A General Photocatalytic Route to Prenylation

Article abstract of DOI:10.1002/ejoc.201900356

Prenylation is an essential reaction on which nature relies to modify properties of molecules and build terpenoids, but remains a challenging chemical reaction. Aiming to capitalize on recent advances in photocatalysis to easily and cleanly generate a broad range of carbon based radicals, we have developed a prenyl transfer reagent that is captured by transiently generated radicals. The reagent can be made in bulk, is bench stable, and broadly applicable such that it can be used with existing photocatalytic methods with very few changes to reaction conditions. Ultimately, this provides a true drop-in solution for prenylation, expanding the scope of substrates that can be readily prenylated.

Full text of DOI:10.1002/ejoc.201900356

A Journal of
Accepted Article
Title: A General Photocatalytic Route to Prenylation
Authors: Manjula D. Rathnayake and Jimmie Dean Weaver
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10.1002/ejoc.201900356
European Journal of Organic Chemistry
COMMUNICATION
A General Photocatalytic Route to Prenylation
Manjula D. Rathnayake and Jimmie D. Weaver*
Scheme 1. Approaches towards prenylated arenes
Abstract: Prenylation is an essential reaction on which nature relies
to modify properties of molecules and build terpenoids, but remains a
challenging chemical reaction. Aiming to capitalize on recent
advances in photocatalysis to easily and cleanly generate a broad
range of carbon based radicals, we have developed a prenyl transfer
reagent that is captured by transiently generated radicals. The
reagent can be made in bulk, is bench stable, and broadly applicable
such that it can be used with existing photocatalytic methods with very
few changes to reaction conditions. Ultimately, this provides a true
drop-in solution for prenylation, expanding the scope of substrates
that can be readily prenylated
.
Introduction
Nature prenylates proteins,[1] indole alkaloids,[2] flavonoids,[3]
coumarins[4] and other aromatics[5] to produce a number of
biological effects. This has resulted in continuous demand for
prenylated molecules and the development of more expansive
prenylation strategies. While it is tempting to assume prenylation
is as well developed as allylation chemistry, which differs subtly
by the replacement of the terminal methylene for a geminal
dimethyl group, the impact should not be underestimated. While
remarkable progress (scheme 1) has been made, these
methods[6] are designed to be used with specific classes of
substrates. In this context, a more generalized solution that could
easily applied to a wide range of substrates would be highly
attractive.
Recently, visible light photocatalysis has proven effective at
catalytically generating a variety of radicals under near ambient
conditions, often resulting in useful reactions that are remarkably
tolerant of functional groups.[7] In a number of cases these
photocatalytically generated radicals have proven capable of
undergoing addition to alkenes.[8] Upon addition, a new alkyl
radical is generated that has been oxidized,[9] reduced,[10] or
subjected to hydrogen atom transfer (HAT)[11] (scheme 2). Of
note, is the inherent selectivity that is observed for the addition to
the less substituted terminus of the double bond. We posited that
we could capitalize on this preference to design a prenylating
reagent that could be broadly used in conjunction with existing
photocatalytic methods as a drop-in solution to accomplish
prenylation.
Scheme 2. Visible light-mediated radical addition to alkene
The literature shows that a number of unactivated alkenes can
easily intercept photocatalytically generated radicals.[12] Thus, we
anticipated that a terminal methylene group of an isoprenyl
molecule would undergo addition to the unsubstituted terminus
with high selectivity. Then, if the alkene were appropriately
substituted with
a
leaving group capable of homolytic
fragmentation it could out-compete other processes, and instead
yield the key double bond.
[a] M. D. Rathnayake, Prof. Dr. J. D. Weaver
Department of Chemistry, Oklahoma State University, 107,
Physical Science, Stillwater, Oklahoma 74078, United States
E-mail: jimmie.weaver@okstate.edu
Homepage: weaverlab.okstate.edu
Supporting information for this article is given via a link at the end
of the document.
