Stereospecific Electrophilic Fluorocyclization of α,β-Unsaturated Amides with Selectfluor

Article abstract of DOI:10.1021/acs.orglett.0c00620

An efficient fluorocyclization of α,β-unsaturated amides through a formal halocyclization process is developed. The reaction proceeds under transition-metal-free conditions and leads to the formation of fluorinated oxazolidine-2,4-diones with excellent regio- and diastereoselectivity. The evaluation of the reaction mechanism based on preliminary experiments and density functional theory calculations suggests that a synergetic syn-oxo-fluorination occurs and is followed by an anti-oxo substitution reaction. The reaction opens a new window in the field of stereospecific fluorofunctionalization.

Full text of DOI:10.1021/acs.orglett.0c00620

pubs.acs.org/OrgLett
Letter
Stereospecific Electrophilic Fluorocyclization of α,β-Unsaturated
Amides with Selectfluor
Haiyang Fei,⊥ Zheyuan Xu,⊥ Hongmiao Wu, Lin Zhu, Hitesh B. Jalani, Guigen Li, Yao Fu,*
and Hongjian Lu*
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ABSTRACT: An efficient fluorocyclization of α,β-unsaturated
amides through a formal halocyclization process is developed.
The reaction proceeds under transition-metal-free conditions and
leads to the formation of fluorinated oxazolidine-2,4-diones with
excellent regio- and diastereoselectivity. The evaluation of the
reaction mechanism based on preliminary experiments and density
functional theory calculations suggests that a synergetic syn-oxo-fluorination occurs and is followed by an anti-oxo substitution
reaction. The reaction opens a new window in the field of stereospecific fluorofunctionalization.
process forming α-fluorocarbonyl compounds have been
he electrophilic halofunctionalization of olefins involves
Tcyclic halonium ions, in which a positively charged shown to take place (Scheme 1B).6 In these fluorofunction-
chlorine, bromine, or iodine is attached to two carbon atoms.1
alization reactions, the stereo information implicit in double
bonds cannot be fully transferred to the final products.
Electrophilic fluorofunctionalization with anti-addition selec-
tivity, which is common in electrophilic halofunctionalization
reactions, is a challenging task and has not been achieved to
date.7,8
These well-documented halonium ions are a key factor in the
origin of stereoselectivity in halofunctionalization reactions.2
One of most important facets of this classical chemistry is the
stereochemical outcome, which is dictated by the anti-addition
of the starting alkenes. This leads to numerous applications
involving the stereoselective construction of halogenated
compounds, including natural products.2,3 However, the
formation of a cyclic fluoronium ion from electrophilic fluorine
reagents is an exception.4 The electrophilic fluorofunctional-
ization of alkenes is mechanistically different from the
functionalization with Cl, Br, or I because it involves an
acyclic cationic key intermediate instead of a cyclic fluoronium
ion, with the consequence that the fluorofunctionalization is
not stereospecific and the substrate scope is largely limited to
electron-rich olefins (Scheme 1A).5 For electron-deficient
olefins, such as α,β-unsaturated ketones, esters, and amides, a
cascade Michael addition and an electrophilic fluorination
Stereoselective fluorocyclization reactions have attracted
much attention9 because the incorporation of a fluorine atom
within the molecular structure significantly modifies the
physicochemical properties of the molecule, and fluorinated
cyclic and heterocyclic compounds are widely used in
pharmaceuticals and agrochemicals.10 With our interest in
the development of fluorocyclization reactions to produce
biologically important fluorine-containing molecules,11 we
herein report the first example of the stereospecific electro-
philic fluorocyclization of α,β-unsaturated amides (Scheme
1C). 5-exo regioselectivity controls this reaction to form a β-
fluorocarbonyl compound that is different from the α-
fluorocarbonyl compound formed in the cascade Michael
addition and the electrophilic fluorination process.6 The
stereochemical outcome is dictated by the geometry of the
starting alkenes with overall anti-addition selectivity. The
stereoselective construction of two adjacent quaternary carbon
centers achieved by this method is also significant because it is
a challenging objective, and the number of strategies to
Scheme 1. Electrophilic Fluorofunctionalization
Received: February 16, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00620
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
a b c
, ,
construct these sterically congested structures is limited by
thermodynamic problems.12
Scheme 2. Scope of Acrylamides
A disubstituted E-acrylamide (1a) was selected as the model
substrate with which to explore the reactivity, regioselectivity,
and stereoselectivity of the fluorocyclization reaction (Table
1). Using commercially available Selectfluor (1-chloromethyl-
a b c
, ,
Table 1. Optimization of the Reaction Conditions
yield
variation from
“condition A”
(2a)
b
c
c
entry
1
R
(%)
dr
rr
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a1
1a2
1a2
Me
Me
Me
Me
Me
Me
Me
Et
none
97
ND
64
90
ND
94
74
86
46
>20:1
>20:1
d
other F+ reagent
30 °C
70 °C
other solvents
MeNO2
additional NaHCO3
none
none
>20:1
>20:1
>20:1
>20:1
e
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
f
9
tBu
tBu
f
10
additional NaHCO3
81
a
Condition A: 1 (0.1 mmol), Selectfluor (0.2 mmol), CH3CN (1
b
mL), 60 °C, 8 h. 1H NMR yield using CH2Br2 as an internal
c
standard. rr and dr were determined by 19F NMR of crude products.
