetates, upon treatment with alkyl halides and triethylamine in DMSO. This peculiar C3-C4
bond fission reactivity was investigated in-depth, from both an experimental and a computational point of view,
in order to shed light on the underlying reaction mechanism.
Introduction
The trifluoromethyl group has a long-standing history and tradition in medicinal chemistry, with H. L.
Yale being one of the first to acknowledge its remarkable potential in 1959.1 Ever since, a broad
diversity of trifluoromethylated compounds has been designed and evaluated, culminating in an
impressive amount of literature contributions and a number of prominent CF3-containing drugs on the
market (such as the antidepressant fluoxetine, the anti-inflammatory agent celecoxib and the antiviral
drug efavirenz). The increasing interest in fluorinated compounds results from the effect of fluorine on
important properties such as pKa, lipophilicity, metabolic stability and bioavailability. In literature
procedures toward CF3-substituted molecules, trifluoromethylation strategies clearly dominate the
landscape, and many powerful routes have been developed in that respect.2 Although these methods
have amply proven their synthetic value, they are less suited in the event that the trifluoromethylation
of sensitive and/or reactive substrates is desired. In such a scenario, the deployment of CF3-substituted
building blocks can offer a convenient alternative for the construction of certain types of
unconventional trifluorinated target systems. For example, three- and four-membered
azaheterocycles are known to exhibit an inherent reactivity associated with their high ring-strain
energy, rendering the trifluoromethylation of such substrates delicate. On the other hand, the intrinsic
reactivity of these synthons allows for the generation of a variety of valuable compounds upon careful
1
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10.1002/asia.201701636
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manipulation, providing access to a broad diversity of novel molecular entities. In that respect, we
embarked on the chemistry of CF3-decorated three- and four-membered nitrogen ring systems a few
years ago with the intention to provide new strategies for the preparation of fluorine-containing
scaffolds.3 Recently, we developed a convenient access to 4-trifluoromethyl-β-lactams as new building
blocks in organic synthesis, and we demonstrated the potential of these systems for reductive ring-
opening reactions toward aminopropanes and for the assembly of stereodefined mono- and spirocyclic
4-CF3-β-lactams.4 In the latter approach, 3-oxo-β-lactams were presented as eligible intermediates en
route to the desired 3-methylene-azetidin-2-ones.
In general, 3-oxo-β-lactams (or azetidine-2,3-diones) can be recognized as versatile precursors for the
synthesis of a broad variety of β-lactam and non-β-lactam products. For example, deployment of 3-
oxo-β-lactams has been reported to afford a variety of 3-amino-β-lactams, 3-hydroxy-β-lactams and
amino acid derivatives.5 4-Trifluoromethyl-3-oxo-β-lactams, however, have not been dealt with in the
literature so far, except for our above-mentioned recent contribution on their utilization as new
substrates to produce the corresponding 3-methylene-4-(trifluoromethyl)azetidin-2-ones.4b As can be
seen from published reactivity studies on trifluoromethylated small-ring heterocycles, the presence of
a CF3-group has a pronounced effect on their overall behavior in terms of synthetic elaboration. In that
respect, previous communications on the chemistry of 2-CF3-aziridines and -azetidines revealed an
unexpected and even opposite reactivity as compared to their 2-alkyl-substituted counterparts.6a-
6c,3a,6d,3c,6e,3d,6f-6i
Another important feature of trifluoromethylated azaheterocycles comprises their
suitability to undergo deprotonation in α-position with respect to the strong electron-withdrawing CF3
group, as exemplified by the generation of the 2-(trifluoromethyl)aziridin-2-yl anion and its subsequent
neutralization by means of different types of electrophiles.2c,3d In that respect, the deployment of 4-
trifluoromethyl-3-oxo-β-lactams might offer new opportunities for the installation of an additional side
chain through abstraction of the acidic C4-proton in α-position with respect to the oxo group and the
CF3 moiety. Consequently, attempts were made in the present work to address this synthetic
challenge, and the results of this study are described below.
Results and discussion
As reported before, 4-trifluoromethyl-3-oxo-β-lactams are rather unstable upon prolonged
preservation and should therefore be freshly prepared and used immediately for further elaboration.
To that end, 3-hydroxy-4-trifluoromethyl-β-lactams 1 were synthesized through hydrogenolysis of the
corresponding 3-benzyloxy-β-lactams, which are easily accessible via [2+2]-cyclocondensation
between trifluoroaldimines, prepared from the commercially available 1-ethoxy-2,2,2-trifluoroethanol
using 4-methoxyaniline or 4-methoxybenzylamine in toluene under Dean-Stark conditions, and the
ketene derived from benzyloxyacetyl chloride.4b A subsequent Albright-Onodera oxidation using P2O5
in DMSO afforded the contemplated 3-oxo-4-(trifluoromethyl)azetidin-2-ones 2 in acceptable yields
(Scheme 1). Having these 3-oxo-β-lactams 2 in hand, their eligibility as substrates for α-alkylation
through the intermediacy of a 3,4-dioxo-2-(trifluoromethyl)azetidin-2-yl anion was assessed next.
However, treatment of these ketones 2 with a variety of bases (LDA, LiHMDS, n-BuLi, NaH, Et3N, NaOH)
under different reaction conditions, including variation of the temperature (0°C, -78°C, -100°C), solvent
(THF, CH2Cl2), and additive (HMPA, TiCl4, Me3SiOTf, ZnBr2), in the presence of 1-iodopropane as an
electrophile always led to the formation of rather complex mixtures. These observations at least
confirmed the intrinsic reactivity/instability of 4-trifluoromethyl-3-oxo-β-lactams.
2
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Remarkably, in one of these many attempts, the combination of 1.5 equiv of 1-iodopropane and 3
equiv of Et3N in DMSO at room temperature resulted in a clean and full conversion of the starting
material 2a. More precisely, this approach provided a mixture of two reaction products in a 87/13
ratio, from which the major product was identified as propyl 2-[(2,2-difluorovinyl)(4-
methoxybenzyl)amino]-2-oxoacetate 3a and the minor product as propyl 2-oxo-2-[(4-
methoxybenzyl)(2,2,2-trifluoroethyl)amino]acetate 4a upon careful spectroscopic analysis.
This unexpected and unprecedented reactivity urged us to explore the scope of this new
transformation in detail. At first, methodology validation was pursued by varying the electrophile and,
besides 1-iodopropane, also allyl bromide, 1-chloro-3-iodopropane, benzyl bromide and iodomethane
were thus deployed. In all cases, 4-trifluoromethyl-3-oxo-β-lactams 2 were successfully converted into
mixtures of N-(2,2-difluorovinyl) amido esters 3 as major products and N-(2,2,2-trifluoroethyl) amido
esters 4 as minor constituents in a 75-92/8-25 ratio (Table 1), which could be easily separated. Instead
of DMSO, also DMF was shown to be a suitable solvent to induce these reactions, albeit resulting in a
lower selectivity (~1/1 mixtures of compounds 3 and 4). Acetonitrile and dichloromethane appeared
to be unfit as solvents and only produced complex reaction mixtures.
Scheme 1. Synthesis of 4-trifluoromethyl-3-oxo-β-lactams 2 and their transformation into amido esters 3 and 4
Table 1. Transformation of 4-trifluoromethyl-3-oxo-β-lactams 2 into 2-[(2,2-difluorovinyl)amino]-2-
oxoacetates 3 and 2-oxo-2-[(2,2,2-trifluoroethyl)amino]acetates 4
Entry
R
R’
3 (yielda)
4 (yielda)
Ratio 3/4b
1
2
PMB
PMB
Et
vinyl
3a (56)
3b (25)
4a (12)
4b (5)
87/13
87/13
3
PMB
1-chloroethyl
3c (42)
4c (10)
80/20
4
5
6
7
8
9
PMB
PMB
PMP
PMP
PMP
PMP
PMP
Ph
H
Et
3d (50)
3e (33)
3f (30)
3g (35)
3h (38)
3i (50)
3j (42)
4d (11)
4e (7)
4f (9)
75/25
80/20
79/21
86/14
90/10
92/8
vinyl
1-chloroethyl
4g (-)c
4h (-)c
4i (-)c
4j (5)
Ph
H
10
88/12
a isolated yield after HPLC purification
b determined by means of 1H NMR analysis (CDCl3) of the reaction mixture
c not isolated
In the next part, efforts were devoted to clarify the peculiar reactivity associated with this unexpected
transformation.7 To that end, each of the reaction parameters was changed in turn in order to see the
effect on the outcome. First, the alkyl halide was omitted, affording only a complex reaction mixture.