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With this in mind, we were attracted to the seminal work by Zard[13]
which provided key insight into how to accelerate the desired
fragmentation. Specifically, using thermally generated radicals
from the homolysis of alkyl xanthate esters, he demonstrated their
efficient addition to alkenes as well as their ability to undergo beta
scission, provided the carbon bond to the leaving group was
sufficiently weak. This is manifested in radical allylation reactions
which have been carried out using allyl-halides, -sulfones, -
stannanes, –Co, and –Ga reagents.[13c, 14] Again, the key feature
among all these reagents is a relatively weak allyl–X bond which
facilitates the homolytic fragmentation, or beta scission. Thus, we
set about trying to develop a reagent amenable to photocatalytic
capable of trapping radicals, suggesting that it might be possible
to identify a prenyl transfer reagent capable of working under
photocatalytic conditions. Thus, we synthesized and tested a
library of isoprenyl sulfones (1j-1q). Use of alkyl sulfone 1j
resulted in trace conversion to the reduced azole 2a’. In sharp
contrast, aryl sulfones generally worked well. Aryl sulfones
bearing electron donating methyl (1m) and methoxy (1n)
substituents were found to give lower yields compared to phenyl
sulfone (1k).
Moreover, phenyl sulfones having electron
withdrawing fluorine substituents (1p) and (1q) or extended
conjugation (1o) also exhibited comparatively lower yields. Thus,
we selected phenyl sulfone (1k) which gave the best yield, 75%
of 2a, for further studies.
reactions, and capable of intercepting
a diverse set of
photocatlytically generated radicals. The ideal prenyl transfer
reagent would be easily handled, shelf stable, non-toxic,
inexpensive, and easily separated from the product.
Reagent 1k (Scheme 3) is a bench stable, crystalline solid that
can be made via allylation of benzene sulfinate, then in a
chromatography free, telescoped fashion, dimethylated yielding
the isolation of 1k in pure form in 75-85%.yield.[24]
Results and Discussion
Given our previous work with the azolyl radicals,[11a, 15] we opted
to use 2-bromoazoles to begin our investigation. Following the
lead of Zard, we started with isoprenyl alcohol derivatives (1a-1i,
Table 1). Not surprisingly, groups 1a-1e are expected to have a
relatively strong C–X bond, and provided very little of the
prenylated product, 2a. Next, we moved to derivatives expected
to have weaker bonds. While 1f and 1g did not provide product,
use of a pyridyl activating group (1h) gave full conversion and
53% yield. Further efforts to optimize the reaction using 1h did
not increase the yield. Unfortunately, recently developed[16]
reagent 1i did not produce 2a in appreciable quantities.[17]
Therefore, 1i could not serve as a general prenylation source. We
expanded our search to include sulfones (1j-1q), since the C–S
bond of sulfones is relatively weak (For MeOH, C–O BDE = 91
kcal/mol while MeSH, C–S BDE = 73 kcal/mol).[18]
Scheme 3. Synthesis of prenyl sulfones
With prenylating reagent 1k in hand, we began exploring recently
developed photocatalytic reactions. Using the same conditions
developed for the hydroazolylation of alkenes[25] and the C–H
azolylation of arenes,[26] along with the addition of reagent 1k in
lieu of the original coupling alkene and arene partners, we
attempted the prenylation of several bromoazoles (Scheme 4).
Table 1. Development of a prenyl transfer reagent
Scheme 4. Prenylation of azoles
The prenyl transfer reagent 1k proved to be general, as the
prenylated azoles (2a-2f) were obtained in 60-78% yield. The
reduced azole, the result of HAT to the azolyl radical, accounted
for the mass balance. Importantly, the reaction displayed both
perfect regioselectivity giving no branched product, and
displaying perfect chemoselectivity for the 2-Br, allowing other
bromine and chlorine substituents (2c, 2d) to remain untouched.
Sulfones are also attractive because they are easily handled,
generally shelf stable, and can be easily elaborated via alkylation
chemistry. Zard[13c] has explored lauroyl peroxide mediated
allylation of xanthate esters with α-substituted allylic alkyl
sulfones, which suggests it should be possible to use sulfones.
