Prenyl Praxis: A Method for Direct Photocatalytic Defluoroprenylation

Article abstract of DOI:10.1021/jacs.8b09156

The prenyl fragment is the quintessential constituent of terpenoid natural products, a diverse family which contains numerous members with diverse biological properties. In contrast, fluorinated and multifluorinated arenes make up an important class of anthropogenic molecules which are highly relevant to material, agricultural, and pharmaceutical industries. While allylation chemistry is well developed, effective prenylation strategies have been less forthcoming. Herein, we describe the photocatalytic defluoroprenylation, a powerful method that provides access to "hybrid molecules" that possess both the functionality of a prenyl group and fluorinated arenes. This approach involves direct prenyl group transfer under very mild conditions, displays excellent functional group tolerance, and includes relatively short reaction times (<4 h), which is the fastest photocatalytic C-F functionalization developed to date. Additionally, the strategy can be extended to include allyl and geranyl (10 carbon fragment) transfers. Another prominent finding is a reagent-dependent switch in regioselectivity of the major product from para to ortho C-F functionalization.

Full text of DOI:10.1021/jacs.8b09156

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Prenyl Praxis: A Method for Direct Photocatalytic Defluoroprenylation
Sonal Priya, and Jimmie D. Weaver
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b09156 • Publication Date (Web): 13 Nov 2018
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Journal of the American Chemical Society
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Prenyl Praxis: A Method for Direct Photocatalytic
Defluoroprenylation
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Sonal Priya and Jimmie D. Weaver III*
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Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74078, United States
ABSTRACT: The prenyl fragment is the quintessential constituent of terpenoid natural products, a diverse family which
contains numerous members with diverse biological properties. In contrast, fluorinated and multifluorinated arenes make
up an important class of anthropogenic molecules which are highly relevant to material, agricultural, and pharmaceutical
industries. While allylation chemistry is well developed, effective prenylation strategies have been less forthcoming. Herein,
we describe the photocatalytic defluoroprenylation, a powerful method that provides access to “hybrid molecules” that
possess both the functionality of a prenyl group and fluorinated arenes. This approach involves direct prenyl group transfer
under very mild conditions, displays excellent functional group tolerance, and relatively short reaction times (<4 h), which
is the fastest photocatalytic C–F functionalization developed to date. Additionally, the strategy can be extended to include
allyl and geranyl (10 carbon fragment) transfers. Another prominent finding is a reagent dependent switch in regioselectivity
of the major product from para to ortho C–F functionalization.
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The prenyl fragment is ubiquitous in a multitude of nat-
ural products, and is the fundamental building block of the
Scheme 1. Allylation and Prenylation of electron defi-
cient perfluoroarenes
biodiverse and efficacious terpenoids which present im-
pressive and diverse biological activities.1 Consequently,
the development of prenylation strategies within the con-
text of natural products2 has been widely studied.2-3 Many
prenylation strategies involve multistep procedures, and
one-step prenylation has only been solved for a narrow
subset of substrates.4 Even recently, Porco employed indi-
rect allylation followed by cross-metathesis to affect
prenylation to access
a
class of polyprenylated
acylphloroglucinols.5
Meanwhile, fluorine substituents have been shown to
impart a number of positive attributes, such as resistance
to metabolic degradation, improved binding, enhanced
lipophilicity, and passive diffusion of compounds across
membranes.6 Not surprisingly, multifluorinated arenes
make up an important class of molecules in pharmaceuti-
cal,7 material,8 and agricultural chemistry,9 but despite
their importance, methods to build these molecules largely
depends on just a handful of rather harsh reactions, such
as the Balz-Schiemann decomposition of an aryl diazo-
nium tetrafluoroborate salt,10 or the high temperature (ca
230 oC) halex process.11 Arguably, this limitation has led to
an overreliance on commercially available pre-fluorinated
building blocks which can simply be incorporated into
other molecules. Almost certainly, this leads to incomplete
structure activity relationships studies.
