Electrochemical Fluorocyclization of N-Allylcarboxamides to 2-Oxazolines by Hypervalent Iodine Mediator

Article abstract of DOI:10.1021/acs.orglett.8b03682

A resource saving protocol for the synthesis of 5-fluoromethyl-2-oxazolines by using electrochemistry has been realized. Thereby, a hypervalent iodine species I(III) is generated by anodic oxidation in the presence of Et₃N·5HF and mediates the

Full text of DOI:10.1021/acs.orglett.8b03682

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Electrochemical Fluorocyclization of N‑Allylcarboxamides to
2‑Oxazolines by Hypervalent Iodine Mediator
John D. Haupt,† Michael Berger,† and Siegfried R. Waldvogel*
Institute of Organic Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, 55128 Mainz, Germany
S
* Supporting Information
ABSTRACT: A resource saving protocol for the synthesis of 5-
fluoromethyl-2-oxazolines by using electrochemistry has been
realized. Thereby, a hypervalent iodine species I(III) is generated
by anodic oxidation in the presence of Et3N·5HF and mediates
the cyclization of N-allylcarboxamide to 5-fluoromethyl-2-oxazo-
line. This method allows application to various substrates
furnishing the 2-oxazolines with yields up to 68%. The protocol
is easy to conduct under constant current conditions offering a
sustainable alternative over conventional reagent-based pathways.
xazolines are an important class of five-membered
heterocycles that have attracted significant interest
species. Employing an excess of chemical oxidizers generates
high amounts of reagent waste and affords a low atom
economy. In contrast to that, selective electrochemical
fluorination of organic compounds using in situ generated
hypervalent iodine mediators is more sustainable.18−20 There-
by, the iodoarene (ArI) is oxidized to the hypervalent iodine
species at the anode. Such an electrochemical approach has
several advantages over conventional, reagent-based synthesis.
Organic electrosynthesis enables the replacement of toxic
and costly chemical oxidizing or reducing agents by electric
current as an inexpensive, renewable, and inherently safe
reagent.21 It increases atom economy and avoids production of
reagent waste, as just the addition or removal of electrons is
required. Hence, electroorganic synthesis attracted much
attention as a powerful tool for green chemistry.22,23 Recently,
an elegant electrochemical approach to oxazolines by
dehydrogenative cyclization of β-amino arylketones was
reported.24 However, an electrochemical approach to fluori-
nated 2-oxazolines is not described yet in literature. In this
case, we present the first example of a sustainable synthesis of
5-fluoromethyl-2-oxazolines by electrochemical fluorocycliza-
tion of simply accessible N-allylcarboxamides using a hyper-
valent iodoarene mediator (Scheme 1).
The electrolysis was conducted in an undivided cell
equipped with a simple two-electrode arrangement using
constant current conditions. The electrolytic reactions were
performed at platinum electrodes in a mixture (1:1) of
dichloromethane and triethylamine pentahydrofluoride (Et3N·
5HF) with a substrate concentration of 0.1 mol·L−1 and
stoichiometrically added ArI. We used Et3N·5HF which allows
for the selective generation of ArIF2,19 whereas Et3N·3HF
could lead to benzylic fluorination of the mediator.20 Due to
the good electric conductivity of the ionic liquid Et3N·5HF, no
O
from synthetic and medicinal chemists. The oxazoline moiety
has wide-ranging applications such as the use of oxazoline-
containing ligands in asymmetric catalysis1 or poly(2-
oxazoline)s as materials for biomedical applications.2 Oxazo-
lines constitute the core moiety of many biologically active
natural compounds.3 Thus, oxazolines play a major role in
medicinal chemistry. Pharmaceuticals involving oxazolines
reported a broad scope of biological activities;4 some
derivatives have been identified as antimitotic5 and antibiotic
agents.6 Recently, numerous synthetic approaches for 2-
oxazolines have been developed such as cyclodehydration of
β-hydroxy amides7 as well as of β-amino alcohols and
protected α-amino acids8 and dehydrogenative cyclization of
β-acylamino ketones.9 Additionally, many cyclization strategies
with N-allylcarboxamides as starting material have been
established.10 Though, in the context of bioactive compounds
the substitution of hydrogen by fluorine has been explored
broadly in molecular editing of drugs.11 Such displacements are
often made in methyl groups, which can modulate potency or
interfere with metabolic modification.12 Because of that,
incorporation of fluorine as a bioisostere of a CH moiety
belongs to one of the most important tasks for today’s
synthetic chemists. Selective chemical fluorination methods
often involve various reagents such as anhydrous HF, XeF2,
SF4, Et2NSF3 (DAST), (PhSO2)2NF (NFSI), or Selectfluor,13
but these reagents are difficult to handle, extremely hazardous,
and expensive. Less dangerous and smoother methods using
hypervalent iodine reagents in fluorocyclization reactions to
generate fluorinated heterocycles have been reported.14,15
Hypervalent iodine reagents are widely used in organic
synthesis as efficient, metal-free oxidizing reagents.16 Lately, a
concise route to fluorinated 2-oxazolines was achieved by
fluorocyclization of N-allylcarboxamides via I(I)/I(III) catal-
ysis.17 Disadvantageously, in the latter example Selectfluor
served as a terminal oxidant to generate the hypervalent I(III)
Received: November 18, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03682
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
electrolysis time + additional reaction time) of 5 h, we initially
explored the amount of charge on the product formation.