Apparently, treatment with Et3N in DMSO does affect the 3-oxo-β-lactam substrate 2, pointing to a
probable deprotonation followed by rapid degradation. Next, the base (Et3N) was left out, resulting in
3
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10.1002/asia.201701636
Chemistry - An Asian Journal
mainly recuperation of the starting material. These observations underline the importance of
combining 1-iodopropane and Et3N to evoke the desired reactivity. As the combination of an alkyl
halide and Et3N in DMSO is known to be characteristic for the Kornblum oxidation,8 the possible
intermediacy of an aldehyde in this reaction was investigated as well. However, replacement of 1-
iodopropane with propanal (the Kornblum oxidation product of 1-iodopropane) did not result in
conversion of the substrate 2.
Based on the ester portion present in the obtained products 3/4, it is clear that an oxygen atom
(probably resulting from water) is introduced during this transformation. In order to verify whether an
alcohol could trigger the same reactivity, 3-oxo-β-lactams 2 were treated with propan-1-ol (instead of
1-iodopropane) in DMSO in the presence of Et3N. Interestingly, this test reaction indeed furnished the
same amido esters 3 and 4 in a 98/2 ratio, pointing to a possible formation and participation of
propanol in the initial 1-iodopropane/Et3N approach to a certain extent. The presence of Et3N seemed
to be inevitable, as treatment with propanol without this base resulted in recuperation of the substrate
only. In order to check this rather curious iodopropane-to-propanol conversion hypothesis, benzoyl
chloride and a fluoride source (TBAF) was added to a solution of 1-iodopropane and Et3N in DMF, after
which formation of a small amount of the corresponding propyl benzoate (the reaction product of the
in situ formed propanol and benzoyl chloride) at r.t. was acknowledged by means of GC-MS. Based on
the above-described results, the mechanism behind this peculiar transformation might (partly) rely on
an initial conversion of the alkyl halide into the corresponding alcohol by residual water, which
subsequently induced β-lactam ring cleavage. Given the fact that Et3N was shown to affect the 3-oxo-
β-lactam substrate 2, the formation of triethylamine hydrofluoride seems reasonable, and this salt
might even act as a catalyst to facilitate the alkyl halide-to-alcohol interconversion according to
literature information.9 To acknowledge the potential role of fluoride as a catalyst, Et3N was replaced
with TBAF, also resulting in the formation of amido esters 3 and 4 in a 97/3 ratio. Possibly, Et3N is
necessary to provide a catalytic amount of Et3N.HF as a fluoride source in this reaction (through
dehydrofluorination of substrates 2). It should also be noted that the alkyl halide/TBAF combination
offers a convenient protocol for the almost exclusive formation of 2-[(2,2-difluorovinyl)amino]-2-
oxoacetates 3 (3/4: 97/3).
To summarize, careful variation of the reaction parameters allowed us to suggest the following
unexpected reaction mechanism to partly account for the formation of 2-[(2,2-difluorovinyl)amino]-2-
oxoacetates 3 and 2-oxo-2-[(2,2,2-trifluoroethyl)amino]acetates 4 upon treatment of 4-
trifluoromethyl-3-oxo-β-lactams 2 with an alkyl halide in the presence of Et3N in DMSO or DMF
(Scheme 2): step 1) (partial) dehydrofluorination of substrates 2 through the action of Et3N, leading to
the formation of Et3N.HF and 4-(difluoromethylene)azetidine-2,3-dione 5; step 2) (Et3N.HF-assisted)
transformation of the alkyl halide into the corresponding alcohol due to residual water present in the
solvent and/or reagents; step 3) addition of this alcohol across the ketone carbonyl group in 3-oxo-β-
lactams followed by subsequent C3-C4 bond fission. Alcohol addition onto 4-trifluoromethyl-3-oxo-β-
lactams 2 provides access to both end products 3 and 4 via the common intermediate 7 (route 3.1),
whereas reaction with the in situ formed 4-difluoromethylene-β-lactam 5 only results in production of
the main compound 3 (route 3.2). Direct fluoride expulsion from 6B to 3 can also be considered.
Pathways 3.1 and 3.2 might be competitive, but only route 3.1 can account for the presence of the
minor product 4. As an experiment in which a 3-oxo-β-lactam 2 was treated with propan-1-ol in DMSO
showed Et3N to be necessary to provoke reaction, a fast proton transfer from 6A to Et3N and
4
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10.1002/asia.201701636
Chemistry - An Asian Journal
subsequent ring opening of anionic intermediate 6B could further support the observed reactivity (as
the more stable corresponding neutral hemiacetal would probably not suffer from ring cleavage).
Scheme 2. Possible mechanistic rationalization of the observed reactivity to (partly) explain the formation of
compounds 3 and 4
The peculiar role of the CF3 group in this story was further acknowledged upon treatment of a 4-phenyl-
and a 4-isopropyl-3-oxo-β-lactam with propanol in DMSO in the presence or absence of Et3N, leading
to complex mixtures or no conversion of the substrate. Apparently, the strong electron-withdrawing
properties of the CF3 group are required to induce C3-C4 ring fission.
The proposed route, based on an initial alkyl halide-to-alcohol interconversion, should most probably
be considered as a minor option in the overall mechanism. Nonetheless, as the formation of a small
amount of propanol (trapped as propyl benzoate) from iodopropane could be demonstrated, this
unexpected pathway should not be ruled out and probably accounts for part of the final product
formation. In order to provide additional support for this peculiar mechanistic proposal, theoretical
calculations were performed to obtain more insight into the preference for the various proposed
reaction pathways. Particular attention was devoted to the dehydrofluorination reaction, necessary to
account for the formation of major compounds 3, as this step could theoretically occur at different
5
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10.1002/asia.201701636
Chemistry - An Asian Journal
stages throughout the proposed overall mechanism. The main objective of this computational study
was merely to verify if this proposal is realistic, not to claim that this is the only right one.
The M06-2X/6-31++G(d,p) level of theory was used for geometry optimizations, since this level of
theory was proven to yield reliable results for reactions involving small N-heterocycles.10,7
Furthermore, M06-2X accounts for dispersion effects to some extent.11 However, a benchmarking
study on dispersion-inclusive DFT methods showed that M06-2X is one of the preferable functionals
for hydrogen-bonded systems while it is less preferred for dispersion-dominated systems.12 Although
Hydrogen bonds play an important role in some pathways under study, most pathways are dispersion-
dominated. Therefore, the electronic energies were determined at the B3LYP-D3/6-311++G(d,p) level
of theory with inclusion of dispersion corrections using the D3 dispersion correction scheme.13 These
corrections, proposed by Grimme et al., account for dispersion effects in complex systems and at long
range.14 This methodology has been applied successfully to (ring-opening) reactions of 3-oxo-ß-
lactams.7 Minima (ground states) and first-order saddle points (transition states) were characterized
by normal mode analysis. The normal modes obtained at the M06-2X/6-31++G(d,p) were used as input
for the thermal corrections at 1 atm and 298 K. A continuum model was used to account for the solvent
environment.15 Adding explicit solvent molecules on top of the reacting molecules, including EtOH, and
the base Et3N would make the system fairly complex to explore all pathways. All computations were
carried out with the Gaussian 09 program package.16
For this theoretical study, R = R’ = Me was chosen. On top of the evidences from the experimental
study, the calculations clearly showed the necessity of Et3N for the reaction to proceed. Whereas
activation barriers of over 300 kJ/mol were found for the dehydrofluoration of 4-trifluoromethyl-3-
oxo-ß-lactam 2 to 4-(difluoromethylene)azetidine-2,3-dione 5 in preliminary calculations without Et3N,
these barriers were lowered tremendously by assistance of Et3N. The Gibbs free energy profile for the
reaction of 2 to 5 (Scheme 2, step 1) with assistance of Et3N is shown in Figure 1.
Figure 1. Gibbs free energy profile for the dehydrofluoration of 4-trifluoromethyl-3-oxo-ß-lactam 2 to 4-
(difluoromethylene)azetidine-2,3-dione 5 with assistance of Et3N (PCM (ε = 46,83) B3LYP-D3/6-311+G(d,p)//PCM
(ε = 46,83) M06-2X/6-31++G(d,p), kJ/mol). Energies relative to the separate reactants. Some critical distances
are given in Å.