Building on the strategy promoted by Braun12, Richmond,13
Uneyama,14 and many others,15 we seek to address this lim-
itation by developing reactions that start with inexpensive
highly fluorinated arenes, and sculpt far more complex
fluorinated arenes via C–F functionalization than have his-
torically been synthetically accessible.16 We were particu-
larly drawn to the prenyl motif due to its ubiquity within
nature as well as its synthetic versatility. Accomplishing
this goal would allow us to wed the natural prenyl group
and the unnatural organofluorines to give hybrid mole-
cules.
While allylation chemistry is relatively well developed,
there are a number of serious challenges that arise as a con-
sequence of the two additional methyl groups found within
a prenyl group. As carbenium ions, they are prone to elim-
4c
ination,4a,
and as anions regioselectivity issues arise
(Scheme 1A).17 The use of a prenyl radical might lead to
selectivity in the addition, but addition to an arene is ex-
pected to be a highly endergonic step.
Several strategies have been explored to achieve related
allylation and isoprenylation on perfluoroarenes18 via C–F
functionalization both directly and indirectly (Scheme 1B-
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C). Sukbok18c has shown that a Cu(NHC) catalyst is capa-
Table 1. Screening of Prenyl sources
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ble of C–H functionalization of highly fluorinated arenes
(Scheme 1B), which has become increasingly relevant with
recent improvements to hydrodefluorination technolo-
gies,15d, 19 but at the very least requires two steps. In an al-
ternative approach, Kambe17 showed (Scheme 1C) that cop-
per (II) chloride could facilitate formation of an prenyl
magnesiate which would then undergo uncatalyzed addi-
tion to the perfluoroarene. The major product arises from
linear addition of the most stable prenyl metal species, but
gives rise to a total of 4 isomers in substantial quantities.
Inspired by the work of Zard who has popularized a
number of allyl radicophiles,20 we envisioned that such a
reagent could be designed to facilitate C–F prenylation.
Previously, we have shown that upon photocatalytic elec-
tron transfer to a perfluoroarene, an unstable radical anion
results, which undergoes mesolytic cleavage to generate a
fluoride and a perfluoroaryl radical.19e, 21 Our hope was that
the radicophile would intercept the perfluoroaryl radical to
regioselectively generate the key C–C bond. Addition
would result in an alkyl radical intermediate that would
undergo homolytic fragmentation of the -leaving group,
unmasking the prenyl group. We anticipated that the na-
ture of the leaving group would be key to preventing sim-
ple hydrogen atom transfer (HAT) to the radical.21e Vital to
the rate of the -fragmentation is the bond strength, and
in this regard Zard has provided insight, demonstrating
that the C–O bond of allyl alcohol (80.1 kcal/mol BDE)22
can be weakened by converting the hydroxy to an aryloxy
group; rendering it susceptible to homolytic fragmenta-
tion.20, 23 This stabilization is mirrored by the phenoxy rad-
ical (PhO–H BDE = 87.3 kcal/mol) which is more stable
than hydroxyl radical (HO–H BDE = 119.3 kcal/mol).24
Thus, we began our investigation with the hope of find-
ing a group capable of activating the C–O bond towards
homolytic fragmentation (Table 1). As expected, reaction
with isoprenyl alcohol (2a) itself simply results in hy-
droarylation of the alkene,21b highlighting the need for an
activating group that can increase the rate of fragmenta-
tion. Next, we assessed the 6-halopyridine motif (2b, 2c)
previously explored by Zard23 in lauroyl peroxide mediated
transfer of xanthates to olefins. The pyridyl group is con-
veniently introduced via SNAr addition of isoprenyl alco-
hol. We were delighted to see the desired prenylated prod-
uct (3a) in 54% and 43% respectively. The mass balance
was primarily comprised of hydrodefluorination (HDF) as
well as an oxidized version of the desired product. How-
ever, reagents 2b and 2c both underwent competitive [3,3]-
sigmatropic rearrangement, which further complicated the
situation and necessitate higher reagent loading to com-
pensate for this background reaction. By blocking the or-
tho position with an ester group and increasing the steric
demand (2d), we hoped to curtail both the rearrangement
and the oxidation. Indeed, we halted the rearrangement,
but unfortunately this reagent did not deliver desired
prenylated product, and instead yielded only
hydrodefluorination (HDF) product. This behavior is
perhaps due to competitive and unproductive electron
transfer to 2d rather than the perfluoroarene.
