Bromofluorination of unsaturated compounds using DMPU/HF as a fluorinating reagent

Article abstract of DOI:10.1016/j.jfluchem.2017.07.016

Bromofluorination reactions were performed by treating of a variety of unsaturated compounds with N-bromosuccinimide (NBS) and DMPU/HF as the fluorinating reagent. The DMPU/HF complex showed to be an efficient fluorinating reagent to convert alkenes into

Full text of DOI:10.1016/j.jfluchem.2017.07.016

Accepted Manuscript
Title: Bromofluorination of Unsaturated Compounds using
DMPU/HF as a Fluorinating Reagent
Authors: Shengzong Liang, Francis J. Barrios, Otome E.
Okoromoba, Zofia Hetman, Bo Xu, Gerald B. Hammond
PII:
S0022-1139(17)30260-9
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2017.07.016
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27-7-2017
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Please cite this article as: Shengzong Liang, Francis J.Barrios, Otome E.Okoromoba,
Zofia Hetman, Bo Xu, Gerald B.Hammond, Bromofluorination of Unsaturated
Compounds using DMPU/HF as a Fluorinating Reagent, Journal of Fluorine
Chemistryhttp://dx.doi.org/10.1016/j.jfluchem.2017.07.016
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Bromofluorination of Unsaturated Compounds using DMPU/HF as a Fluorinating
Reagent
Shengzong Liang,a Francis J. Barrios,b Otome E. Okoromoba,a Zofia Hetman,a Bo Xuc and
Gerald B. Hammonda*
a Department of Chemistry, University of Louisville, Louisville, Kentucky 40292, United
States
b Department of Chemistry and Physics, Bellarmine University, Louisville, Kentucky, 40205,
United States
cCollege of Chemistry, Chemical Engineering and Biotechnology, Donghua University,
Shanghai 201620, China
*Corresponding author E-mail: gb.hammond@louisville.edu
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GRAPHICAL ABSTRACT
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Highlights
 Novel nucleophilic fluorinating reagent was used for bromofluorination of alkenes.
 The mechanism relied on the formation of bromonium ion intermediate followed by
nucleophilic attack of fluoride.
 Both high yield and regioselectivity were obtained.
3