Therefore, charge was applied from 2 to 6 F (Table 1, entries
1−5). A control experiment (= 0 F, no conversion of starting
material) indicated that the anodic oxidation of the iodoarene
mediator seemed to be crucial for the conversion of the
substrate. For the oxidation of iodoarene I(I) to hypervalent
I(III) a theoretical charge amount of 2 F is required (Scheme
3). But the applied charge of 2 F did not lead to full conversion
of the N-allylbenzamide (1a) to the oxazoline 2a (Table 1,
entry 1). An amount of 3 F gave the product in suitable yield
(Table 1, entry 2). As the applied charge was further increased,
significantly higher yields were not obtained (Table 1, entries
3−5). Based on these findings, the following experiments were
conducted with an applied charge of 3 F. Additionally, the
influence of current density was studied with an increased
reaction time of 15 h. A lower current density came along with
lower yield (Table 1, entry 6). Meanwhile, higher current
densities promoted the product formation to higher yield
(Table 1, entries 7−9). Thus, further studies were performed
at 50 mA·cm−2. High current densities are favorable due to the
shorter electrolysis time and better space−time yields. Smaller
amounts of the iodoarene mediator caused a lower yield
(Table 1, entry 10). In the absence of ArI species no oxazoline
formation was observed (Table 1, entry 11), which confirms
the role of the mediator. Variation of the substituent in
position 4 of the iodoarene mediator showed lower yields for
the anisyl (Table 1, entry 12) and the phenyl iodide (Table 1,
entry 13). With 4-acetylphenyl iodide as the mediator, no
product was found (Table 1, entry 14). However, 4-
methyliodobenzene proved to exhibit even more potential
than the tert-butyl derivative. This mediator achieved almost
quantitative yield (Table 1, entry 15). The use of carbon-based
electrode materials such as boron-doped diamond (BDD) or
glassy carbon led to a drop in yield (Table 1, entries 16 and
17).
Scheme 1. Conventional vs Electrochemical Generation of
I(III) Species for Fluorocyclization of N-Allylcarboxamides
further supporting electrolyte was necessary. Evaluation of
electrochemical parameters was conducted within several
initial screening experiments in small Teflon cells.25 Thereby,
N-allylbenzamide (1a) served as a test substrate and the
conversion to the corresponding 2-phenyloxazoline 2a as
benchmark reaction for the elaboration of optimal electrolytic
conditions, such as the amount of charge and the current
density (Table 1). Furthermore, various iodoarene mediators
as well as different electrode materials were tested. For
optimization experiments the yield was determined by 19F
NMR with ethyl fluoroacetate as the internal standard.
With 1.0 equiv of 4-tert-butyliodobenzene as the mediator, a
current density of 10 mA·cm−2, and a reaction time (tR,
Table 1. Optimization of Reaction Conditions for the
Electrochemical Fluorocyclization of Substrate 1a to
a
Oxazoline 2a
Subsequently, with a general method developed (optimal
reaction conditions in Table 1, entry 15) we focused on
establishing the scope of the electrochemical fluorocyclization
of N-allylcarboxamides with various substitution patterns of
the aryl ring (Scheme 2). Under the optimized conditions in
Scheme 2, the benchmark substrate 1a gave the 2-oxazoline 2a
in 59% isolated yield. Reduction of the isolated yield is a result
of hydrolysis during column chromatography, something that
has been observed previously.17 The electrosynthesis of
compound 2a was also conducted on a 2.5 mmol scale with
45% isolated yield. In comparison to the unsubstituted scaffold
2a, alkyl-substituted derivatives 2b−d were obtained in similar
yields (up to 66% for 2d). To explore the effects of electron-
withdrawing and electron-releasing substituents attached to the
aryl moiety, N-allylbenzamides involving the 4-CF3, 4-NO2,
and 4-OCH3 groups were exposed to the standard reaction
conditions. The electron-rich aryl moiety led to lower yields
(2e vs 2a), whereas the electron-poor derivative afforded the
oxazoline in higher yields (2f vs 2a). But as expected, due to
cathodic side reactions of the nitro-substituted N-allylbenza-
mide the desired product 2g was found in traces only.