6
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An activation barrier of 79.0 kJ/mol is found for the deprotonation step, whereas an energy barrier of
104.5 kJ/mol has to be overcome for defluorination by the protonated base Et3NH+. The latter barrier
is relatively high and it may be assumed that the defluorination of the deprotonated 3-oxo-ß-lactam 2
will thus not take place. On the other hand, the protonated base Et3NH+, resulting from deprotonation
of 2, can facilitate the transformation of e.g. ethyl halide to ethanol (Scheme 2, step 2).
The Gibbs free energy profile for the addition of ethanol across the ketone carbonyl group in 3-oxo-ß-
lactam 2 (Scheme 2, step 3.1, first part) is shown in Figure 2. An activation barrier of 74.7 kJ/mol is
found for the reaction with assistance of Et3N, which substracts the hydroxylic hydrogen atom from
ethanol during the reaction, whereas a barrier of over 150 kJ/mol was found from preliminary
calculations without Et3N, showing the necessity of Et3N for the addition of ethanol (which is also in
agreement with the experimental observations).
Figure 2. Gibbs free energy profile for the addition of ethanol to 3-oxo-ß-lactam 2 with assistance of Et3N (PCM
(ε = 46,83) B3LYP-D3/6-311+G(d,p)//PCM (ε = 46,83) M06-2X/6-31++G(d,p), kJ/mol). Energies relative to the
separate reactants. Some critical distance are given in Å.
Thus, the activation barrier for the addition of ethanol to 2 (Scheme 2, step 3.1, first part) is lower than
the activation barrier for the conversion of 2 to 5, further suggesting that the dehydrofluoration of 3-
oxo-ß-lactam 2 (step 1) will not take place. Additionally, assistance of ethanol in the defluorination of
the deprotonated 3-oxo-ß-lactam 2 (Scheme 2, step 1) was investigated. However, the assistance was
found not to lower the activation barrier (see Figure S1 of the Supporting Information).
Whereas hemiacetal 6 can easily be deprotonated at the hydroxyl group on the C3 position,
deprotonation at the C4 carbon atom and dehydrofluoration with formation of 8 are very unlikely. On
the other hand, ring opening of 6B can lead to intermediate 7, which will be readily protonated with
formation of the minor product 4, or direct ring opening of 6B with simultaneous defluorination can
lead to the major product 3 (Scheme 2, step 3.1, last part). Ring opening of 6 with simultaneous proton
transfer and direct formation of the minor product 4 is less likely since protonated Et3N cannot easily
approach the carbon atom which has to be protonated. The Gibbs free energy profiles for the pathways
for the formation of products 3 and 4 from 6B are shown in Figure 3.
7
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10.1002/asia.201701636
Chemistry - An Asian Journal
Figure 3. Gibbs free energy profiles for the conversion of intermediate 6B to products 3 and 4 with assistance of
Et3N (PCM (ε = 46,83) B3LYP-D3/6-311+G(d,p)//PCM (ε = 46,83) M06-2X/6-31++G(d,p), kJ/mol). Energies relative
to reactants 2 with ethanol and Et3N. Some critical distance are given in Å.
A clearly lower activation barrier is found for the formation of the major product 3 if ring opening of
6B occurs simultaneously with defluorination (ΔG‡ = 59.9 kJ/mol versus 69.1 kJ/mol for the formation
of the minor product 4), explaining why 3 is the major product. On the other hand, the difference
between the activation barriers of both pathways is less than 10 kJ/mol, explaining the possibility for
the formation of 4 as a side product.
In summary, these calculations showed that deprotonation of 3-oxo-ß-lactam 2 by Et3N (Scheme 2,
step 1) could result in formation of the protonated base Et3NH+, which facilitates the transformation
of ethyl halide to ethanol (Scheme 2, step 2). Subsequently, ethanol can add across the ketone carbonyl
group in 3-oxo-ß-lactam 2 (Scheme 2, step 3.1) with formation of intermediate 6, which is transferred
to the major product 3 by ring opening with concomitant defluorination. Alternatively, ring opening
can lead to intermediate 7, which will be readily protonated with formation of the minor product 4. In
other words, although this mechanistic route probably only accounts for a minor fraction of the final
products, the calculations show that it concerns a realistic pathway.
Nonetheless, it is clear that other mechanistic options to explain the observed reactivity cannot be
ruled out based on the above-described findings. For example, an at first sight more reasonable
approach is based on the O-alkylation of the enolate anion 10 formed after deprotonation by Et3N,
producing enol ether 11. Re-protonation at C4 then affords an electrophilic oxonium ion 12, which
suffers from water addition to afford hemiacetal 13. The latter intermediate finally undergoes a C3-C4
bond fission (with or without concomitant dehydrofluorination) to result in final structures 3 and 4
(Scheme 3). Unfortunately, attempts to provide evidence for the intermediacy of enol ethers 11 by
means of NMR or MS were unsuccessful.
8
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Chemistry - An Asian Journal
Scheme 3. Alternative mechanism for the formation of compounds 3 and 4 via an enol ether intermediate 11
Although the participation of water seems to be necessary at some point to account for the presence
of three oxygen atoms in the final products, the role of this adventitious water remains curious. In
order to demonstrate the intervention of water during the process, a final experiment was performed
involving treatment of 3-oxo-β-lactam 2a with allyl bromide in dry DMSO in the presence of 10 equiv
of 18O-labeled water. The detection of the corresponding molecular m/z ion 313 in MS for structure 3
(with a M+2 mass as compared to the O16-containing counterpart) confirmed the incorporation of
H218O during the reaction pathway, and only the expected m/z 311 ion was observed when no 18O-
labeled water was used. Based on NMR analysis before and after aqueous work-up, we suppose that
water participation during work-up constitutes an important pathway in the overall mechanism, and
that the role of adventitious water present in the solvent or reagents is probably minimal.
Conclusion
Treatment of 4-trifluoromethyl-3-oxo-β-lactams with an alkyl halide and triethylamine in DMSO
unexpectedly resulted in the formation of 2-[(2,2-difluorovinyl)amino]-2-oxoacetates as major
products, accompanied by minor amounts of 2-oxo-2-[(2,2,2-trifluoroethyl)amino]acetates, through
an unprecedented C3-C4 β-lactam bond fission. This peculiar reactivity was investigated from both an
experimental and a computational point of view in order to shed light on the underlying reaction
mechanism. Furthermore, the alkyl halide/TBAF combination was shown to offer a convenient
alternative protocol for the selective formation of 2-[(2,2-difluorovinyl)amino]-2-oxoacetates 3 from
9
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4-CF3-3-oxo-β-lactams 2. Given the current pharmaceutical interest in fluorinated building blocks,
these newly obtained fluorinated amido esters might be of importance for further studies as well.
Experimental Section
Synthesis of propyl 2-[(2,2-difluorovinyl)(4-methoxybenzyl)amino]-2-oxoacetate 3a and propyl 2-
[(4-methoxybenzyl)(2,2,2-trifluoroethyl)amino]-2-oxoacetate 4a
As a representative example, the synthesis of propyl 2-[(2,2-difluorovinyl)(4-methoxybenzyl)amino]-2-
oxoacetate 3a and propyl 2-oxo-2-[(4-methoxybenzyl)(2,2,2-trifluoroethyl)amino]acetate 4a is
described. To a solution of 1-(4-methoxybenzyl)-4-trifluoromethyl-3-oxoazetidin-2-one 2a (0.37 mmol)
in DMSO (10 mL) was added 1-iodopropane (0.05 mL, 0.55 mmol) and triethylamine (0.15 mL, 1.11
mmol) at room temperature. The resulting mixture was stirred for 2 hours at the same temperature.
The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x 10 mL).
The combined organic phases were washed with brine (5 x 10 mL). Drying (MgSO4), filtration of the
drying agent, and removal of the solvent in vacuo afforded the crude product as a mixture of propyl 2-
[(2,2-difluorovinyl)(4-methoxybenzyl)amino]-2-oxoacetate
3a
and
propyl
2-oxo-2-[(4-
methoxybenzyl)(2,2,2-trifluoroethyl)amino]acetate 4a in a ratio of 87:13, which was separated by
means of preparative HPLC (Supelco Ascentis C18, H2O-CH3CN, 35:65) giving pure propyl 2-[(2,2-
difluorovinyl)(4-methoxybenzyl)amino]-2-oxoacetate 3a in a yield of 56% and propyl 2-oxo-2-[(4-
methoxybenzyl)(2,2,2-trifluoroethyl)amino]acetate 4a in a yield of 12%.
