Benzylic Fluorination of Aza-Heterocycles Induced by Single-Electron Transfer to Selectfluor

Article abstract of DOI:10.1002/anie.201801280

A selective and mild method for the benzylic fluorination of aromatic azaheterocycles with Selectfluor is described. These reactions take place by a previously unreported mechanism, in which electron transfer from the heterocyclic substrate to the electrophilic fluorinating agent Selectfluor eventually yields a benzylic radical, thus leading to the desired C?F bond formation. This mechanism enables high intra- and intermolecular selectivity for aza-heterocycles over other benzylic components with similar C?H bond-dissociation energies.

Full text of DOI:10.1002/anie.201801280

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Accepted Article
Title: Benzylic Fluorination of Azaheterocycles Induced by Single
Electron Transfer to Selectfluor®
Authors: Kelley E Danahy, Julian C Cooper, and Jeffrey Van Humbeck
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201801280
Angew. Chem. 10.1002/ange.201801280
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Benzylic Fluorination of Azaheterocycles Induced by Single Electron
Transfer to Selectfluor®
Kelley E. Danahy, Julian C. Cooper, and Jeffrey F. Van Humbeck*
Abstract: We have investigated a selective and mild method for the
benzylic fluorination of aromatic azaheterocycles with Selectfluor®.
These reactions take place via a previously unreported mechanism,
in which electron transfer from the heterocyclic substrate to the
electrophilic fluorinating agent Selectfluor® eventually yields a
benzylic radical, leading to the desired C–F bond formation. This
mechanism enables high intra and intermolecular selectivity for
azaheterocycles over other benzylic components with similar C–H
bond-dissociation energies.
Aromatic azaheterocycles and carbon-fluorine bonds are key
building blocks in small molecules designed for medicinal chemistry.
As of 2014, over 250 FDA approved medicines contained aromatic
azaheterocycles (Figure 1),[1,2] demonstrating why methods to
selectively modify these substructures remain in demand. Likewise,
the unique properties and increasing prevalence of fluorine in
pharmaceuticals and radiotracers have led to its inclusion in 20% of
pharmaceutical small molecules and 30–40% of agrochemicals, [3,4]
and consequently, the development of new fluorination methods is
Figure 1. Examples of medically relevant 4-alkyl-N-heterocycles.
an active area of research.
While several notable methods to add difluoroalkyl[4] and
are typically divided into three categories: electrophilic,[8]
trifluoromethyl[5] groups to heterocycles are known, direct addition
nucleophilic,[9] and radical.[10] The latter emerged recently with
of monofluoroalkyl groups has so far remained limited to a-
Sammis’ demonstration that ‘electrophilic’ fluorine sources, such as
fluorocarbonyl fragments.[6] Heterobenzylic monofluorination of an
unactivated alkyl group has been rarely reported, most notably in
Sanford’s palladium-catalyzed fluorination of 8-methylquinoline,
Groves’ 18F manganese-salen catalyzed fluorination of papaverine,
and recently Britton’s N-fluorobenzenesulfonamide (NFSI)
promoted fluorinations of pyridines and pyrimidines.[7] Britton’s
work, the most comprehensive to date, used NFSI to activate
heterocycles by N-sulfonylation. C–F bond formation then follows
an ionic mechanism, in which the increased acidity at the
heterobenzylic position allows deprotonation by mild bases.
Pyridine substrates were efficiently monofluorinated under mild
conditions (60 ºC, MeCN). The requirement for N-sulfonylation
makes other substrates challenging, however: pyrimidine substrates
required 120-150 ºC to provide significant conversion.
NFSI and Selectfluor®, can function as radical fluorine sources.[10a]
Since their seminal work, numerous examples of radical fluorination
have been reported.[10]
However, attempts to use radical
mechanisms for C-H fluorination adjacent to azaheterocycles face a
significant challenge: even modestly complex molecules may
feature multiple reactive C–H bonds (e.g. benzylic). Thus, reactions
selective for heterobenzylic C–H bonds over other weak bonds are
needed to allow for predictable fluorination in advanced
intermediates.
Based on our recent studies on site selective methylene
oxidation,[11] we speculated that abundant Lewis acids such as
copper and iron might alter the radical reactivity of coordinated
heterocycles. Our initial investigations pitted 4-ethylpyridine (1)
against ethylbenzene (2), and used known radical initiators (e.g.
VAZOTM 88, NHPI) (Table 1). We were excited to see selective
fluorination with both metals, albeit in low yield (entries 1 and 2).