d
e
F-2, F-3, or F-4 was screened. PhCH3, tBuCN, 1,4-dioxane, MeOH,
a
b
Condition A, see footnote a in Table 1. Condition B: condition A
f
c
DMF, or DMSO was screened. 2.0 equiv NaHCO3.
with additional NaHCO3 (2.0 equiv). Isolated yield and rr (5-exo/6-
endo products) and dr (anti-/syn-addition product) were determined
by 19F NMR, 6-endo products were not observed in most cases, and
relative stereochemistry was tentatively assigned by analogy to 2a and
4-fluoro-1,4-diazoniabicyclo [2.2.2]octane bis-
(tetrafluoroborate), F-1), the 5-exo, anti-addition product
(2a) was obtained in 97% yield with excellent diastereo- (dr >
20/1) and regioselectivity (rr > 20/1) (entry 1). 2a is a known
compound, and its relative configuration was confirmed by X-
ray crystallographic analysis.11a Other F+ reagents failed to
produce 2a (entry 2), revealing the unique character of
Selectfluor.13 Lower yields were produced when the reaction
temperature was decreased or increased (entries 3 and 4).
When MeNO2 was used as the solvent, 2a was provided in
good yield (entries 5 and 6), and the yield decreased slightly
under basic conditions (entry 7). In an effort to broaden the
substrate scope, different ester groups were examined.
Compounds containing an ethoxy group gave a good yield
(entry 8), but those with a tert-butoxy group gave a
significantly decreased yield (entry 9), possibly due to the
instability of tert-butyl esters under the acidic reaction
conditions. The addition to the reaction of NaHCO3 improved
the yield of 2a to 81% (entry 10).
d
e
4c based on 19F NMR. (See Table S6.) 5 mmol of 1a. Ethyl ester as
f
g
substrate. Contaminated with <10% side product. Isolated yield of
5-exo product and 6-endo product was observed as a minor product.
h
i
j
3.3:1 (rr). 13:1 (rr). 1.5:1 (rr).
Z-α-phenyl-β-alkyl acrylamides were compatible with these
reaction conditions, giving 2f and 2g, respectively. The spiro
compound 2h was formed with exclusive anti-addition
selectivity when a cyclic acrylamide was used. From a
medicinal chemistry point of view, both CH2F group and
heterocycles are very important groups that are often involved
in the pharmacophores of bioactive compounds.14 With
terminal acrylamides, heterocycles carrying a CH2F group,
products 2i−k were formed in moderate to high yield,
illustrating the utility of the method. Because of steric
hindrance, it is generally difficult to achieve good reactivity
and regioselectivity in the fluorofunctionalization of tetrasub-
stituted olefins, and only a few symmetrical tetrasubstituted
olefins have been used in fluorofunctionalizations.15 This
noncatalytic system has the ability to functionalize fully
substituted acrylamides, leading to the stereoselective con-
struction of two contiguous quaternary carbon centers (2l−w),
which otherwise is a challenge.12 The structure of 2v was
confirmed by X-ray crystallographic analysis (CCDC
1794728). With trialkyl-substituted acrylamides, excellent
The scope of the variously substituted acrylamides was then
investigated under optimal conditions (Scheme 2). Substrates
with different substituents on the acrylamide nitrogen were
examined. Both electron-donating and electron-withdrawing
aryl and alkyl substituents are tolerated, leading to moderate to
good yields of N-aryl(alkyl)-oxazolidine-2,4-diones (2b−e)
with exclusive regio- and diastereoselectivity. E-α,β-dialkyl and
B
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diastereoselectivity was achieved (dr > 20/1) but with
moderate regioselectivity (rr = 1.5/1 to 13/1, 2x−A). When
the reaction was performed on the 5 mmol scale, 2a was
obtained in 84% yield. The isomeric E- and Z-acrylamide (1)
can produce isomer products (2), respectively, with exclusive
diastereoselectivity (2l vs 2m, 2n vs 2o, 2p vs 2q, 2r vs 2s, 2t
vs 2u, 2x vs 2y, and 2z vs 2A), and the anti-(cascade Michael
addition/fluorination) was observed to be regioselective.