Furthermore, more recently Ollivier,[19] Kamijo,[20] Zhu,[21] Chen[22]
and Flechsig[23] have shown that photocatalytically generated
radicals can react with a range of sulfonyl reagents which are
As
seen
previously,
photocatalytic
reaction
of
2-
bromobenzimidazole was sluggish,[15b] and the reaction did not go
to completion.
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Aryl diazonium salts have attracted attention as an excellent
precursor of aryl radicals, in part, because of ease of their
reduction.[27] Recently, Kꢀnig has demonstrated the visible light
mediated, eosin Y catalyzed direct C–H arylation of heteroarenes
with aryl diazonium salts via photocatalysis.[9d] However, the use
of diazonium salts can undermine the utility of the method
because the shelf-stability of diazonium salts can vary widely from
substrate to substrate. Furthermore, their use often raises
significant safety concerns[28] that might limit their applications on
scale. For this reason, Ranu has developed a method for the in
situ generation of the diazonium salt from anilines and
demonstrated their use within photocatalysis. In this reaction,
tert-butylnitrite converts the aryl amine into the diazonium salt
which is consumed as it is made, and to some extent, helps
circumvent some of the aforementioned issues with
diazoniums.[29] Thus, we inspected whether this method could be
adapted to allow prenylation of aryl amines (scheme 5).
towards prenylation than electron deficient aryl iodide, potentially
because of challenges associated with the initial electron transfer
from the photocatalyst due to their extremely negative potentials.
As expected halogens[31] lighter than iodide were tolerated in the
reaction, (4c, and 4e) and should allow advanced synthetic
manipulation. Even a sterically hindered aryl iodide gave
moderate amount of prenylated product (4d), highlighting the
ability of the radical and the reagent to form sterically demanding
bonds. In fact, yields may have been higher, but the carbonates
of 4d were somewhat unstable under the reaction conditions, as
we observed some deprotection of carbonates during the reaction
and made no attempt to optimize the reaction.
Scheme 6. Prenylation of aryl iodides
Scheme 5. Prenylation of anilines
Visible light promoted reductive dehalogenation[32] and
alkenylation[9c] reactions of α-carbonyl alkyl bromides/ chlorides
and benzyl bromides have been reported. Using conditions also
developed by Stephenson,[32] we attempted the prenylation of α-
bromo carbonyls using reagent 1k (Scheme 7).
Scheme 7. Prenylation of α-carbonyl bromides
Indeed, the desired prenylated arene was formed as the major
product in reasonable yield along with a minor amount of the
reduced arene. Further optimizations were carried out to improve
the yields (see SI). The reaction worked well for arenes with
electron withdrawing- (3a, 3b, 3e, 3f and 3g), and neutral-groups
(3c). However, more electron rich aryl amines were somewhat
sluggish and gave slightly lowered yields (3h and 3j). The mild
reaction conditions are compatible with a wide range of functional
groups such as a nitro, ester, cyano, bromide, chloride and
carboxylic acid. The broad functional group tolerance should
facilitate further synthetic elaboration.
2+
Unactivated carbon-iodide bonds have decidedly negative
reduction potentials. For example, the reduction potential of
iodobenzene has been measure to be -1.59 V versus SCE.[30]
Stephenson[31] and coworkers have introduced a protocol to
generate radicals from unactivated alkyl, alkenyl and aryl iodide
in the presence of fac-Ir(ppy)3 upon irradiation. In these cases,
the radicals underwent hydrogen atom abstraction (HAT) or
intramolecular cyclization. Based on their protocol, we looked at
prenylation of aryl iodides using prenyl transfer reagent 1k. The
Changing the photocatalyst from Ru(bpy)3 to fac-Ir(ppy)3 and
some minor tweaking of reaction conditions, made it is possible to
obtain prenylated carbonyl products as the major product. The
acid 5a serves as a valuable precursor for many synthetic
sequences,[33] and this procedure should expedite access to this
compound. Additionally, the reaction works well for ketones (5b),
esters (5c), and diesters (5d).
