Selective Radical Fluorination of Tertiary Alkyl Halides at Room Temperature

Article abstract of DOI:10.1002/anie.201708197

Direct fluorination of tertiary alkyl bromides and iodides with Selectfluor is described. The halogen-exchange fluorination proceeds efficiently in acetonitrile at room temperature under metal-free conditions and exhibits a wide range of functional group compatibility. Furthermore, the reactions are highly selective in that alkyl chlorides and primary and secondary alkyl bromides remain intact. A radical mechanism is proposed for this selective fluorination.

Full text of DOI:10.1002/anie.201708197

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Accepted Article
Title: Selective Radical Fluorination of Tertiary Alkyl Halides at Room
Temperature
Authors: He Chen, Zhonglin Liu, Ying Lv, Xinqiang Tan, Haigen Shen,
Hai-Zhu Yu, and Chaozhong Li
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201708197
Angew. Chem. 10.1002/ange.201708197
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10.1002/anie.201708197
Angewandte Chemie International Edition
COMMUNICATION
Selective Radical Fluorination of Tertiary Alkyl Halides at Room
Temperature
He Chen,[a] Zhonglin Liu,[a] Ying Lv,[b] Xinqiang Tan,[a] Haigen Shen,[a] Hai-Zhu Yu,*, [b] and Chaozhong
Li*, [a], [c]
Abstract: Direct fluorination of tertiary alkyl bromides and iodides bis(tetrafluoroborate))[8] via the intermediacy of alkyl radicals[1c, 9,
with Selectfluor reagent is described. The halogen-exchange 10] (Figure 1).
fluorination proceeds efficiently in acetonitrile at room temperature
under metal-free conditions and exhibits a wide range of functional
group compatibility. Furthermore, the reactions are highly selective
in that alkyl chlorides and primary and secondary alkyl bromides
remain intact. A radical mechanism is proposed for this selective
fluorination.
The prominent roles of organofluorine compounds in various
disciplines such as pharmaceuticals and agrochemicals have
spurred a considerable interest in the development of new
methods for C–F bond formations, especially in site-specific
manner.[1] In this regard, the halogen-exchange fluorination of
Figure 1. Fluorination of tertiary alkyl halides.
alkyl halides is particularly attractive because of the easy
Table 1: Halogen-exchange fluorination of tertiary alkyl bromide Br-1a.[a]
availability of organohalides.[2–7] A number of methods have
been developed for these site-specific C(sp3)–F bond formations,
including nucleophilic fluorination of allylic,[2] primary[3] and
secondary[3] alkyl halides. Furthermore, Doyle et al. successfully
introduced the palladium-catalyzed enantioselective fluorination
2c, 2f]
of allylic chlorides and bromides.[2b,
However, the
formidable
fluorination of tertiary alkyl halides remains
a
challenge.[4–7] The halogen-exchange fluorination with Cu2O-HF-
Yield (%)[b]
THF[4] or AgF[5], and the oxidative deiodinative fluorination[6] with
Entry
[F]
1a
93
23
35
2
0
3
0
4
0
F2,[6a] XeF2,[6c–6e] p-iodotoluene difluorides[6b,
or iodonium
6f]
fluoride[6g]
, were reported for tertiary alkyl halides. These
1
2
3
4
Selectfluor
AgF
reactions proceed via carbocationic intermediacy (Figure 1), and
thus suffer from the competing solvolysis, elimination or
rearrangement reactions (also vide infra). As a consequence,
their applications are mainly limited to bridgehead halides in
which the side reactions can be suppressed. More recently,
Nishikata et al. reported the copper-catalyzed fluorination of α-
bromo-N-arylamides with CsF.[7] However, this method is not
applicable to ordinary tertiary alkyl halides. Herein we report the
selective fluorination of tertiary alkyl halides with Selectfluor
37
21
10
55
p-Me-C6H4IF2
NFSI
trace trace
No reaction
[a] Reagents and conditions: Br-1a (0.2 mmol), [F] (0.6 mmol), CH3CN (2 mL),
rt, 12 h. [b] Isolated yield based on Br-1a. Phth = phthalyl; Selectfluor = 1-
chloromethyl-4-fluorodiazoniabicyclo[2,2,2]octane bis(tetrafluoroborate); NFSI
= N-fluorobis(benzenesulfonyl)imide.
reagent
(1-chloromethyl-4-fluoro-diazoniabicyclo[2,2,2]octane
We recently reported the Ag(I)-catalyzed decarboxylative
radical fluorination of aliphatic carboxylic acids with
Selectfluor.[11] This method was successfully extended to the
[a]
Dr. H. Chen, Dr. Z. Liu, X. Tan, H. Shen, Prof. Dr. C. Li
Key Laboratory of Organofluorine Chemistry and Collaborative
Innovation Center of Chemistry for Life Sciences, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai 200032, P. R. China.
