Radical Hydroarylation of Functionalized Olefins and Mechanistic Investigation of Photocatalytic Pyridyl Radical Reactions

Article abstract of DOI:10.1021/jacs.8b10238

We report the photoredox alkylation of halopyridines using functionalized alkene and alkyne building blocks. Selective single-electron reduction of the halogenated pyridines provides the corresponding heteroaryl radicals, which undergo anti-Markovnikov addition to the alkene substrates. The system is shown to be mild and tolerant of a variety of alkene and alkyne subtypes. A combination of computational and experimental studies support a mechanism involving proton-coupled electron transfer followed by medium-dependent alkene addition and rapid hydrogen atom transfer mediated by a polarity-reversal catalyst.

Full text of DOI:10.1021/jacs.8b10238

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Article
Radical Hydroarylation of Functionalized Olefins and Mechanistic
Investigation of Photocatalytic Pyridyl Radical Reactions
Ciaran P Seath, David B Vogt, Zihao Xu, Allyson J Boyington, and Nathan T. Jui
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b10238 • Publication Date (Web): 24 Oct 2018
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Radical Hydroarylation of Functionalized Olefins and Mechanistic
Investigation of Photocatalytic Pyridyl Radical Reactions
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Ciaran P. Seath, David B. Vogt, Zihao Xu, Allyson J. Boyington and Nathan T. Jui*
Department of Chemistry and Winship Cancer Institute, Emory University, Atlanta, Georgia 30322
Supporting Information Placeholder
ABSTRACT: We report the photoredox alkylation of halopyridines using functionalized alkene and alkyne building blocks. Selective
single-electron reduction of the halogenated pyridines provides the corresponding heteroaryl radicals, which undergo anti-Markovnikov
addition to the alkene substrates. The system is shown to be mild and tolerant of a variety of alkene and alkyne subtypes. A combination of
computational and experimental studies support a mechanism involving a proton-coupled electron transfer, followed by medium-dependent
alkene addition and rapid hydrogen atom transfer mediated by a polarity-reversal catalyst.
solely on the reaction solvent (Figure 1). For example, in
Introduction
aqueous DMSO, pyridyl radicals selectively engage
Functionalized pyridines are ubiquitous structural
electron-poor alkenes through a radical conjugate
elements in bioactive small molecules that span a wide
addition (RCA) mechanism.10a However, the use of 2,2,2-
range of applications.1 Accordingly, a number of
trifluoroethanol (TFE) solvent enables highly-selective
powerful synthetic strategies have been developed to
hydroarylation with simple, electron-neutral olefins.11
effectively access this heterocyclic family.2 In addition to
Importantly, this protocol delivers the desired pyridyl
classical methods for pyridine construction using acyclic
products with complete regiocontrol with respect to both
precursors,3 diversification of pyridine units using
the heterocyclic and olefinic subunits (anti–
transition-metal based cross-coupling4 and C–H
Markovnikov addition), as a complement to recent
functionalization5 strategies play key roles in modern
drug discovery, as do nucleophilic aromatic substitution
Figure 1. Catalytic intermolecular reactions of pyridyl
reactions.6 Due, in part, to the orthogonal reactivity of
radical intermediates
radical intermediates to acidic (i.e. X–H) or Lewis-basic
functional groups,7 Minisci radical addition to pyridines
remains a tremendously impactful retrosynthetic tool in
complex pyridine synthesis.8 However, the typical
requirement for strong oxidants coupled with pronounced
substrate-dependent regiocontrol limit the applicability of
this strategy in many cases.9
Among others, we have utilized an alternative approach
to complex (hetero)arene synthesis that operates through
single electron reduction of halogenated aryl units to give
rise to aryl radicals in a regiospecific manner.10-11 In
contrast to arenediazonium salts, this approach draws
from a vast collection of stable, often commercially
available substrates as radical precursors.12 While arene
activation in this manner requires the action of strong
reductants, the introduction of photoredox catalysis has
enabled the formation of highly reactive aryl radicals
under mild conditions.13 Our studies in this area have
centered on the intermolecular reaction of pyridyl radicals
with an array of olefin subtypes. Interestingly, we have
developed conditions that enforce divergent reactivity
profiles of these typically ambiphilic radicals, based
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radical hydroarylation systems by Herzon14 and Shenvi15 While the use of nitroxyl-based HAT catalysts NHPI17
and HOBt18 did not significantly alter reaction outcome,
employment of cyclohexanethiol (5 mol% loading)
resulted in significantly improved production of 2 (63%
yield).19 Here, a much cleaner reaction profile was
observed where pyridine production (via radical
hydrodehalogenation) was the major alternative pathway.