Propyl 2-[(2,2-difluorovinyl)(4-methoxybenzyl)amino]-2-oxoacetate (3a): Yellow oil (56%); HPLC
(Supelco Ascentis C18; H2O-CH3CN, 35:65; flow rate 6 mL min-1; detection at 220 nm; tR = 33.61-33.99
min); 2 rotamers (81/19); IR (ATR): νmax = 1744 (C=O), 1674 (C=O), 1513, 1416, 1243, 1174, 1032, 800
cm-1.
Major rotamer
1H NMR (CDCl3, 400 MHz): δH = 7.21 (d, 2 H, J = 8.6 Hz), 6.87 (d, 2 H, J = 8.6 Hz), 5.31 (dd, 1 H, J = 18.0,
3.0 Hz), 4.62 (s, 2 H), 4.22 (t, 2 H, J = 7.0 Hz), 3.80 (s, 3 H), 1.73 (sextet, 2 H, J = 7.0 Hz), 0.97 ppm (t, 3
H, J = 7.0 Hz); 13C NMR (CDCl3, 100.6 MHz): δC = 162.2, 161.8 (t, J = 2.2 Hz), 159.5, 158.5 (dd, J = 298.1,
292.4 Hz), 130.1, 126.8, 114.16, 85.5 (dd, J = 49.1, 15.1 Hz), 67.8, 55.27, 49.8 (t, J = 1.6 Hz), 21.7, 10.1
ppm; 19F NMR (CDCl3, 376.5 MHz): δF = -83.54 (dd, 1 F, J = 27.1, 18.0 Hz), -93.21 ppm (dd, 1 F, J = 27.1,
3.0 Hz).
Minor rotamer (detectable signals)
1H NMR (CDCl3, 400 MHz): δH = 5.52 (d, 1 H, J = 21.5 Hz), 4.57 (s, 2 H), 4.25 (t, 2 H, J = 7.1 Hz), 3.80 (s, 3
H), 1.73 (sextet, 2 H, J = 7.1 Hz), 0.95 ppm (t, 3 H, J = 7.1 Hz); 13C NMR (CDCl3, 100.6 MHz): δC = 162.3,
161.2, 159.7, 156.9 (d, J = 294.7 Hz), 129.0, 126.4, 114.24, 84.3 (dd, J = 51.6, 12.8 Hz), 68.1, 55.30, 52.0
(d, J = 3.5 Hz), 21.7, 10.2 ppm; 19F NMR (CDCl3, 376.5 MHz): δF = -82.73 (dd, 1 H, J = 42.1, 21.5 Hz), -
97.29 ppm (d, 1 F, J = 42.1 Hz).
10
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MS (70eV): 314 [M + H]+; HR-MS (ESI) for C15H18F2NO4: m/z calcd: 314.1198; found: 314.1204 [M + H]+.
Propyl 2-oxo-2-[(4-methoxybenzyl)(2,2,2-trifluoroethyl)amino]acetate (4a): Yellowish oil (12%);
HPLC (Supelco Ascentis C18; H2O-CH3CN, 35:65; flow rate 6 mL min-1; detection at 220 nm; tR = 40.11-
40.25 min); 2 rotamers (66/34); IR (ATR): νmax = 1737 (C=O), 1673 (C=O), 1514, 1445, 1249, 1154, 1111,
1031, 831 cm-1.
Major rotamer
1H NMR (CDCl3, 400 MHz): δH = 7.22 (d, 2 H, J = 8.6 Hz), 6.91 (d, 2 H, J = 8.6 Hz), 4.53 (s, 2 H), 4.27 (t, 2
H, J = 6.7 Hz), 3.88 (q, 2 H, J = 8.9 Hz), 3.82 (s, 3 H), 1.71-1.81 (m, 2 H), 0.95-1.01 ppm (m, 3 H); 13C NMR
(CDCl3, 100.6 MHz): δC = 162.6, 162.4, 160.0, 129.6, 125.4, 124.2 (q, J = 281.2 Hz), 114.53, 68.1, 55.4,
51.3, 42.8 (q, J = 34.2 Hz), 21.8, 10.24 ppm; 19F NMR (CDCl3, 376.5 MHz): δF = -68.44 ppm (t, 3 F, J = 8.9
Hz).
Minor rotamer
1H NMR (CDCl3, 400 MHz): δH = 7.20 (d, 2 H, J = 8.3 Hz), 6.90 (d, 2 H, J = 8.3 Hz), 4.71 (s, 2 H), 4.26 (t, 2
H, J = 6.7 Hz), 3.94 (q, 2 H, J = 8.9 Hz), 3.81 (s, 3 H), 1.71-1.81 (m, 2 H), 0.95-1.01 ppm (m, 3 H); 13C NMR
(CDCl3, 100.6 MHz): δC = 161.8, 161.7, 159.7, 130.0, 126.4, 123.9 (q, J = 282.9 Hz), 114.46, 68.2, 55.3,
48.2, 46.6 (q, J = 28.9 Hz), 21.7, 10.15 ppm; 19F NMR (CDCl3, 376.5 MHz): δF = -69.87 ppm (t, 3 F, J = 8.
9 Hz).
MS (70eV): 356 [M + Na]+; HR-MS (ESI) for C15H19F3NO4: m/z calcd: 334.1261; found: 334.1268 [M + H]+.
Allyl 2-[(2,2-difluorovinyl)(4-methoxybenzyl)amino]-2-oxoacetate (3b): Yellow oil (25%); HPLC
(Supelco Ascentis C18; H2O-CH3CN, 45:55; flow rate 6 mL min-1; detection at 220 nm; tR = 52.93-53.89
min); 2 rotamers (83/17); IR (ATR): νmax = 1745 (C=O), 1674 (C=O), 1514, 1414, 1243, 1172, 1032, 937,
800 cm-1.
Major rotamer
1H NMR (CDCl3, 400 MHz): δH = 7.21 (d, 2 H, J = 9.0 Hz), 6.87 (d, 2 H, J = 9.0 Hz), 5.93 (ddt, 1 H, J = 16.9,
10.4, 6.2 Hz), 5.40 (dq, 1 H, J = 16.9, 1.2 Hz), 5.32 (dq, 1 H, J = 10.4, 1.2 Hz), 5.30 (dd, 1 H, J = 18.2, 3.1
Hz), 4.74 (dt, 2 H, J = 6.2, 1.2 Hz), 4.62 (s, 2 H), 3.80 ppm (s, 3 H); 13C NMR (CDCl3, 100.6 MHz): δC =
161.7, 161.5 (t, J = 2.2 Hz), 159.5, 158.4 (dd, J = 298.9, 293.0 Hz), 130.5, 130.1, 126.7, 120.3, 114.2, 85.5
(dd, J = 49.1, 15.1 Hz), 66.6, 55.28, 49.8 ppm (t, J = 2.2 Hz); 19F NMR (CDCl3,376.5 MHz): δF = -83.26 (dd,
1 F, J = 26.6, 18.2 Hz), -93.00 ppm (dd, 1 F, J = 26.6, 3.1 Hz).
Minor rotamer (detectable signals)
1H NMR (CDCl3, 400 MHz): δH = 7.20 (d, 2 H, J = 8.8 Hz), 6.88 (d, 2 H, J = 8.8 Hz), 5.87-5.97 (m, 1 H), 5.51
(dd, 1 H, J = 21.3, 1.4 Hz), 4.77 (dt, 2 H, J = 6.1, 1.2 Hz), 4.56 (s, 2 H), 3.81 ppm (s, 3 H); 13C NMR (CDCl3,
100.6 MHz): δC = 161.8, 160.8, 159.7, 130.4, 129.1, 126.3, 120.5, 114.3, 84.3 (dd, J = 51.5, 12.9 Hz),
66.9, 55.30, 52.0 ppm (d, J = 3.9 Hz); 19F NMR (CDCl3, 376.5 MHz): δF = -82.55 (dd, 1 F, J = 41.6, 21.3 Hz),
-97.09 ppm (d, 1 F, J = 41.6 Hz).
MS (70eV): 312 [M + H]+; HR-MS (ESI) for C15H16F2NO4: m/z calcd: 312.1042; found: 312.1044 [M + H]+.
11
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Allyl 2-oxo-2-[(4-methoxybenzyl)(2,2,2-trifluoroethyl)amino]acetate (4b): Yellow oil (5%); HPLC
(Supelco Ascentis C18; H2O-CH3CN, 45:55; flow rate 6 mL min-1; detection at 220 nm; tR = 63.36-64.73
min); 2 rotamers (68/32); IR (ATR): νmax = 1742 (C=O), 1675 (C=O), 1515, 1446, 1258, 1250, 1117, 1031,
832 cm-1.