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The importance of a weak C–O bond can be observed in
low yields of 2e and 2f, which would be expected to work
better if the C–O bond were to break heterolytically.
However, substrates 2g and 2h were expected to have a
weaker C–O bond and still failed to give improved yields.
We next evaluated aryl ethers formed from the
perfluoroarene (2i and 2j). We were pleased to see that
these prenyl transfer reagents afforded the desired
product, with HDF as the only by-product.
Table 2. Optimization of reactions
It is possible that the fluorines on the reagent serve to
prevent rearrangement and sterically reduce the activity of
the resulting aryloxy radical, potentially involved in the
formation of the previously observed oxidized product.
However, 2k displayed significantly decreased activity
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even though it contained two prenyl groups. Given the
positive results and the simple nature of 2j we opted to use
it for further reaction development.
Using conditions that had facilitated C–F reductive al-
kylation,21b using Blue LEDs we irradiated methyl pen-
tafluorobenzoate and diisopropylethyl amine (DIPEA) as
the electron source, along with 6 equiv of 2j at 0 oC. Previ-
ously, we observed that lowering the temperature could re-
duce the amount of competitive HDF in the related C–F
arylation reaction.21c We were pleased to see that the de-
sired C−C-coupled product was formed as the major prod-
uct in decent yield, albeit along with a significant amount
of HDF product (Table 2, entry 1).25
on the reaction. Unexpectedly, the presence of water sig-
nificantly accelerated the reaction from 18 h to 4 h and im-
proved product: HDF ratio (entry 10-11). One explanation
could be the increase in exothermicity of the reaction due
to hydration of fluoride.26 An alternative explanation is
that water acidifies the pentafluorophenol generated in
situ.27 By doping the reaction mixture with pentafluoro-
phenol we observed its inhibitory effect on the reaction
progress. This effect was diminished upon the addition of
water.27 Recently, Wu showed that the competitive reduc-
tion pathway could be minimized by the addition of
TEMPO,28 we found it initially helped but ultimately
slowed the reaction.29
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Ultimately, using 0.1 M substrate, 1.8 equiv DIPEA, 0.3
mol% fac-Ir(ppy)3 and 10 equiv H2O, we began evaluating
substrate scope. Under these conditions a number of per-
fluoroarenes smoothly underwent C–F defluoroprenyla-
tion in good to modest yields. The reaction tolerates a
number of functional groups including esters (Table 3, 3a-
3c), nitriles (3d), CF3 (3e), and perfluoroheterocyclic arenes
(3g). Hexafluorobenzene, devoid of any additional elec-
tron-withdrawing functional group also proceeded to form
3f, though it required the use of 2b as the prenyl source.
3h-l are noteworthy as they demonstrate the preference for
chlorine fragmentation over that of fluorine despite the po-
sition on the ring. Given that many chlorofluoro-starting
materials are commercially available, it provides a conven-
ient strategy for accessing complementary regioisomers.
When a chlorine was placed at the site of preferential fluo-
rine fragmentation (4 position for pyridine), it displayed
moderately shorter reaction time compared to pentafluor-
opyridine (i.e. 3h compared to 3g).