The beneficial effect of thiol catalyst was also observed
using the isomeric pyridyl radical precursor 3 as the
limiting reagent, thus delivering the desired adduct 4 in
65% yield. A range of thiol HAT catalysts were surveyed,
although no clear trend was observed between thiol
electronics and reaction efficiency. Control reactions
revealed that both photocatalyst and light were necessary
for effective conversion and, in line with our previous
results, acidic additives such as AcOH or NH4Cl
increased the yield. (see SI for details).
We then applied our optimized conditions to a variety
of functional alkenes (containing heteroatom-
substitution) that were absent from the current
hydroarylation literature as well as common polymer
feedstocks (Table 1).20 Halogenated alkenes were
particularly appealing, due to the broad utility of the
products for further functionalization. Vinyl bromide was
an effective coupling partner under the reaction
conditions, affording alkyl bromide 6 in 78% yield, with
no further reduction to the corresponding ethylpyridine.
Exposure of the crude mixture to silica gel resulted in
rapid, quantitative conversion to the corresponding vinyl
pyridine, a product typically accessed through Stille
cross-coupling with vinyl stannane.21 2-Chloropropene
was similarly effective, providing secondary alkyl
chloride 7 in 70% yield, again without undesired
reduction of the resulting chloroalkane and elimination
during purification was not observed in this case. The
reaction conditions were also tolerant of alkenyl
fluorides, producing alkyl fluoride 8 in good yield.
Robust methods for the synthesis of alkyl fluorides are
highly prized, particularly where SN2-type approaches are
competitive with elimination by-products.22
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(Markovnikov addition). Here, we describe the
development of a system—based on this mechanistic
blueprint—that allows for radical hydroarylation of a
diverse collection of olefinic substrate classes. Many of
these are shown for the first time as substrates under this
synthetic disconnection, giving rise to densely
functionalized alkylpyridines. In addition, we offer a
mechanistic evaluation of these complementary
pathways.
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Results and Discussion
At the outset of this investigation, we treated the
feedstock reagent vinyl acetate with 4-bromopyridine (1)
under conditions that we recently described for anti-
Markovnikov hydroarylation of aliphatic olefins.11 More
specifically, we employed the commercial iridium-based
photoredox catalyst [Ir(ppy)2dtbbpy]•PF6 (1 mol%) and
Hantzsch ester (HEH, 1.3 equiv) as a stoichiometric
reductant using TFE as the reaction solvent. We found
that irradiation of this mixture for 16 h with blue light
furnished the desired pyridylethylacetate 2 in low yield
(17%), and that the use of trifluoroethanol was crucial to
product formation. However, significant amounts of
oligomeric byproducts where pyridyl units coupled with
multiple vinyl acetate equivalents (pyridine:olefin ratios
of 1:2, 1:3, etc) were formed. We reasoned that increasing
the rate of hydrogen atom transfer (HAT) to the
nucleophilic α-oxy radical intermediate—resulting from
radical addition to vinyl acetate—would preclude further
olefin incorporation.16 As such, we surveyed a number of
electrophilic polarity reversal catalysts (Scheme 1).
Scheme
1.
Anti-Markovnikov
vinyl
acetate
hydroarylation using HAT catalystsa
In a complimentary process to the recently described
work of Aggarwal,23 alkenyl boronic esters also
underwent the reaction smoothly under the reaction
conditions. Homobenzylic alkyl boronic ester 9 was
effectively synthesized through this method (58%),
without any undesired protodeboronation or oxidation.
Alkenes substituted with main group elements were also
readily incorporated, despite relatively scarce examples
of the hydroarylation of these moieties and a dearth of
knowledge around the reactivity of the resulting α-
heteroatomic radicals.24 Alkenes substituted with Si, S,
and P were all tolerated, delivering 10, 11, and 12 in good
yields (41-68%). We envision this method to be
applicable towards the synthesis of novel bidentate P, N
or S, N ligands that are non-trivial to access through other
methods.25
aPerformed with Ir(ppy)2(dtbbpy)•PF6 (1 mol%), Hantzsch ester
(1.3 equiv), halopyridine (1 equiv), vinyl acetate (3 equiv) in 2,2,2-
trifluoroethanol (0.1 M) at 23 °C for 16 h, yields determined by 1H
NMR analysis. b4-bromopyridine hydrochloride used as substrate.