Major rotamer
1H NMR (CDCl3, 400 MHz): δH = 7.22 (d, 2 H, J = 8.6 Hz), 6.91 (d, 2 H, J = 8.6 Hz), 5.90-6.01 (m, 1 H), 5.42
(dq, 1 H, J = 17.1, 1.4 Hz), 5.33 (dd, 1 H, J = 10.4, 0.8 Hz), 4.78-4.80 (m, 2 H), 4.53 (s, 2 H), 3.88 (q, 2 H,
J = 8.9 Hz), 3.82 ppm (s, 3 H); 13C NMR (CDCl3,100.6 MHz): δC = 162.2, 161.9, 160.0, 130.4, 129.7, 125.3,
124.2 (q, J = 282.3 Hz), 120.6, 114.52, 66.9, 55.35, 51.3, 42.8 ppm (q, J = 34.5 Hz); 19F NMR (CDCl3,376.5
MHz): δF = -68.43 ppm (t, 3 F, J = 8.9 Hz).
Minor rotamer
1H NMR (CDCl3, 400 MHz): δH = 7.19 (d, 2 H, J = 8.6 Hz), 6.89 (d, 2 H, J = 8.6 Hz), 5.90-6.01 (m, 1 H), 5.43
(dq, 1 H, J = 17.4, 1.7 Hz), 5.34 (dd, 1 H, J = 10.5, 1.2 Hz), 4.78-4.80 (m, 2 H), 4.71 (s, 2 H), 3.93 (q, 2 H,
J = 8.8 Hz), 3.81 ppm (s, 3 H); 13C NMR (CDCl3,100.6 MHz): δC = 161.4, 161.2, 159.7, 130.4, 130.1, 126.3,
123.9 (q, J = 281.0 Hz), 120.4, 114.45, 67.0, 55.33, 48.2, 46.5 ppm (q, J = 34.7 Hz); 19F NMR (CDCl3,376.5
MHz): δF = -69.79 ppm (t, 3 F, J = 8.8 Hz).
GC-MS: m/z (%) = 331 (M+, 7), 290 (60), 218 (20), 137 (72), 121 (100), 78(13), 41 (10).
3-Chloropropyl 2-[(2,2-difluorovinyl)(4-methoxybenzyl)amino]-2-oxoacetate (3c): Yellow oil (42%);
HPLC (Supelco Ascentis C18; H2O-CH3CN, 43:57; flow rate 6 mL min-1; detection at 220 nm; tR = 32.72-
33.30 min); 2 rotamers (83/17); IR (ATR): νmax = 1745 (C=O), 1674 (C=O), 1513, 1417, 1244, 1173, 1031,
957, 801 cm-1.
Major rotamer
1H NMR (CDCl3, 400 MHz): δH = 7.21 (d, 2 H, J = 8.5 Hz), 6.87 (d, 2 H, J = 8.5 Hz), 5.32 (dd, 1 H, J = 18.1,
2.7 Hz), 4.62 (s, 2 H), 4.42 (t, 2 H, J = 6.2 Hz), 3.81 (s, 3 H), 3.63 (t, 2 H, J = 6.2 Hz), 2.10-2.20 ppm (m, 2
H); 13C NMR (CDCl3, 100.6 MHz): δC = 161.89, 161.4 (t, J = 2.8 Hz), 159.6, 158.5 (dd, J = 298.0, 293.1 Hz),
130.1, 126.6, 114.2, 85.5 (dd, J = 48.9, 15.1 Hz), 62.8, 55.28, 49.9 (t, J = 2.2 Hz), 40.6, 31.1 ppm; 19F
NMR (CDCl3, 376.5 MHz): δF = -83.61 (dd, 1 H, J = 26.5, 18.1 Hz), -92.77 ppm (dd, 1 F, J = 26.5, 2.7 Hz).
Minor rotamer
1H NMR (CDCl3, 400 MHz): δH = 7.18 (d, 2 H, J = 9.0 Hz), 6.89 (d, 2 H, J = 9.0 Hz), 5.55 (dd, 1 H, J = 21.3,
1.1 Hz), 4.58 (s, 2 H), 4.43 (t, 2 H, J = 6.2 Hz), 3.81 (s, 3 H), 3.56 (t, 2 H, J = 6.2 Hz), 2.10-2.20 ppm (m, 2
H); 13C NMR (CDCl3,100.6 MHz): δC = 161.94, 160.8, 159.7, 155.5 (dd, J = 295.6, 286.0 Hz), 128.9, 126.4,
114.3, 84.5 (dd, J = 51.5, 12.7 Hz), 63.0, 55.32, 52.1 (d, J = 3.6 Hz), 40.6, 31.0 ppm; 19F NMR (CDCl3,
376.5 MHz): δF = -82.57 (dd, 1 F, J = 41.7, 21.3 Hz), -97.15 ppm (d, 1 F, J = 41.7 Hz).
MS (70eV): 370 [M + Na]+; HR-MS (ESI) for C15H17ClF2NO4: m/z calcd: 348.0809; found: 348.0814 [M +
H]+.
3-Chloropropyl 2-oxo-2-[(4-methoxybenzyl)(2,2,2-trifluoroethyl)amino]acetate (4c): Yellowish oil
(10%); HPLC (Supelco Ascentis C18; H2O-CH3CN, 43:57; flow rate 6 mL min-1; detection at 220 nm; tR =
12
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38.47-38.97 min); 2 rotamers (65/35); IR (ATR): νmax = 1740 (C=O), 1673 (C=O), 1514, 1446, 1249, 1155,
1113, 1025, 831, 656 cm-1.
Major rotamer
1H NMR (CDCl3, 400 MHz): δH = 7.21 (d, 2 H, J = 8.6 Hz), 6.91 (d, 2 H, J = 8.6 Hz), 4.55 (s, 2 H), 4.467 (t,
2 H, J = 6.2 Hz), 3.90 (q, 2 H, J = 8.9 Hz), 3.82 (s, 3 H), 3.60 (t, 2 H, J = 6.2 Hz), 2.14-2.23 ppm (m, 2 H);
13C NMR (CDCl3, 100.6 MHz): δC = 162.0, 161.4, 160.0, 129.5, 125.4, 124.1 (q, J = 281.5 Hz), 114.6, 63.1,
55.4, 51.4, 43.1 (q, J = 34.3 Hz), 40.64, 31.0 ppm; 19F NMR (CDCl3, 376.5 MHz): δF = -68.49 ppm (t, 3 F, J
= 8.9 Hz).
Minor rotamer
1H NMR (CDCl3, 400 MHz): δH = 7.19 (d, 2 H, J = 8.5 Hz), 6.90 (d, 2 H, J = 8.5 Hz), 4.71 (s, 2 H), 4.463 (t,
2 H, J = 6.2 Hz), 3.95 (q, 2 H, J = 8.8 Hz), 3.81 (s, 3 H), 3.65 (t, 2 H, J = 6.2 Hz), 2.14-2.23 ppm (m, 2 H);
13C NMR (CDCl3, 100.6 MHz): δC = 162.3, 161.3, 159.7, 130.0, 126.7 (q, J = 282.4 Hz), 126.2, 114.5, 63.2,
55.3, 48.4, 46.6 (q, J = 35.0 Hz), 40.62, 31.1 ppm; 19F NMR (CDCl3, 376.5 MHz): δF = -69.95 ppm (t, 3 F, J
= 8.8 Hz).
MS (70eV): 368 [M + H]+; HR-MS (ESI) for C15H18ClF3NO4: m/z calcd: 368.0871; found: 368.0857 [M +
H]+.
Benzyl 2-[(2,2-difluorovinyl)(4-methoxybenzyl)amino]-2-oxoacetate (3d): White solid (50%); Mp
32°C; HPLC (Supelco Ascentis C18; H2O-CH3CN, 55:45; flow rate 6 mL min-1; detection at 220 nm; tR =
65.01-66.96 min); 2 rotamers (82/18); IR (ATR): νmax = 1744 (C=O), 1674 (C=O), 1513, 1416, 1243, 1169,
1031, 801, 746, 697 cm-1.