Therefore, the nitro-substituted substrate 1g was exposed to an
ex-cell procedure, whereby the substrate was added after
anodic generation of the I(III) mediator. This way, oxazoline
2g was obtained in 34% yield. However, the ex-cell mode is not
an efficient method in general due to the instability of ArIF2
(see decreased yield for 2d, in-cell 66%, ex-cell 13%). But it
b
applied
current density
mediator
(R = )
yield
(%)
entry
charge (F)
(mA·cm−2
)
tR (h)
1
2
3
4
5
6
7
8
9
2
3
4
5
6
3
3
3
3
3
3
3
3
3
3
3
3
10
10
10
10
10
5
30
50
60
50
50
50
50
50
50
50
50
5
5
5
5
5
15
15
15
15
15
15
15
15
15
15
15
15
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
−
OMe
H
COMe
Me
Me
46
79
72
84
82
65
87
94
91
42
0
14
41
0
≥95
71
46
c
10
11
12
13
14
15
d
16
e
17
Me
a
Standard reaction conditions: Undivided cell, Pt electrodes, N-
allylbenzamide (0.5 mmol), iodoarene mediator (1.0 equiv), CH2Cl2
(2.5 mL), Et3N·5HF (2.5 mL), tR = electrolysis time + additional
b
reaction time. Determined by 19F NMR using ethyl fluoroacetate
c
d
(1.0 equiv) as the internal standard. Mediator (0.5 equiv). BDD ||
e
BDD. Glassy carbon || glassy carbon.
B
DOI: 10.1021/acs.orglett.8b03682
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthesis of 5-Fluoromethyl-2-oxazoline
Derivatives by Electrochemical Fluorocyclization
Scheme 3. Proposed Mechanism for the Fluorocyclization
of 1a to 2a Mediated by Anodically Generated I(III)
Mediator
a
economic. In addition, considering the simple setup with an
undivided cell and a two-electrode arrangement as well as no
reagent-based oxidants needed, this method affords an
attractive approach to 2-oxazolines containing a fluoromethyl
group as a potential building block for medicinal chemistry. An
important detail to mention is that the electrochemical
approach is inherently safe. Easily switching off the electric
current avoids runaway reactions.
a
Standard reaction conditions: Undivided cell, Pt electrodes, N-
allylcarboxamide (0.5 mmol), 4-methyliodobenzene (1.0 equiv),
CH2Cl2 (2.5 mL), Et3N·5HF (2.5 mL), 3 F, 50 mA·cm−2, rt, 15 h.
Yields refer to isolated product, ex-cell experiments in parentheses.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03682.
turned out to be an alternative approach to avoid electro-
chemical side reactions. For example, after in-cell reaction of 2-
phenyl derivative 1h intramolecular coupling has been
observed as a side reaction, whereas the ex-cell procedure
gave oxazoline 2h in higher yield with no formation of side
products. N-Allylbenzamides exhibiting a halo group were well-
tolerated, affording the corresponding oxazolines with different
substitution patterns and halogen atoms in yields up to 52%
(2i−n). Starting from thiophenyl and furanyl derivatives,
oxazolines 2o and 2p were obtained in low yields as a result of
incomplete conversion. However, an increase of applied charge
and longer reaction times did not lead to full conversion.
In Scheme 3, a proposed reaction mechanism for the
electrosynthesis of the fluorinated oxazoline 2a is displayed.
After anodic oxidation of the iodoarene 3a the activated
hypervalent iodine atom in 3b is attacked by the nucleophilic
double bond in 1a forming the iodonium species 4a.26
Intramolecular ring opening of the three-membered hetero-
cycle by the carbonyl forms the 5-(λ3-iodanyl)methyl
oxazoline 4b, which is converted into product 2a after an
SN2-type substitution with fluoride acting as the nucleophile.
In conclusion, we have established a sustainable synthesis of
5-fluoromethyl-2-oxazolines by hypervalent iodoarene-medi-
ated fluorocyclization using electric current as the only oxidant
for the first time. This electrochemical protocol provided
access to fluorinated oxazolines starting from easily available
N-allylcarboxamides with yields up to 68%. Besides, the 4-
methyliodobenzene mediator could be partly isolated after
electrolysis; 4-tert-butyliodobenzene was isolated even quanti-
tatively. Thus, the stoichiometrical use of ArI species is still
General experimental procedure, synthetic details, and
characterization including NMR and MS spectra for all
products and intermediate compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: waldvogel@uni-mainz.de.
ORCID
Siegfried R. Waldvogel: 0000-0002-7949-9638
Author Contributions
†J.D.H. and M.B. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
J.D.H. acknowledges the Friedrich Ebert Foundation for
granting a fellowship and S.R.W. the Carl Zeiss Foundation
for the research network ELYSION.
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