Among the different classes of substrates we have studied, there
are assuredly mechanistic variations. However, a generic
mechanism is outlined below (Scheme 8). All reactions begin with
the irradiation of the photocatalyst to give an excited state catalyst
standard
conditions
i.e.
photocatalyst,
N,
N-
diisopropylethylamine, formic acid, and aryl iodide were used
along with 1k to give prenylated product in moderate to good
yields (Scheme 6). Electron rich aryl iodides were more sluggish
(PC*).
From PC* single electron transfer (SET) to the
halogenated (or pseudo-halogenated) substrate occurs,
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10.1002/ejoc.201900356
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converting the photocatalyst to its more oxidized state which is
then reduced by the sacrificial reductant. Meanwhile, mesolytic
fragmentation of the halide (or pseudo-halide) takes place and
generates a carbon based radical. We recognize that in some
cases reductive quenching of the photocatalyst may be operative,
but still results in an electron transfer to the halide which proceeds
as described. Addition of radical to isoprenyl sulfone (1k)
generates the β-sulfonyl radical. Finally, elimination a sulfinyl
radical generates the key double bond, providing the prenylated
aryl or alkyl product. The sulfinyl radical abstracts a hydrogen
atom from an H-atom donor[34] to generate sulfinic acid, the
presence of which has been confirmed by doping experiments
(see SI). During the prenylation reaction, we observed that some
of 1k underwent a formal 1,3-rearrangement to form the
thermodynamically more stable, linear, and non-productive
prenylated sulfone. Uguen[35] and coworkers has shown that
allylic sulfones undergo allylic isomerization when treated with
arenesulfinic acid. Importantly, the rate of isomerization 1k
increases with temperature. Additional 1k can be added to
compensate for loss of the reactant due to isomerization (Scheme
8, iso-1k).
prenylated thiol was formed as the major product in high yield.[38]
This suggests that 1k is also useful with oxidative fragmentions
reactions. Visible light photocatalysis conditions are often tolerant
of various functional groups and the synthetic community
continues to find new uses.
However, selectivity within
photocatalytic pathways is less explored despite that many
conditions are orthogonal, or rely on different phenomena.[39] To
demonstrate selective photocatalysis, we performed the selective
prenylation of different photocatalytically active substrates by
judicious choice of reaction conditions. We observed selective
prenylation of CF3-aniline via selective reduction of the in situ
generated diazonium by eosin Y (Scheme 10, eqn 1). Electron
transfer from eosin Y to the bromo-ketone or the aryl iodide, would
be endothermic, and consequently happens infrequently.
2+
Similarly, use of a more reducing Ru(bpy)3 (eqn 2) allows the
reduction of the bromo-ketone but only very sluggishly reduces
the aryl iodide, and does not affect the aniline. We had hoped to
accomplish prenylation of the aryl iodide (-1.59 V) [30] selectively
over the bromo-ketone (-0.78 V)[40] via Marcus-selectivity,[41] i.e.
such an overpotential of the more easily reduced substrate that
the SET to it becomes sluggish instead allowing SET to the less
easily reduced substrate (eqn 3). While we did observe a relative
increase in the rate of consumption of the aryl iodide compared to
Scheme 8. General mechanism
the bromide, it was not synthetically useful.
A potential
explanation for why we fail to see the complete selectivity could
be due, not to unselective electron transfer from the photocatalyst
to the iodide, but rather because the radical anion of the aryl
iodide undergoes exothermic SET to the bromo-ketone faster
than mesolytic fragmentation of the iodide. Nonetheless, it is still
remarkable to see that the relative preference for the more easily
reduced bromide is significantly lessened, and suggests that
Marcus selectivity may find applications in other systems.