Major rotamer
1H NMR (CDCl3, 400 MHz): δH = 7.33-7.37 (m, 5 H), 7.18 (d, 2 H, J = 8.7 Hz), 6.85 (d, 2 H, J = 8.7 Hz), 5.27
(s, 2 H), 5.19 (dd, 1 H, J = 18.1, 3.5 Hz), 4.59 (s, 2 H), 3.78 ppm (s, 3 H); 13C NMR (CDCl3, 100.6 MHz): δC
= 161.9, 161.5 (t, J = 2.3 Hz), 159.5, 158.5 (dd, J = 305.1, 299.5 Hz), 134.3, 130.1, 128.86, 128.76, 128.72,
126.7, 114.16, 85.3 (dd, J = 49.1, 14.9 Hz), 67.8, 55.3, 49.8 ppm (t, J = 1.7 Hz); 19F NMR (CDCl3, 376.5
MHz): δF = -83.17 (dd, 1 F, J = 26.1, 18.1 Hz), -92.77 ppm (dd, 1 F, J = 26.1, 3.5 Hz).
Minor rotamer
1H NMR (CDCl3, 400 MHz): δH = 7.33-7.37 (m, 5 H), 7.11 (d, 2 H, J = 8.3 Hz), 6.83 (d, 2 H, J = 8.3 Hz), 5.50
(dd, 1 H, J = 21.3, 1.2 Hz), 5.30 (s, 2 H), 4.48 (s, 2 H), 3.79 ppm (s, 3 H); 13C NMR (CDCl3, 100.6 MHz): δC
= 161.9, 160.8, 159.7, 154.1 (d, J = 296.2 Hz), 134.1, 130.1, 128.96, 128.94, 128.74, 126.3, 114.20, 84.3
(dd, J = 51.4, 12.8 Hz), 68.1, 55.3, 51.9 ppm (d, J = 3.7 Hz); 19F NMR (CDCl3, 376.5 MHz): δF = -82.56 (dd,
1 F, J = 41.6, 21.3 Hz), -92.16 ppm (d, 1 F, J = 41.6 Hz).
MS (70eV): 362 [M +H]+; HR-MS (ESI) for C19H18F2NO4: m/z calcd: 362.1198 ; found: 362.1200 [M + H]+.
Benzyl 2-oxo-2-[(4-methoxybenzyl)(2,2,2-trifluoroethyl)amino]acetate (4d): Yellowish oil (11%);
HPLC (Supelco Ascentis C18; H2O-CH3CN, 55:45; flow rate 6 mL min-1; detection at 220 nm; tR = 77.04-
77.39 min); 2 rotamers (68/32); IR (ATR): νmax = 1739 (C=O), 1672 (C=O), 1514, 1445, 1266, 1248, 1153,
1111, 1026, 831, 736, 696 cm-1.
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10.1002/asia.201701636
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Major rotamer
1H NMR (CDCl3, 400 MHz): δH = 7.32-7.42 (m, 5 H), 7.14 (d, 2 H, J = 8.7 Hz), 6.86 (d, 2 H, J = 8.7 Hz),
5.321 (s, 2 H), 4.45 (s, 2 H), 3.862 (q, 2 H, J = 8.9 Hz), 3.80 ppm (s, 3 H); 13C NMR (CDCl3, 100.6 MHz): δC
= 162.3, 162.0, 159.9, 134.07, 129.6, 128.8, 128.74, 128.72, 125.3, 124.2 (q, J = 280.9 Hz), 114.5, 68.1,
55.3, 51.2, 42.9 ppm (q, J = 34.5 Hz); 19F NMR (CDCl3, 376.5 MHz): δF = -68.43 ppm (t, 3 F, J = 8.9 Hz).
Minor rotamer
1H NMR (CDCl3, 400 MHz): δH = 7.32-7.42 (m, 5 H), 7.18 (d, 2 H, J = 8.4 Hz), 6.88 (d, 2 H, J = 8.4 Hz),
5.316 (s, 2 H), 4.69 (s, 2 H), 3.858 (q, 2 H, J = 8.8 Hz), 3.80 ppm (s, 3 H); 13C NMR (CDCl3, 100.6 MHz): δC
= 161.43, 161.37, 159.7, 134.10, 130.1, 129.0, 128.9, 126.3, 125.4, 123.8 (q, J = 280.8 Hz), 114.5, 68.2,
55.3, 48.2, 46.5 ppm (q, J = 34.4 Hz); 19F NMR (CDCl3, 376.5 MHz): δF = -68.78 ppm (t, 3 F, J = 8.8 Hz).
MS (70eV): 382 [M + H]+; HR-MS (ESI) for C19H22F3N2O4: m/z calcd: 399.1526; found: 399.1523 [M +
NH4]+.
Methyl 2-[(2,2-difluorovinyl)(4-methoxybenzyl)amino]-2-oxoacetate (3e): Yellow oil (33%); HPLC
(Supelco Ascentis C18; H2O-CH3CN, 55:45; flow rate 6 mL min-1; detection at 220 nm; tR = 54.99-66.94
min); 2 rotamers (82/18); IR (ATR): νmax = 1745 (C=O), 1674 (C=O), 1513, 1412, 1243, 1200, 1031, 800
cm-1.
Major rotamer
1H NMR (CDCl3, 400 MHz): δH = 7.20 (d, 2 H, J = 8.6 Hz), 6.87 (d, 2 H, J = 8.6 Hz), 5.32 (dd, 1 H, J = 18.3,
3.0 Hz), 4.63 (s, 2 H), 3.86 (s, 3 H), 3.80 ppm (s, 3 H); 13C NMR (CDCl3, 100.6 MHz): δC = 162.3, 161.4 (t,
J = 2.1 Hz), 159.6, 158.4 (dd, J = 299.5, 292.7 Hz), 130.1, 126.7, 114.2, 85.5 (dd, J = 49.2, 15.1 Hz), 55.28,
52.8, 49.9 ppm (t, J = 2.1 Hz); 19F NMR (CDCl3, 376.5 MHz): δF = -83.64 (dd, 1 F, J = 27.4, 18.3 Hz), -93.21
ppm (dd, 1 F, J = 27.4, 3.0 Hz).
Minor rotamer
1H NMR (CDCl3, 400 MHz): δH = 7.19 (d, 2 H, J = 8.6 Hz), 6.89 (d, 2 H, J = 8.6 Hz), 5.50 (dd, 1 H, J = 21.3,
1.4 Hz), 4.57 (s, 2 H), 3.89 (s, 3 H), 3.81 ppm (s, 3 H); 13C NMR (CDCl3, 100.6 MHz): δC = 162.5, 160.8,
159.7, 155.6 (dd, J = 297.2, 286.2 Hz), 129.1, 126.3, 114.3, 84.3 (dd, J = 51.3, 12.8 Hz), 55.3, 53.0, 52.1
ppm (d, J = 3.5 Hz); 19F NMR (CDCl3, 376.5 MHz): δF = -82.51 (dd, 1 F, J = 41.2, 21.3 Hz), -97.04 ppm (d,
1 F, J = 41.2 Hz).
MS (70eV): 286 [M + H]+; HR-MS (ESI) for C13H14F2NO4: m/z calcd: 286.0885; found: 286.0885 [M +H]+.
Methyl 2-oxo-2-[(4-methoxybenzyl)(2,2,2-trifluoroethyl)amino]acetate (4e): Yellowish oil (7%); HPLC
(Supelco Ascentis C18; H2O-CH3CN, 55:45; flow rate 6 mL min-1; detection at 220 nm; tR = 73.28-86.52
min); 2 rotamers (66/34); IR (ATR): νmax = 1744 (C=O), 1672 (C=O), 1514, 1249, 1153, 1113, 1028, 829
cm-1.
Major rotamer
1H NMR (CDCl3, 400 MHz): δH = 7.22 (d, 2 H, J = 8.9 Hz), 6.91 (d, 2 H, J = 8.9 Hz), 4.53 (s, 2 H), 3.912 (s,
3 H), 3.88 (q, 2 H, J = 8.9 Hz), 3.82 ppm (s, 3 H); 13C NMR (CDCl3, 100.6 MHz): δC = 162.6, 162.3, 160.0,
14
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10.1002/asia.201701636
Chemistry - An Asian Journal
129.6, 125.4, 124.1 (q, J = 282.9 Hz, CF3), 114.6, 55.4, 53.0, 51.4, 42.8 ppm (q, J = 34.7 Hz); 19F NMR
(CDCl3, 376.5 MHz): δF = -68.44 ppm (t, 3 F, J = 8.9 Hz).