When Z-α,β-diaryl acrylamides (3) were used as the
substrate, the desired anti-addition products were obtained,
with, however, a small amount of syn-addition products (4a
and 4b, anti-/syn-addition (dr) = 14/1, Scheme 3A). Although
3D (see similar results for the acrylamides used in Scheme 2,
shown in the SI), and the anti-addition product (4c) was
obtained with high diastereoselectivity. These results offer an
opportunity to prepare products with the desired diaster-
eoselectivity by adding base or tuning the ester group in the
substrates.
Because indoline is a key fragment of some promising
anticancer, anti-inflammatory, and antihypertensive agents,16
the fluorocyclization of indoles in a pyrrole ring, forming
fluorine-containing indolines, has been investigated but was
found, however, to have low to moderate diastereocontrol.17
When indoles with the substituent in the two- or three-position
were investigated in this reaction, the biheterocyclic spiro
compounds (6a and 6b) were obtained in good yield with
excellent regio- and diastereoselectivity (Scheme 4A). The
Scheme 3. Scope of α,β-Diaryl Acrylamides
Scheme 4. Applications in Dearomatization and Hydrolysis
relative configuration of 6a was confirmed by X-ray crystallo-
graphic analysis (CCDC 1974729). The hydrolysis of product
2a under different basic conditions provided an α-hydroxy-β-
fluoroamide (7a) and an oxirane-2-carboxamide (8a),18
respectively, with no effect on the relative configuration
(Scheme 4B).
To gain an understanding of the mechanism, several
experiments were carried out and are described in Scheme 5.
Scheme 5. Mechanistic Studies
the level of diastereoselectivity achieved is high, it differs from
the results in Scheme 2, revealing the exclusive formation of
anti-addition products. Interestingly, the formal syn-addition
selectivity was observed when E-α,β-diaryl acrylamides (3)
were used (Scheme 3B). The syn-addition products were
produced in good to high yield and with high diastereose-
lectivity (4c−f′, anti-/syn-addition (dr) = 1/12 to 1/15) when
N-alkyl or N-phenyl substrates were used. Acrylamides with a
4-NO2C6H4 or 4-MeC6H4 group in the α-position were
tolerated (4g′ and 4h′). When the ester group was studied, it
was found that the diastereoselectivity of the reaction could be
controlled by varying the ester functionality (Scheme 3C).
When the methoxyl was replaced by tert-butoxyl, the dr value
of products changed from 1/11 to 8.3/1 under condition A,
providing 4c as the major product (entry 4, Scheme 3C). The
relative structure of 4c was confirmed by X-ray crystallographic
analysis (CCDC 1794730). In addition, basic conditions could
promote the anti-addition selectivity, as observed in Scheme
When the substrate (1j-D) containing one deuterium atom in
the terminal position of the double bond was used, the product
2j-D was achieved with good diastereoselectivity (Scheme 5A).
The relative stereochemistry of 2j-D has not yet been
determined. When a cyclopropyl group was used as a radical
probe under basic condition B, no ring-opened products were
observed, and the 5-exo product (2B) was achieved with
exclusive diastereoselectivity (Scheme 5B), suggesting that no
radical intermediate was involved. When an alkyl olefin was
C
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used in place of compounds containing an electron-deficient
double bond, the expected 5-exo product (2C) was formed,
but with low diastereoselectivity (Scheme 5C), implying that
the carbonyl group of acrylamides is critical.19 When the
reaction of E-α,β-diphenyl acrylamide (3c) was performed
with a reduced reaction time under the reaction condition A,
the double-bond isomer of 3c (3a) was observed in 42% yield,
and the syn-addition product (4c′) was the major product
(Scheme 5D). Under condition B, a small amount of the
double-bond isomer (3a) was found, and the anti-addition
product (4c) was the major product (Scheme 5E). These
results show that the overall syn-addition products were
observed in some cases, possibly due to the isomerization of
double bond under the acidic reaction conditions and that the
use of base could prevent the isomerization of the acrylamides.