However, our control experiments revealed that the selective
fluorination of pyridine was optimal with merely a slight excess of
Selectfluor® (5) and no other additives, resulting in ≤10%
overreaction to difluorinated products. Addition of base, or
modification of our fluorine source, proved detrimental to the yield
(entries 4–8). We were pleased to find that these conditions
delivered complimentary results to those reported using NFSI
(Figure 2). Alkylpyridines are reactive towards Selectfluor® at room
temperature, though they generally deliver slightly lower yields than
those reported by Britton.[7c] Importantly, we observe different
behavior in the case of electron-poor heterocycles. Pyrimidines,
quinazolines, and purines, including an electron-poor pyrimidine
We questioned whether radical mechanisms could expand the
scope of azaheterocycle fluorination. C–F bond forming methods
[*]
K. E. Danahy, J. C. Cooper
Department of Chemistry, Massachusetts Institute of Technology
77 Massachusetts Ave., Cambridge, Massachusetts, 02139 (USA)
Prof. Dr. J. F. Van Humbeck
Department of Chemistry, University of Calgary
2500 University Drive N.W., Calgary, Alberta, T2N 1N4 (Canada)
E-mail: jeffrey.vanhumbec1@ucalgary.ca
Supporting information for this article is given via a link at the end of
the document.
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Table 1. Conditions screened for radical fluorination on N-heterocycles.
Entry
Additive
Solvent
“F+” source
Yield
(%)
3:4
Ratio
[a]
1
2
3
4
5
6
7
8
Cu(OTf)2
MeCN-d3
MeCN-d3
DMF-d7
Selectfluor®
Selectfluor®
Selectfluor®
Selectfluor®
Selectfluor®
Selectfluor®
Selectfluor®[d]
NFSI
28
25
20
67
50
50
53
44
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
[b]
FeCl3
None
None
MeCN-d3
MeCN-d3
MeCN-d3
MeCN-d3
MeCN-d3
DABCO[c]
[c]
Li2CO3
None
None
[a] 5 mol% copper and 5 mol% 1,1’-azobis(cyclohexanecarbonitrile) as a radical
inititator; [b] 5 mol% iron and 5 mol% N-hydroxyphthalimide as a radical initiator;
[c] 1 equiv. of base; [d] 2 equivalents Selectfluor®. All reactions were at 25 ºC.
(15), proved to be reactive at only 40 ºC. We found that the inclusion
of catalytic amounts of the iron(III) complex [FeCl4][FeCl2(dmf)3]
provided increased yields, through a currently unknown effect. In all
cases where another benzylic position was present (11, 14, 17),
selective fluorination adjacent to the azaheterocycle was observed.
We initially suspected an ionic mechanism given that
transition metals and radical initiators were not needed to observe
reactivity. An analogous mechanism to that proposed for NFSI[7c] is
shown in Scheme 1. Acidification of the benzylic position due to
pyridinium cation formation (19) would allow for deprotonation and
dearomatization (20). Then, attack by the now–nucleophilic
benzylic position onto another equivalent of electrophilic fluorine
would yield our desired C–F bond (21). Pyridinium 21 could then
transfer fluorine to another equivalent of substrate, delivering the
observed product and regenerating the pyridinium intermediate 19.
However, several observations called this mechanism into
question. During our optimization studies, we had observed the
complete failure of both N-fluorocollidinium (22) and N-
fluoropyridinum (23) to promote the desired transformation. Given
that an ionic mechanism using Selectfluor® demands fluorine
transfer between N-fluoropyridiniums, the failure of these reagents
strongly suggests that the presented ionic mechanism does not occur.
Additionally, no pyridinium fluoride peaks (from 19 or 21) were
observed during NMR studies. Furthermore, the successful
fluorination of 4-alkylpyrimidines under mild conditions would be
unusual for an ionic mechanism, as the formation of pyrimidinium
fluorides typically requires both harsh fluorinating reagents like
hypofluorites, as well as oxidation to the pyrimidinone state.[12]
A mechanistic insight appeared during the fluorination of 4-
benzylpyridine 24 (Scheme 2). Though the primary product was the
expected monofluorinated structure (9), dimeric byproduct 25 was
Figure 2. Substrate scope for benzylic fluorination. Conditions: a) acetonitrile,
1.2 equiv. Selectfluor®, 25ºC; b) 5% dimer observed – see Scheme 3; c) DMF,
2.5 mol% [FeCl4][FeCl2(dmf)3], 1.5 equiv. Selectfluor®, 40 ºC d) DMF, 2.5 mol%
[FeCl4][FeCl2(dmf)3], 1.2 equiv. Selectfluor®, 40ºC. e) With 2% starting material.
observed via GC/MS, and confirmed by independent synthesis. The
alkene stereochemistry was confirmed as E by hydrogenation to the
known racemic dipyridyldiphenylethane 26.[13] In our reaction, with
only Selectfluor®, substrate, and acetonitrile present, it is difficult to
explain the formation of this dimer without invoking radical 27. As
radical dimerization would lead to the saturated product 26, we then
confirmed that Selectfluor® is able to further oxidize the saturated
intermediate to the observed product.
To reconsider a radical mechanism, we had to contend with
the failure of substrate 8 (Figure 2) to rearrange as a radical clock.