Minor rotamer
1H NMR (CDCl3, 400 MHz): δH = 7.19 (d, 2 H, J = 8.6 Hz), 6.90 (d, 2 H, J = 8.6 Hz), 4.71 (s, 2 H), 3.96 (q, 2
H, J = 8.8 Hz), 3.906 (s, 3 H), 3.81 ppm (s, 3 H); 13C NMR (CDCl3, 100.6 MHz): δC = 161.9, 161.3, 159.7,
130.0, 126.3, 124.0 (q, J = 283.7 Hz), 114.5, 55.3, 53.2, 48.4, 46.6 ppm (q, J = 34.4 Hz); 19F NMR (CDCl3,
376.5 MHz): δF = -69.97 ppm (t, 3 F, J = 8.8 Hz).
MS (70eV): 306 [M + H]+; HR-MS (ESI) for C13H15F3NO4: m/z calcd: 306.0948; found: 306.0940 [M +H]+.
Propyl 2-[(2,2-difluorovinyl)(4-methoxyphenyl)amino]-2-oxoacetate (3f): Yellow oil (30%); Rf = 0.19
(PE-EtOAc, 15:1); 2 rotamers (86/14); IR (ATR): νmax = 1743 (C=O), 1681 (C=O), 1509, 1236, 1030, 922,
839, 795, 672 cm-1.
Major rotamer
1H NMR (CDCl3, 400 MHz): δH = 7.21 (d, 2 H, J = 8.9 Hz), 6.89 (d, 2 H, J = 8.9 Hz), 6.08 (d, 1 H, J = 19.2
Hz), 3.93 (t, 2 H, J = 7.1 Hz), 3.82 (s, 3 H), 1.45 (sextet, 2 H, J = 7.1 Hz), 0.80 ppm (t, 3 H, J = 7.1 Hz); 13C
NMR (CDCl3, 100.6 MHz): δC = 161.8, 161.1 (d, J = 1.8 Hz), 159.9, 155.3 (dd, J = 296.8, 284.2 Hz), 130.8,
128.7, 114.6, 87.2 (dd, J = 51.3, 10.3 Hz), 67.6, 55.5, 21.5, 10.2 ppm; 19F NMR (CDCl3, 376.5 MHz): δF =
-84.40 (dd, 1 F, J = 42.2, 19.2 Hz), -98.70 ppm (d, 1 F, J = 42.2 Hz).
Minor rotamer (detectable signals)
1H NMR (CDCl3, 400 MHz): δH = 7.25 (d, 2 H, J = 9.0 Hz), 6.93 (d, 2 H, J = 9.0 Hz), 5.73 (dd, 1 H, J = 17.4,
3.4 Hz), 4.28 (t, 2 H, J = 7.2 Hz), 3.82 (s, 3 H), 1.78 (sextet, 2 H, J = 7.2 Hz), 1.01 ppm (t, 3 H, J = 7.2 Hz);
13C NMR (CDCl3, 100.6 MHz): δC = 162.4, 161.4 (d, J = 2.9 Hz), 158.9, 131.4, 126.6, 114.6, 87.8 (dd, J =
64.2, 15.7 Hz), 67.9, 55.5, 21.8, 10.2 ppm; 19F NMR (CDCl3, 376.5 MHz): δF = -84.15 (dd, 1 F, J = 26.4,
17.4 Hz), -93.58 ppm (dd, 1 F, J = 26.4, 3.4 Hz).
MS (70eV): 300 [M + H]+; HR-MS (ESI) for C14H16F2NO4: m/z calcd: 300.1042; found: 300.1054 [M + H]+.
Propyl 2-oxo-2-[(4-methoxyphenyl)(2,2,2-trifluoroethyl)amino]acetate (4f): Yellowish oil (9%); Rf =
0.18 (PE-EtOAc, 15:1); IR (ATR): νmax = 1744 (C=O), 1682 (C=O), 1510, 1248, 1217, 1134, 1029, 838, 573
cm-1.
1H NMR (CDCl3, 400 MHz): δH = 7.21 (d, 2 H, J = 8.9 Hz), 6.90 (d, 2 H, J = 8.9 Hz), 4.34 (q, 2 H, J = 8.6 Hz),
3.91 (t, 2 H, J = 7.1 Hz), 3.82 (s, 3 H), 1.45 (sextet, 2 H, J = 7.1 Hz), 0.80 ppm (t, 3 H, J = 7.1 Hz); 13C NMR
(CDCl3, 100.6 MHz): δC = 162.7, 161.9, 160.1, 131.4, 129.4, 123.7 (q, J = 280.5 Hz), 114.8, 67.5, 55.5,
48.7 (q, J = 34.3 Hz), 21.5, 10.2 ppm; 19F NMR (CDCl3, 376.5 MHz): δF = -68.78 ppm (t, 3 F, J = 8.6 Hz).
MS (70eV): 320 [M + H]+; HR-MS (ESI) for C14H17F3NO4: m/z calcd: 320.1104; found: 320.1112 [M + H]+.
Allyl 2-[(2,2-difluorovinyl)(4-methoxyphenyl)amino]-2-oxoacetate (3g): Yellow oil (35%); Rf = 0.19
(PE-EtOAc, 18:1); 2 rotamers (85/15); IR (ATR): νmax = 1745 (C=O), 1681 (C=O), 1510, 1386, 1345, 1236,
1120, 1030, 920, 839, 794, 674 cm-1.
Major rotamer
15
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1H NMR (CDCl3, 400 MHz): δH = 7.20 (d, 2 H, J = 8.9 Hz), 6.88 (d, 2 H, J = 8.9 Hz), 6.07 (d, 1 H, J = 19.1
Hz), 5.62 (ddt, 1 H, J = 17.0, 10.7, 6.1 Hz), 5.19 (dq, 1 H, J = 17.0, 1.2 Hz), 5.17 (dq, 1 H, J = 10.7, 1.2 Hz),
4.45 (dt, 2 H, J = 6.1, 1.2 Hz), 3.82 ppm (s, 3 H); 13C NMR (CDCl3, 100.6 MHz): δC = 161.3, 160.8, 159.9,
155.3 (dd, J = 296.8, 284.3 Hz), 130.7, 130.4, 128.7, 119.9, 114.6, 87.1 (dd, J = 51.3, 10.4 Hz), 66.4, 55.5
ppm; 19F NMR (CDCl3, 376.5 MHz): δF = -84.27 (dd, 1 F, J = 42.0, 19.1 Hz), -98.59 ppm (d, 1 F, J = 42.0
Hz).
Minor rotamer (detectable signals)
1H NMR (CDCl3, 400 MHz): δH = 7.25 (d, 2 H, J = 8.8 Hz), 6.93 (d, 2 H, J = 8.8 Hz), 5.98 (ddt, 1 H, J = 16.9,
11.2, 5.7 Hz), 5.72 (dd, 1 H, J = 17.3, 3.1 Hz), 5.45 (d, 1 H, J = 16.9 Hz), 5.36 (d, 1 H, J = 11.2 Hz), 4.80 (d,
2 H, J = 5.7 Hz), 3.82 ppm (s, 3 H); 13C NMR (CDCl3, 100.6 MHz): δC = 161.9, 158.9, 131.3, 130.5, 126.6,
120.5, 114.6, 87.8 (d, J = 33.6 Hz), 66.7, 55.5 ppm; 19F NMR (CDCl3, 376.5 MHz): δF = -83.90 (dd, 1 F, J =
25.9, 17.3 Hz), -93.36 ppm (dd, 1 F, J = 25.9, 3.1 Hz).
MS (70eV): 298 [M + H]+; HR-MS (ESI) for C14H14F2NO4: m/z calcd: 298.0885; found: 298.0892 [M + H]+.
3-Chloropropyl 2-[(2,2-difluorovinyl)(4-methoxyphenyl)amino]-2-oxoacetate (3h): Yellow oil (38%);
Rf = 0.10 (PE-EtOAc, 9:1); 2 rotamers (88/12); IR (ATR): νmax = 1745 (C=O), 1679 (C=O), 1509, 1372, 1237,
1029, 921, 839, 793, 672, 554 cm-1.
Major rotamer
1H NMR (CDCl3, 400 MHz): δH = 7.21 (d, 2 H, J = 9.3 Hz), 6.91 (d, 2 H, J = 9.3 Hz), 6.06 (dd, 1 H, J = 19.1,
0.7 Hz), 4.13 (t, 2 H, J = 6.2 Hz), 3.83 (s, 3 H), 3.34 (t, 2 H, J = 6.2 Hz), 1.88 ppm (quintet, 2 H, J = 6.2 Hz);
13C NMR (CDCl3, 100.6 MHz): δC = 161.6, 160.7, 160.0, 155.4 (dd, J = 297.0, 284.7 Hz), 130.6, 128.6,
114.8, 87.1 (dd, J = 51.3, 10.4 Hz), 62.5, 55.5, 40.5, 31.1 ppm; 19F NMR (CDCl3, 376.5 MHz): δF = -84.04
(dd, 1 H, J = 41.2, 19.1 Hz), -98.36 ppm (d, 1 F, J = 41.2 Hz).