deboronofluorination
of
alkylboronates
and
to
the
fluorofunctionalization of unactivated alkenes.[12] These results
urged us to test whether alkyl halides could also undergo radical
fluorination with Ag(I)/Selectfluor. Thus, N-(3-bromo-3-methyl-
butyl)phthalimide (Br-1a) was selected as the model substrate to
explore this possibility. However, after a careful screening of
reaction conditions (see Table S1 in the Supporting Information
(SI) for details), we were surprised to find that direct treatment of
Br-1a with a stoichiometric amount of Selectfluor in acetonitrile
at room temperature for 36 hours led to the clean formation of
the corresponding alkyl fluoride 1a in 86% yield. No silver
catalyst was required. Use of excess (3 equiv) Selectfluor
speeded up the fluorination, and 1a was isolated in 93% yield
E-mail: clig@mail.sioc.ac.cn;
[b]
[c]
Y. Lv, Prof. Dr. H.-Z. Yu
AnHui Province Key Laboratory of Chemistry for Inorganic/Organic
Hybrid Functionalized Materials, Anhui University, Hefei, Anhui
230601, P. R. China.
E-mail: yuhaizhu@ahu.edu.cn
Prof. Dr. C. Li
School of Materials and Chemical Engineering, Ningbo University of
Technology, 201 Fenghua Road, Ningbo 315211, P. R. China
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201708197
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within 12 hours (entry 1, Table 1). As a comparison, the reaction
of Br-1a with dry AgF in acetonitrile gave the mixture of fluoride
1a (23%), alkenes 2 (37%) and 3 (21%), and amide 4 (10%)
(entry 2, Table 1). The oxidative fluorination of Br-1a with p-
iodotoluene difluoride afforded the mixture of 1a (35%), 4 (55%)
and traces of 2 and 3 (entry 3, Table 1). In contrast, no reaction
nucleophilic fluorination conditions,[7] was not observed at all.
Given that tertiary alkyl bromides are easily prepared by
conventional methods[14] such as bromination of tertiary alkyl
alcohols,[14a] bromofunctionalization[14b] or hydrobromination[14c]
of alkenes (see also SI), this method nicely complements the
available fluorination methods. It is worth mentioning that direct
hydrofluorination of alkenes suffer from either harsh reaction
conditions or limited substrate scope,[15] while direct deoxy-
fluorination of tertiary alkyl alcohols, unlike that of primary or
secondary alkyl alcohols, is challenging.[16] Also note that the
method is site-specific compared to the recently developed C–H
fluorination.[17]
occurred
between
Br-1a
and
NFSI
(N-
fluorobis(benzenesulfonyl)imide)[13] (entry 4, Table1). These
experiments clearly indicate that the reaction of Br-1a with
Selectfluor proceeds via a mechanism different from that with
AgF or p-iodotoluene difluoride.
We next extended the above method to the fluorination of
tertiary alkyl iodides, and the results are summarized in Table 3.
As for the reaction of alkyl bromides, tertiary alkyl iodides I-1
also underwent smooth halogen-exchange fluorination with
Table 2: Fluorination of tertiary alkyl bromides Br-1.[a]
Selectfluor and gave the corresponding products
satisfactory yield.
1
in
Table 3: Fluorination of tertiary alkyl iodides I-1.[a]
[a] Reagents and conditions: I-1 (0.2 mmol), Selectfluor (0.6 mmol), CH3CN (2
mL), rt, 12 h. Yields of isolated products are given. [b] Reaction time: 24 h.
[a] Reagents and conditions: Br-1 (0.2 mmol), Selectfluor (0.6 mmol), CH3CN
(2 mL), rt, 12 h. Yields of isolated products are given. [b] Reaction time: 48 h.
[c] Reaction time: 24 h. [d] Br-1n was recovered in 55% yield. Ts = p-
toluenesulfonyl; Bz = benzoyl.
Unlike tertiary alkyl bromides and iodides, primary and
secondary alkyl chlorides and bromides were unreactive towards
Selectfluor. This difference in reactivity allowed the
implementation of chemoselective fluorination of alkyl halides.
Thus, tertiary alkyl bromides 5a–5i containing another alkyl
halide moiety, were subjected to the treatment with Selectfluor in
CH3CN at room temperature. The results are grouped in Table 4.
The reactions of tertiary alkyl bromides bearing a primary,
secondary or tertiary alkyl chloride moiety afforded the
corresponding tertiary alkyl fluorides 6a–6d in high yield while
the chloride moiety remained intact. Dibromides 5e–5g and even
tribromide 5h underwent chemoselective monofluorination to
provide tertiary alkyl fluorides 6e–6h in excellent yield.