However, radical clocks have often failed to provide evidence for
radical intermediates in transformations with Selectfluor®, yet ESI-
MS has observed radical cation intermediates that implicate a radical
mechanism despite a lack of rearranged products.[14,15] Thus, in
regards to 8, two possible explanations exist. First, radical
fluorination may outcompete opening of the cyclopropane. Second,
while cyclopropylmethyl radical clocks are known to yield
rearranged products, the rate of ring closure for aryl
cyclopropylmethyl radical clocks (k = 5.4·106 s-1) is faster than the
rate of opening (k = 6.1·104 s-1).[16] This suggests an equilibrium
favoring the closed form of the cyclopropane ring. As a result, the
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Scheme 3. Proposed radical mechanism for fluorination with Selectfluor®.
complexes between aromatic groups and Selectfluor® allowed for
highly para-selective C-H functionalization via a radical pathway.[18]
We reconsidered a radical mechanism for this transformation
(Scheme 3). First, we needed to address the high chemoselectivity
in our system. Pyridine itself is more easily oxidized in acetonitrile
than benzene (E1/2 vs. Ag/AgNO3: 1.82 V for pyridine, 2.04 V for
benzene),[19] and so selective electron transfer may naturally follow.
However, substrates such as 14 contain an anisole-type fragment,
which should be much more easily oxidized in acetonitrile (E1/2 vs.
Ag/AgNO3: 1.40 V for anisole,[19] 1.30 V for diphenyl ether[20]), and
yet do not deliver C–F bond formation adjacent to the anisole-type
ring. In these cases, we speculated that formation of a charge transfer
complex (28) may lead to the observed selectivity—either through a
stepwise electron transfer/deprotonation pathway or a concerted
proton-coupled electron transfer (PCET) pathway.
Scheme 1. Top: Proposed ionic mechanism for pyridylic fluorination with
Selectfluor®. Bottom: Failure of N-fluoropyridinium reagents.
closed cyclopropane ring of 8 does not confirm or oppose either
mechanistic pathway.
Previous studies have suggested that fluorination with
Selectfluor® may proceed via single-electron transfer (SET)
preceded by the formation of
a charge-transfer complex.
Calculations by Liu and coworkers predict that even simple
electrophilic aromatic substitution with Selectfluor® should not
follow the classic two-electron mechanism.[17] And, moving beyond
theory, Ritter and coworkers recently found that charge-transfer
We evaluated the formation of a pyridine-Selectfluor® charge
transfer complex in solution using UV/Vis spectophotometry
(Figure 3). At identical concentrations, a 4-ethylpyridine solution
showed a maximum absorbance at 255 nm, but an identically
concentrated reaction sample showed an absorbance nearly two-and-
a-half times as intense, although its wavelength (252 nm) was nearly
identical to the pyridine maximum. Further, a broad shoulder began
around 270 nm and tailed to nearly 350 nm. These spectra contain
all three characteristics (intensity, overlap of pyridyl charge-transfer
absorbances with the uncomplexed pyridine absorbance, and tailing)
also seen in the well-studied pyridine-I2 and pyridine-Br2 charge-
transfer complexes.[21]
In an attempt to distinguish between PCET and a stepwise
mechanism, we analyzed the kinetic isotope effect in an
intermolecular competition between protonated and deuterated 4-
1
ethylquinoline. H NMR results indicated a primary kH/kD of 3.0,
consistent with either concerted PCET or reversible SET, followed
by irreversible deprotonation.[22] Detailed studies are required to
differentiate between these two pathways.
Scheme 2. Proposed radical mechanism for the formation of dimer 25.
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4.5
4-Ethylpyridine (100 nM)
Reaction Solution (100 nM)
Selectfluor® (100 nM)
4
3.5
3
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0.5
0
200
250
300
350
400
Wavelength (nm)
Figure 3. Qualitative UV/Vis spectra for pyridine, Selectfluor®, and a diluted
aliquot of reaction solution.
In summary, we have observed the ability of Selectfluor® to
directly fluorinate sp3 C–H bonds adjacent to heterocycles. The
formation of substrate dimers such as 25 suggest a radical
mechanism, and the formation of charge transfer complexes may
explain site-selectivity in cases where oxidation potentials do not
predict the correct position of reaction. No additive is required for
selectivity, though a catalytic amount of iron(III) may be added for
optimum yield. This approach, which seems to be mechanistically
distinct from NFSI-based reactions, provides a complementary
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N-sulfonylated intermediates, such as medically relevant
pyrimidines and quinazolines.
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Acknowledgements
We thank Krysta A. Dummit and Dr. Keith W. Bentley for their
assistance with preparation of this manuscript. J.C.C gratefully
acknowledges the NSF for receipt of a graduate fellowship (NSF-
GFRP). Financial support was provided by MIT start-up funds.
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Keywords: fluorine • nitrogen heterocycles • charge transfer •
C–H activation • regioselectivity
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We have investigated a selective and
mild method for the benzylic
Kelley E. Danahy, Julian C. Cooper,
Prof. Dr. Jeffrey F. Van Humbeck*
fluorination of aromatic
Page No. – Page No.
azaheterocycles. These reactions take
advantage of the oxidizing power of
the electrophilic fluorinating agent
Selectfluor®. Either proton-coupled
electron-transfer or single-electron
transfer—followed by deprotonation—
yields a benzylic radical adjacent to
the heterocycle, leading to selective
C–F bond formation.
Benzylic Fluorination of
Azaheterocycles Induced by Single
Electron Transfer to Selectfluor®
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Author(s), Corresponding Author(s)*
((Insert TOC Graphic here))
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Title
Text for Table of Contents
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