Minor rotamer (detectable signals)
1H NMR (CDCl3, 400 MHz): δH = 7.25 (d, 2 H, J = 7.9 Hz), 6.94 (d, 2 H, J = 7.9 Hz), 5.74 (dd, 1 H, J = 17.2,
3.3 Hz), 4.48 (t, 2 H, J = 6.2 Hz), 3.83 (s, 3 H), 3.67 (t, 2 H, J = 6.2 Hz), 2.22 ppm (quintet, 2 H, J = 6.2 Hz);
13C NMR (CDCl3, 100.6 MHz): δC = 159.0, 126.6, 126.1, 114.7, 87.8 (d, J = 30.5 Hz), 62.9, 52.5, 40.6, 31.1
ppm; 19F NMR (CDCl3, 376.5 MHz): δF = -84.28 (dd, 1 H, J = 26.6, 17.2 Hz), -93.13 ppm (dd, 1 F, J = 26.6,
3.3 Hz).
MS (70eV): 334 [M + H]+; HR-MS (ESI) for C14H15ClF2NO4: m/z calcd: 334.0652; found: 334.0653 [M +
H]+.
Benzyl 2-[(2,2-difluorovinyl)(4-methoxyphenyl)amino]-2-oxoacetate (3i): Yellow oil (50%); Rf = 0.26
(PE-EtOAc, 15:1); 2 rotamers (87/13); IR (ATR): νmax = 1743 (C=O), 1680 (C=O), 1509, 1361, 1235, 1030,
919, 838, 735, 696 cm-1.
Major rotamer
1H NMR (CDCl3, 400 MHz): δH = 7.25-7.33 (m, 3 H), 7.08-7.11 (m, 4 H), 6.72 (d, 2 H, J = 9.0 Hz), 6.04 (dd,
1 H, J = 19.1, 0.6 Hz), 5.00 (s, 2 H), 3.78 ppm (s, 3 H); 13C NMR (CDCl3, 100.6 MHz): δC = 161.5, 160.8 (d,
J = 2.0 Hz), 159.8, 155.3 (dd, J = 296.9, 284.4 Hz), 134.0, 130.4, 128.87, 128.6, 128.54, 128.48, 114.5,
16
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10.1002/asia.201701636
Chemistry - An Asian Journal
87.1 (dd, J = 51.3, 10.4 Hz), 67.6, 55.4 ppm; 19F NMR (CDCl3, 376.5 MHz): δF = -84.22 (dd, 1 F, J = 41.6,
19.1 Hz), -95.58 ppm (d, 1 F, J = 41.6 Hz).
Minor rotamer (detectable signals)
1H NMR (CDCl3, 400 MHz): δH = 7.36-7.43 (m, 5 H), 7.22 (d, 2 H, d, J = 8.4 Hz), 6.91 (d, 2 H, d, J = 8.4 Hz),
5.60 (dd, 1 H, J = 17.1, 3.4 Hz), 5.33 (s, 2 H), 3.80 ppm (s, 3 H); 13C NMR (CDCl3, 100.6 MHz): δC = 162.1,
161.1, 158.9, 134.3, 131.3, 128.9, 128.8, 126.6, 114.6, 87.8 (d, J = 15.2 Hz), 68.0, 55.5 ppm; 19F NMR
(CDCl3, 376.5 MHz): δF = -83.79 (dd, 1 F, J = 25.1, 17.1 Hz), -93.13 ppm (dd, 1 F, J = 25.1, 3.4 Hz).
MS (70eV): 348 [M + H]+; HR-MS (ESI) for C18H16F2 NO4: m/z calcd: 348.1042; found: 348.1034 [M + H]+.
Methyl 2-[(2,2-difluorovinyl)(4-methoxyphenyl)amino]-2-oxoacetate (3j): Yellow oil (42%); HPLC
(Supelco Ascentis C18; H2O-CH3CN, 55:45; flow rate 6 mL min-1; detection at 220 nm; tR = 85.11-90.56
min); 2 rotamers (83/17); IR (ATR): νmax = 1746 (C=O), 1681 (C=O), 1509, 1380, 1238, 1122, 1029, 839,
794, 673 cm-1.
Major rotamer
1H NMR (CDCl3, 400 MHz): δH = 7.20 (d, 2 H, J = 8.9 Hz), 6.89 (d, 2 H, J = 8.9 Hz), 6.06 (dd, 1 H, J = 19.1,
0.5 Hz), 3.82 (s, 3 H), 3.58 ppm (s, 3 H); 13C NMR (CDCl3, 100.6 MHz): δC = 162.0, 160.8 (d, J = 1.7 Hz),
159.9, 155.4 (dd, J = 295.9, 283.4 Hz), 130.7, 128.6, 114.6, 87.2 (dd, J = 51.3, 10.4 Hz), 55.5, 52.5 ppm;
19F NMR (CDCl3, 376.5 MHz): δF = -84.20 (dd, 1 F, J = 41.8, 19.1 Hz), -98.52 ppm (d, 1 F, J = 41.8 Hz).
Minor rotamer
1H NMR (CDCl3, 400 MHz): δH = 7.24 (d, 2 H, J = 9.2 Hz), 6.93 (d, 2 H, J = 9.2 Hz), 5.75 (dd, 1 H, J = 17.3,
3.0 Hz), 3.92 (s, 3 H), 3.58 ppm (s, 3 H); 13C NMR (CDCl3, 100.6 MHz): δC = 162.5, 161.0, 159.0, 158.8
(dd, J = 298.7, 293.3 Hz), 131.4, 126.7, 114.6, 87.8 (dd, J = 48.9, 14.2 Hz), 55.5, 53.0 ppm; 19F NMR
(CDCl3, 376.5 MHz): δF = -84.29 (dd, 1 F, J = 26.4, 17.3 Hz), -93.61 ppm (dd, 1 F, J = 26.4, 3.0 Hz).
MS (70eV): 272 [M + H]+; HR-MS (ESI) for C12H12F2NO4: m/z calcd: 272.0729; found: 272.0726 [M + H]+.
Methyl 2-oxo-2-[(4-methoxyphenyl)(2,2,2-trifluoroethyl)amino]acetate (4j): Yellow oil (5%); HPLC
(Supelco Ascentis C18; H2O-CH3CN, 55:45; flow rate 6 mL min-1; detection at 220 nm; tR = 99.55-105.33
min); IR (ATR): νmax = 1748 (C=O), 1682 (C=O), 1510, 1395, 1224, 1132, 1028, 838, 781, 676 cm-1.
1H NMR (CDCl3, 400 MHz): δH = 7.20 (d, 2 H, J = 8.9 Hz), 6.90 (d, 2 H, J = 8.9 Hz), 4.34 (q, 2 H, J = 8.7 Hz),
3.83 (s, 3 H), 3.57 ppm (s, 3 H); 13C NMR (CDCl3, 100.6 MHz): δC = 162.5, 162.1, 160.1, 131.3, 129.3,
123.6 (q, J = 280.6 Hz), 114.8, 55.5, 52.4, 48.8 ppm (q, J = 34.3 Hz); 19F NMR (CDCl3, 376.5 MHz): δF = -
68.80 ppm (t, 3 F, J = 8.7 Hz).
MS (70eV): 292 [M + H]+; HR-MS (ESI) for C12H13F3NO4: m/z calcd: 292.0791; found: 292.0783 [M + H]+.
Supporting information
Cartesian coordinates of the optimized geometries (M06-2X/6-31++G(d,p)) of the transition states. Full
reference of Gaussian 09.
17
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10.1002/asia.201701636
Chemistry - An Asian Journal
Acknowledgments
The authors are indebted to the Research Foundation-Flanders (FWO, project G0F4816N) and to the
National Foundation for Science and Technology Development, Vietnam (NAFOSTED, project FWO-
104-2015.01) for financial support in the framework of a FWO-NAFOSTED bilateral research
cooperation. The authors are also indebted to Ghent University-Belgium (Special Research Fund, BOF)
for financial support. The Research Board of Ghent University is acknowledged for financial support.
Computational resources and services used in this work were provided by Ghent University (Stevin
Supercomputer Infrastructure).
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