The possible reason why the antiselectivity was achieved in the
reaction of substrate 3c2 (Scheme 3C) is that its electrophilic
fluorocyclization might be faster than the isomerization of the
double bond.
quaternary C−F bond were also constructed. The carbonyl
group of acrylamides is critical in the selectivity problem
encountered with other alkenes and serves as a device that can
deliver regio- and diasterocontrol in the fluorocyclization
process. The use of the easily handled Selectfluor reagent,
readily prepared acrylamides, and mild reaction conditions are
important features of this reaction. Preliminary experiments
and DFT calculations demonstrate that this transformation
goes through a cascade synergetic syn-oxo-fluorination
followed by an anti-oxo-substitution process. The results
obtained in this study provide a foundation for the further
development of the stereocontrolled synthesis of fluorinated
compounds through the fluorofunctionalization of olefins with
predictable anti-addition selectivity.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00620.
To further investigate the reaction mechanism, density
functional theory (DFT) calculations were conducted on the
reaction of 1f (Scheme 6). The syn-oxo-fluorination of olefin
Experimental procedures and copies of 1H and 13C
NMR spectra for all new compounds (PDF)
Accession Codes
Scheme 6. DFT Calculations for the Reaction of 1f
CCDC 1974728−1974730 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Yao Fu − Hefei National Laboratory for Physical Sciences at the
Microscale, CAS Key Laboratory of Urban Pollutant
Conversion, Anhui Province Key Laboratory of Biomass Clean
Energy, iChEM, University of Science and Technology of China,
Hefei, Anhui 230026, China; orcid.org/0000-0003-2282-
4839; Email: fuyao@ustc.edu.cn
Hongjian Lu − Institute of Chemistry and BioMedical Sciences,
Jiangsu Key Laboratory of Advanced Organic Materials, School
of Chemistry and Chemical Engineering, Nanjing University,
Nanjing 210093, China; orcid.org/0000-0001-7132-3905;
Email: hongjianlu@nju.edu.cn
for the reaction of 1f with Selectfluor is achieved through 1f-1-
TS with an active free energy of 24.4 kcal/mol. In comparison,
the anti-oxo-fluorination of olefin through 1f-2-TS, is a
pathway associated with an active free energy of 29.8 kcal/
mol. The electrostatic interaction between the CO of the
amide and the ammonium ion of Selectfluor may induce the
syn-oxo-fluorination of olefin. The formation of the cyclic
oxonium ion intermediate 1f-1 is exothermic by 25.6 kcal/mol.
The subsequent anti-oxo substitution of 1f-1 is essentially
barrierless and leads exothermically to intermediates 1f-3 and
1f-4, which can generate the same overall anti-addition product
2f. This mechanism suggests an unusual synergetic syn-oxo-
fluorination process of electron-deficient olefins, which may
find broader applications in the stereospecific synthesis of
fluorinated molecules.
In conclusion, we have developed a stereospecific, electro-
philic fluorocyclization reaction, whose regio- and diaster-
eoselectivity are similar to those of the classical electrophilic
halofunctionalizations. Using acrylamides as substrates, this
reaction provides fluorinated oxazolidine-2,4-diones with
excellent regio- and diastereoselectivity. Products containing
two contiguous quaternary carbon centers including a
Authors
Haiyang Fei − Institute of Chemistry and BioMedical Sciences,
Jiangsu Key Laboratory of Advanced Organic Materials, School
of Chemistry and Chemical Engineering, Nanjing University,
Nanjing 210093, China
Zheyuan Xu − Hefei National Laboratory for Physical Sciences
at the Microscale, CAS Key Laboratory of Urban Pollutant
Conversion, Anhui Province Key Laboratory of Biomass Clean
Energy, iChEM, University of Science and Technology of China,
Hefei, Anhui 230026, China
Hongmiao Wu − Institute of Chemistry and BioMedical
Sciences, Jiangsu Key Laboratory of Advanced Organic
Materials, School of Chemistry and Chemical Engineering,
Nanjing University, Nanjing 210093, China
Lin Zhu − Institute of Chemistry and BioMedical Sciences,
Jiangsu Key Laboratory of Advanced Organic Materials, School
of Chemistry and Chemical Engineering, Nanjing University,
Nanjing 210093, China
D
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Letter
Trifluoromethylation, and Trifluoromethylthiolation Reactions. Chem.
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Hitesh B. Jalani − Department of Pharmacy and Yonsei Institute
of Pharmaceutical Science, Yonsei University, Incheon 21983,
South Korea; orcid.org/0000-0002-2442-9798
Guigen Li − Department of Chemistry and Biochemistry, Texas
Tech University, Lubbock, Texas 79409-1061, United States;
orcid.org/0000-0002-9312-412X
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00620
Author Contributions
⊥H.F. and Z.X. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We are grateful for financial support by the National Natural
Science Foundation of China (21871131, 21702107), the
Natural Science Foundation of Jiangsu Province
(BK20191244), and the Fundamental Research Funds for
the Central Universities (020514380131).
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