Table 3. Scope of prenylation
Table 4. Scope of allylation
Control studies demonstrated the necessity of light, cat-
alyst, and amine (entry 2-3). Carrying out the reaction at
lower temperature increased the reaction time with no sig-
nificant improvement in 3a:3a’ ratio (entry 4). While de-
creasing the DIPEA loading slowed the reaction, increasing
amine resulted in more HDF (entry 5-7); ultimately, 1.8
equivalents of DIPEA produced the optimal yield. There
appears to be a rate dependency on catalyst concentration
(entries 8 and 9). Next, we investigated the effect of water
This could be because fragmentation of chloride ion is
more exothermic than fluoride, resulting in a faster frag-
mentation event. Furthermore, the presence of chlorine
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substituents create greater steric demand than fluorine
tially at the position ortho to the substituent on the per-
fluoroaryl ring (c.a. ortho: para 1.6:1). This is particularly
noteworthy as it is the first time that we have observed an
external reagent capable of influencing the C–F regioselec-
tivity in a photocatalytic C–F functionalization.31
Furthermore, while, 7a-7d were produced as ortho-para
isomers, it demonstrated perfect diastereoselectivity, giv-
ing only the E-alkene.32 This selectivity is in stark contrast
to the unsymmetric allyl derivative, 5f, which was pro-
duced as a mixture.
In conclusion, we have developed a strategy and reagents
that enable photocatalytic defluoro-allylation, -prenyla-
tion, and -geranylation of perfluoroarenes. Further, as we
moved from prenylation to geranylation, we observed a
change in the regioselectivity of the major product from
para-C–F functionalization to ortho-C–F functionalization.
Our approach allows direct allyl, prenyl and geranyl sub-
stitution of C–F bonds using very mild conditions and
short reaction times. This strategy should facilitate inves-
tigations involving synthesis of hybrid fluorinated analogs
of natural products. Additionally, this reaction presents a
number of interesting mechanistic facets which are cur-
rently being studied, and the findings will be reported in
due course.
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substituents, and could result in a relative increase the
ground state energy.30 Likewise, steric repulsion between
the substituents in the radical anion may also accelerate its
breakdown, leading to faster fragmentation. Interestingly,
prenylation at the meta position was also possible but re-
quired longer reaction time (3i and 3j vs 3g). Whereas the
mesolytic fragmentation of fluoride is highly regioselec-
tive, chloride is generally less regioselective and is temper-
ature dependent (3g vs 3k and 3l), but still results in useful
selectivities. This method can be used to access heterocy-
clic substituted perfluoroarenes like oxazoles (3m), ben-
zimidazoles (3n) and benzothiazoles (3o). In all these re-
actions, HDF made up the mass balance.
Looking to expand the utility of the method, we applied
this strategy towards allyl transfer to perfluoroarenes. As
expected, allylation with transposition of the double bond
proceeded smoothly to yield 5a-5f (Table 4) in good yield.
Substitution at both the -position (5c and 5d), and the -
position were well tolerated (5e and 5f). While the yield
was acceptable, in the case of unsymmetric 5f, the E/Z-se-
lectivity was very modest (1.3:1) and did not display signifi-
cant temperature dependence (See SI for details), which
may limit its use in cases where the olefin geometry is es-
sential.
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ASSOCIATED CONTENT
Encouraged by our success with prenyl transfer, we hoped
to extend our strategy to geranyl transfer, adding a 10 car-
bon unit. Using the same optimized conditions, we re-
acted perfluoroarenes with pentafluoroisogeranyl ether (6,
Table 5). We were concerned that the alkyl radical formed
upon addition to the alkene would undergo intramolecular
addition to the additional olefin (i.e. 5-exo-trig cyclization)
faster than fragmentation of the pentafluorophenoxy radi-
cal.
Supporting Information. Includes procedures, additional
experiments, compound characterization, and spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
Jimmie.Weaver@OKSTATE.EDU.
Funding Sources
Table 5. Scope of geranylation
We gratefully acknowledge NIH NIGMS (5R01GM115697) for
financial support of this work. Acknowledgement is made to
the Donors of the American Chemical Society Petroleum Re-
search Fund for partial support of this research.
ACKNOWLEDGMENT
We thank Jon Day for help in editing this manuscript and art-
work.
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27. See SI for a working mechanism.
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