ABSTRACT
Bromofluorination reactions were performed by treating of a variety of unsaturated compounds
with N-bromosuccinimide (NBS) and DMPU/HF as the fluorinating reagent. The DMPU/HF
complex showed to be an efficient fluorinating reagent to convert alkenes into their corresponding
bromofluoro compounds. It showed to have high reactivity and the process afforded
bromofluorinated products with good Markovnikov regioselectivity. These fluorinated compounds
are useful starting materials and serve as building blocks for many fluorinated biologically active
molecules.
Keywords: Bromofluorination, Alkenes, Regioselective, N-bromosuccinimide, DMPU/HF
1. Introduction
The synthesis of fluorinated organic molecules has gained demand in recent years and has
attracted attention from pharmaceutical, chemical and agrochemical industries [1,2]. The
incorporation of fluorine into organic compounds is a strategy used to tune the biological properties
of molecules as they change their lipophilicity and metabolic activity [3]. One efficient method for
the incorporation of fluorine into molecules is the halofluorination of unsaturated compounds.
Accordingly, there has been an extensive effort for the development of methodologies and reagents
for the effective synthesis of bromofluoro compounds [4,5]. Existing synthetic strategies to
effectively pursue bromofluorination of alkenes relied on utilizing different reagents such as
tetrabutylammonium bifluoride [6] and BrF3 [7]. It has been shown that the combination N-
bromosuccinimide (NBS) and triethylamine trihydrofluoride (Et3N/3HF) was an efficient way of
producing bromofluoro compounds from alkenes [8]. In this case, NBS was acting as electrophilic
bromine source and Et3N/3HF is the nucleophilic fluorinating specie. An alternative bromonium
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ions source was 1,3-dibromo-5,5-dimethylhydantoin [9]. And other HF-based reagents such as
pyridine hydrofluoride (Olah’s Reagent) [10], potassium fluoride poly(hydrogen fluoride) [11] and
tetrabutylphosphonium dihydrogen trifluoride [12] have been used as the nucleophilic source of
fluorine.
Recently, our research group has designed an efficient fluorinating reagent DMPU/HF (DMPU:
1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone); when compared with other commonly used
fluorinating reagents such as Et3N/3HF and Olah’s Reagent, DMPU/HF is superior due to the non-
nucleophilic, weakly basic and weakly coordinating properties of DMPU. We also demonstrated
the synthetic utility and effectiveness of DMPU/HF in some nucleophilic fluorination reactions: the
gold-catalyzed hydrofluorination of alkynes [13], fluoro-Prins cyclization reactions [14] and ring-
opening fluorination of aziridines [15]. DMPU/HF exhibited high reactivity and selectivity
compared with the other aforementioned HF-based reagents. Herein, we report our studies on the
bromofluorination of alkenes using DMPU/HF as fluorinating reagent, and described its efficiency
to provide products with good regioselectivity.
The strategy for bromofluorination relies on the acid-catalyzed attack of the pi electrons of an
alkene to the positive bromine in NBS to form the electrophilic bromonium ion intermediate. Then,
the bromonium ion opens by the attack of nucleophilic fluoride to provide the desired product
(Scheme 1).
Scheme 1. Strategy for the bromofluorination of alkenes using NBS and DMPU/HF
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2. Results and discussion
A series of alkenes were used to examine the capability of DMPU/HF in producing the
corresponding fluorinated products. The results are summarized in Table 1. The products were
isolated in good to excellent yields (66-89%) and good regioselectivity. Specifically, alkenes
derived from aryl vinyl substituted with halogens and an ether group (compounds 1b-1d) furnished
the corresponding bromofluoro compound when using 7 equivalents of DMPU/HF in the presence
of 1.5 equivalents of NBS in CH2Cl2. In each case, only the Markovnikov regioselective product
was obtained, resulting from fluoride attack at the more substituted carbon atom of the bromonium
ion intermediate. This strategy was subsequently applied to allylbenzylic compounds substituted
with electron-withdrawing and electron-donating groups (compounds 1f-1h). These substrates
generated a mixture of bromofluorinated regioisomers products under these conditions with the
Markovnikov product being the major isomer. Furthermore, this reaction appeared to be
stereoselective with substrates bearing an internal double bond. In the case of (E)-1-phenylpropene
(1i), the major product observed was anti-2-bromo-1-fluoro-1-phenylpropane (2i). In a similar
fashion, the treatment of cis-stilbene (1j) with NBS followed by DMPU/HF provided threo-1-
bromo-2-fluoro-1,2-diphenylethane (2j) as the sole product.
Table 1. Bromofluorination of alkenes.
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Next, we turned our attention to the bromofluorination of phenyl ether derivatives. We wanted
to compare the regioselectivity of our fluorinated reagent with Et3N/3HF and Olah’s reagent.