Scheme 10. Navigating photocatalysis
All the prenylation examples discussed thus far, generated
radicals via reductive fragmentation. However, we believe the
prenylation method should also include oxidatively generated
radicals. Thus, we looked at the one-electron photocatalytic
oxidation of thiols described by Yoon[36] and Ananikov[37] to
generate a thiol radical cation which mesolytically fragments into
a proton and an electrophilic thiyl radical, which we believed
would react with 1k to accomplish the prenylation of thiols
(scheme 9).
Scheme 9. Prenylation of thiophenol
In this case, we used the similar conditions of photoredox thiol-
yne click reaction developed by Ananikov.[37] Indeed, the desired
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In conclusion, we have developed a visible light photoredox-
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bromo-azoles, aryl iodides, α-bromo-carbonyls, and anilines via
their in situ generated diazoniums using bench stable, and easy
to handle iso-prenyl sulfone, 1k. We anticipate that this reagent,
along with rapid advancement of visible light photocatalysis will
greatly facilitate prenylation efforts.
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General procedure for the photocatalytic prenylation
Prenylation of ary or alkyl halides:
A 12×75 mm borosilicate tube fitted with a rubber septum was charged
with fac-tris(2-phenyl pyridinato-C2, N) Iridium(III) (Ir(ppy)3) (0.6 mM, 0.6
mL in MeCN), ary or alkyl halide (2-bromoazoles, aryl iodides or α carbonyl
bromides) (0.12 mmol, 1 equiv), amine (0.36 mmol, 3 equiv), formic acid
(0.36 mmol, 3 equiv) and ((2-methylbut-3-en-2-yl)sulfonyl)benzene (1k)
( 0.6 mmol, 5 equiv). Then the reaction mixture was degassed via Ar
bubbling for 10 min and then left under positive Ar pressure by removing
the exit needle. The tube was placed in a light bath (see SI) and the lower
portion of the tube was submerged under the water bath which was
maintained at corresponding temperature. The reaction was monitored by
TLC,GC-MS or NMR. After the complete consumption of ary or alkyl halide,
MeCN was removed via rotovap and the residue was treated with sat.
NaHCO3 solution (2 mL) and extracted with DCM (3 x 2 mL). The organic
portions were combined and dried over anhydrous MgSO4. The crude
product was concentrated in vacuo and purified via column
chromatography.
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Prenylation of aniline:
A 12×75 mm borosilicate tube fitted with a rubber septum was charged
with Eosin Y (0.6 mM, 0.6 mL in DMSO), aniline (0.12 mmol, 1 equiv), t-
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BuONO
(0.24
mmol,
2
equiv)
and
((2-methylbut-3-en-2-
yl)sulfonyl)benzene ( 0.6 mmol, 5 equiv). Then the tube was placed in a
light bath and the lower portion of the tube was submerged under the water
bath which was maintained at 22 oC. The reaction was monitored by TLC
and GC-MS. After completion of the reaction, water (5 mL) was added and
extracted with ethyl acetate (3 mL). The organic fraction was washed with
water (10 mL) and brine (10 mL). Then the organic phase was dried over
MgSO4 and evaporated to leave the crude product, which was purified by
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Acknowledgments
Attempts to use 1i failed to give any more than 2%
We thank the NSF (CHE-1453891).
prenylation with any
this work.
of
the substrate classes studied in
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Keywords: prenylation • radical • sulfones • photocatalysis • beta
scission
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900356
European Journal of Organic Chemistry
COMMUNICATION
COMMUNICATION
Key Topic* Photocatalytic
Prenylation
A new bench stable reagent that is
and easily synthesized and handled
is investigated for its use in radical
prenylation of diverse organic
molecules. It has demonstrated high
functional group compatibility and
can be used as is with numerous
photocatalytic methods to give
prenylated products from aryl-
iodides, bromides, anilines, thiols
and alkyl halides.
Manjula D. Rathnayake, and Jimmie D.
Weaver*
Page No. – Page No.
A General Photocatalytic Route to
Prenylation
This article is protected by copyright. All rights reserved.