Furthermore, for substrate 5i having two different tertiary alkyl
bromide motifs, the fluorination occurred exclusively at the all-
alkyl-substituted carbon to give product 6i in 82% yield whereas
the α-carbamoyl bromide moiety remained unchanged. This
We then aimed to define the scope of this metal-free
fluorination method. As shown in Table 2, a wide range of
differentially substituted tertiary alkyl bromides were readily
converted to the corresponding tertiary alkyl fluorides 1a–1p in
good to excellent yield. The reaction was tolerant of a number of
functional groups such as ether, ketone, ester, amide, imide,
nitro, sulfone, and sulfonate. Notably, fluorinated amino acid 1j,
a key building block for the synthesis of the drug odanacatib,[5a]
was achieved in 73% yield from the corresponding bromide Br-
1j by this method. In contrast, the reaction of Br-1j with AgF
under various conditions gave 1j in no more than 30% yield, and
byproducts such as alkenes and γ-lactone were also formed in
significant amounts, as reported by Otting and Easton et al.[5a] Of
particular note, fluorinated sulfonates 1g and 1h were obtained
in excellent yield, while further nucleophilic fluorination or
bromination of these sulfonates that is hardly avoidable under
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10.1002/anie.201708197
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COMMUNICATION
selectivity is opposite to that in the copper-catalyzed fluorination
with CsF.[7]
at room temperature for 30 minutes provided the chemoselective
monofluorination product 10 in 51% yield (Eq. 2).
To gain further insight into the fluorination, the following
experiments were carried out. When Selectfluor was treated with
excess t-BuBr in CH3CN at room temperature overnight, a white
precipitate was observed. After the usual workup, N-
bromoaminium salt 11 was obtained in 80% yield (Eq. 3). The
reaction of optically pure (-)-5e led to racemic product (±)-6e.
Finally, the fluorination of radical probe 12 was performed (Eq.
4). Both uncyclized (13) and cyclized (14) products were
observed, albeit in low yield, probably due to the competition of
allylic C–H fluorination[17] and the bromination of the alkene with
11.
Table 4: Selective fluorination of tertiary alkyl bromides 5.[a]
Figure 2. Proposed mechanism.
[a] Reagents and conditions: 5 (0.2 mmol), Selectfluor (0.6 mmol), CH3CN (2
mL), rt, 12 h. Yields of isolated products are given. [b] Reaction time: 24 h.
A plausible mechanism for the fluorination is shown in Figure
2. First, aminium radical cation A is generated by single electron
reduction of Selectfluor[18] (presumably by tertiary alkyl bromide).
The intermediate A then abstracts a bromine atom from tertiary
alkyl bromide to produce N-bromoaminium salt 11 and the
corresponding alkyl radical. Subsequent fluorine transfer[10] from
Selectfluor to the alkyl radical affords the fluorination product
and regenerates an aminium radical cation A. Theoretical
calculations at M062X/6-31G(d) level showed that the bromine
atom transfer from t-BuBr to A is endergonic by 20.7 kcal/mol.
For comparison, the incorporation of a solution phase single
point energy calculation at M06-2X/6-311++G(2df,2p) level (with
IEFPCM model and CH3CN solvent) reveals a higher energy
demand of 27.8 kcal/mol. Meanwhile, the subsequent fluorine
transfer (from Selectfluor to t-butyl radical) is highly exergonic by
48.1 and 51.8 kcal/mol for the gas phase and solution phase
calculations, respectively. These calculations suggest that the
Br-transfer is the rate-determining step in the overall
transformation. Our kinetic experiments on the fluorination of Br-
1a indicated that the rate of product formation has a first-order
dependence on the substrate, in support of this assumption (see
Figure S1 in the SI). Electron-rich alkyl bromides facilitate the
Br-transfer because of the electrophilic nature of aminium radical
cation A. This accounts for the chemoselectivity of fluorination
illustrated in Table 4.
The reactivity of primary and secondary alkyl iodides
towards Selectfluor was also tested. Secondary alkyl iodide 7
underwent fast reaction with Selectfluor at room temperature.
However, no expected fluorination product could be observed.
Instead, alcohol 8 was obtained in 84% yield after the quenching
of the reaction with H2O (Eq. 1). Primary alkyl iodides underwent
slow decomposition on treatment with Selectfluor, and no
desired alkyl fluorides were observed. In another case, the
reaction of diiodide 9 with a slightly excess amount of Selectfluor
The fluorination of tertiary alkyl iodides can also be
explained by the mechanism depicted in Figure 2. In contrast,
secondary alkyl iodides are less reactive, and their reaction with
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10.1002/anie.201708197
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In conclusion, we have developed a practical protocol for the
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As the procedure is operationally simple, free from metal ions,
broad in scope, and tolerant of sensitive functional groups, the
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Acknowledgements
This project was supported by the 973 Program (Grant
2015CB931900), by the NFSC (Grants 21421002, 21472220,
21532008, 21672001, and 21602239), and by the Strategic
Priority Research Program of the Chinese Academy of Sciences
(Grant XDB20020000).
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Keywords: fluorination • radicals • halogen-exchange • alkyl
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He Chen, Zhonglin Liu, Ying Lv,
Xinqiang Tan, Haigen Shen, Hai-Zhu
Yu*, Chaozhong Li*
Page No. – Page No.
Selective Radical Fluorination of
Tertiary Alkyl Halides at Room
Temperature
The reactions of tertiary alkyl bromides and iodides with Selectfluor proceed
smoothly at room temperature to give the corresponding fluorination products in
good yield. This metal-free method is highly selective in that alkyl chlorides and
primary and secondary alkyl bromides remain intact.
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