Specifically, the reaction of allyphenyl ether with NBS followed by DMPU/HF provided a mixture
of the Markovnikov product and its regioisomer in a 1.1:1, 2.2:1 and 5:1 ratio in the presence of
Et3N/3HF, Olah’s reagent and DMPU/HF, respectively (Scheme 2). Additionally, the treatment of
homoallylphenyl ether with DMPU/HF reagent gave a 5:1 ratio of the Markovnikov product and
its regioisomer (Scheme 3). Lastly, when ((3-methylbut-3-en-1-yl)oxy)benzene was reacted with
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NBS and DMPU/HF it provided 97% yield of 6:1 mixture of the bromofluoride products (Scheme
4). All the regioisomers ratios were calculated after 19F NMR analysis of the crude reaction mixture.
Scheme 2. Bromofluorination reaction of allylphenyl ether.
Scheme 3. Bromofluorination of homoallylphenyl ether.
Scheme 4. Bromofluorination phenyl ether derivative.
3. Conclusions
In summary, we have demonstrated the utility of DMPU/HF as a fluorinating reagent to generate
vicinal bromofluoro products from a broad scope of alkenes. This strategy is effective and afforded
products in good yields and with good regioselectivity.
4. Experimental
4.1 Materials and methods
NMR spectra were recorded on a Varian 400 MR system (400 MHz) with automated sampling,
locking, shimming, and tuning. The DMPU/HF reagent was prepared by condensing gaseous HF
dispensed from a PTFE manifold into a cooled PTFE cylinder that contained pre-weighted DMPU.
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HDPE vials and bottles purchased from VWR. All operations involving HF were conducted in a
well-ventilated fume hood.
4.2 General experimental procedure
The reaction was performed in a plastic vial. A mixture of NBS (53.4 mg, 0.3 mmol) and alkene
(0.20 mmol) in CH2Cl2 (1 mL) was treated with DMPU/HF (41.2 μL, 1.4 mmol) and stirred for 24
h at room temperature. Next, water (2 mL) was added and the resultant mixture was extracted with
CH2Cl2 (3 × 2 mL). The organic layer was dried over Na2SO4 and concentrated under reduced
pressure. SiO2 flash chromatography (9:1 hexanes/EtOAc) afforded the bromofluoride compounds
as mixtures of regioisomers in some cases.
(2-bromo-1-fluoroethyl)benzene (2a). 1H NMR (400 MHz, CDCl3) δ 7.50 (m, 5H), 5.60 (dd, J =
47.1, 7.8, 4.1 Hz, 1H), 3.66 (ddd, J = 15.3, 11.3, 7.8 Hz,1H), 3.58 (ddd, J = 26.0, 11.3, 4.2Hz, 1H),
19F NMR (376 MHz, CDCl3) δ -175.0 (m), Colorless oil.
1-(2-Bromo-1-fluoroethyl)-4-chlorobenzene (2b). 1H NMR (400 MHz, CDCl3) δ 7.41 (dm, 7.3Hz,
2H), 7.32 (dm, 7.3Hz, 2H), 5.62 (ddd, J = 46.6, 7.3, 4.5 Hz, 1H), 3.68 (ddd, J = 16.3, 11.3, 7.3
Hz,1H), 3.61 (ddd, J = 24.4, 11.3, 4.4Hz, 1H), 19F NMR (376 MHz, CDCl3) δ -174.5 (m), Yellow
oil.
1
1-(2-Bromo-1-fluoroethyl)-4-Fluorobenzene (2c). H NMR (400 MHz, CDCl3) δ 7.33 (m, 2H),
7.09 (m, 2H), 5.62 (ddd, J = 46.6, 7.3, 4.5 Hz, 1H), 3.68 (ddd, J = 16.3, 11.3, 7.3 Hz,1H), 3.63 (m,
2H), 19F NMR (376 MHz, CDCl3) δ -112.0 (m), -171.6 (m). Yellow oil.
1-(2-bromo-1-fluoroethyl)-4-methoxybenzene (2d). 19F NMR yield, 19F NMR (376 MHz, CDCl3)
δ -171.2 (m), Yellow oil.
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19
19
(3-Bromo-2-fluoropropyl)benzene (2e). F NMR yield. F NMR (376 MHz, CDCl3) δ -175.4
(m), Yellow oil.
1
1-(3-bromo-2-fluoropropyl)-4-fluorobenzene (2f). H NMR (400 MHz, CDCl3) δ 7.21 (dd, J =
8.4, 5.5 Hz, 2H), 7.01 (t, J = 8.7 Hz, 2H), 4.93 – 4.70 (m, 1H), 3.53 – 3.33 (m, 2H), 3.17 – 2.99 (m,
2H). 19F NMR (376 MHz, CDCl3) δ -115.5 (td, J = 8.7, 4.3 Hz), -175.5 (m), Yellow oil.
1-(3-bromo-2-fluoropropyl)-4-methoxybenzene (2g). 1H NMR (400 MHz, CDCl3) δ 7.15 (d, J =
8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 4.90 – 4.69 (m, 1H), 3.78 (s, 3H), 3.54 – 3.33 (m, 2H), 3.02
(dd, J = 20.7, 6.1 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ -175.5 (m), Yellow oil.
1-(3-bromo-2-fluoropropyl)-4-methylbenzene (2h). 1H NMR (400 MHz, CDCl3) δ 7.13 (m, 4H),
19
4.73 – 4.9 (m, 1H), 3.54 – 3.34 (m, 2H), 3.05 (dd, J = 20.6, 6.2 Hz, 2H), 2.33 (s, 3H); F NMR
(376 MHz, CDCl3) δ -175.32 (ddt, J = 47.2, 38.7, 20.4 Hz), Yellow oil.
(2-bromo-1-fluoropropyl)benzene (2i). 19F NMR (376 MHz, CDCl3) δ -177. 9 (m), Yellow oil.
(1-bromo-2-fluoroethane-1,2-diyl)dibenzene (2j). 1H NMR (400 MHz, CDCl3) δ 7.32 (m, 10H),
5.84 (dd, J = 46.0, 6.7 Hz, 1H), 5.12 (dd, J = 15.0, 6.6 Hz, 1H). 19F NMR (376 MHz, CDCl3) δ -
169. 8 (m), Yellow oil.
(3-Bromo-2-fluoropropoxy)benzene (2k). 19F NMR yield of regioisomer mixtures. 19F NMR (376
MHz, CDCl3) δ -183.7 (m, 2k), -217.1 (m, 2k’).
(4-Bromo-3-fluorobutoxy)benzene (2l). 19F NMR yield of regioisomer mixtures. 19F NMR (376
MHz, CDCl3) δ -181.0 (m, 2l), -211.2 (m, 2l’).
(4-Bromo-3-fluoro-3-methylbutoxy)benzene (2m). 19F NMR yield of regioisomer mixtures. 19F
NMR (376 MHz, CDCl3) δ -144.7 (m, 2m), -137.97 (m, 2m’)
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Acknowledgements
We are grateful to the National Institutes of Health for financial support (1R01GM121660-01) and
to the Division of Fluorine Chemistry of the American Chemical Society for awarding a Moissan
Summer Undergraduate Research Fellowship to Zofia Hetman.
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