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Table 1. Anti-Markovnikov hydroarylation with pyridyl radicals: Scope of the functionalized olefina
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aIsolated yields. Performed with [Ir(ppy)2dtbbpy]•PF6 (1 mol%), Hantzsch ester (1.3 mmol), 2-bromo-6-methylpyridine (1 mmol), alkene (3
mmol) and CySH (5 mol%) in 2,2,2-trifluoroethanol (0.1 M) at 23 °C for 16 h. bReaction performed on 0.1 mmol scale. cReaction performed
on 0.25 mmol scale.
The polymer feedstocks vinyl acetate and ethyl vinyl
ether both combined with bromopyridine 5 in good yields
(57% and 62% yield, respectively) where the remainder
of the mass balance was hydrodehalogenated 5, and not
higher order oligomers. Alkyl enol ethers smoothly
participated in the reaction to give 14 and 16 both in 72%
isolated yield. In addition to heteroatom-substituted
alkenes, a number of alkynes were smoothly converted by
this system to provide the corresponding vinyl pyridines
17–19 as 1:1 mixtures of geometrical isomers (66%–83%
yield). In particular, these transformations were
unaffected by unprotected alcohols and primary alkyl
chlorides. This method provides an alternative to classical
Mizoroki-Heck chemistry, which is typically intolerant of
such sensitive functionality.26
We next explored the scope of the halopyridine
component using isopropenyl acetate as the olefinic
coupling partner (as indicated in Table 2). The conditions
were tolerant of alkyl substituents on the radical precursor
(20, 24–25), in addition to other electron donating groups
including alkoxy 23 and carbamate functions 27, with
only minor deviations in yield (42–57%). Alkyne-
containing pyridine 30 could also be synthesized under
the reaction conditions (26%), providing exclusive
chemoselectivity for alkene addition, leaving a useful
functional handle for further manipulation. Fused
heterocycles were likewise tolerated, pyrrolopyrimidine
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Table 2. Scope of the halogenated pyridinea
regioisomers, grey asterisk indicates connectivity of the minor
regioisomer.
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26 and azaindole 31 being formed in moderate yields (38–
55%). Moreover, 3,4-dibromopyridine underwent
chemoselective reaction at the more electron-poor 4-
position to provide alkylated bromopyridine 28 without
subsequent reductive dehalogenation (38%). Here,
radical anion fragmentation occurs selectivity through
cleavage of the weaker C–Br bond (at the 4-position), and
3-bromopyridine comprised the mass balance (formed via
hydrodebromination). To further illustrate the generality
of the process for all pyridine regioisomers, a
representative portion of the alkene scope were coupled
to 3- and 4-halopyridines (Table 2, 32–42). To further
demonstrate the scope of the alkene-coupling partner, the
anti-diabetic Pioglitazone27 was prepared in a short
synthetic sequence (Table 2, 43, 64%) that utilizes an aryl
vinyl ether as olefinic partner. The unique disconnection
afforded by this hydroarylation protocol allows for a
highly modular synthesis, which would be appealing for
early stage discovery programs.28
This photoredox process was amenable to gram-scale
synthesis without erosion of isolated yield (71 vs 76%).
Compound 20 was synthesized on a 10 mmol scale
without any specialized equipment using only 0.1 mol%
Ir catalyst (Figure 2). It has been well demonstrated that
scale up of photocatalytic processes can be limited by
light penetration;29 a common solution to this issue is the
use of continuous flow methods,30 which have facilitated
the large scale production of active pharmaceutical
ingredients.31 To demonstrate that our method is
amenable to such scale up procedures, we performed the
reaction in a custom-built flow reactor. Using a plug-flow
regime with a residence time of 20 minutes the alkylated
product was formed in 75% yield, corresponding to a
continuous flow production of 4.5 mmol/h. Further
optimization of the flow reactor setup is ongoing within
our laboratory.
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Figure 2. Enol acetate hydroarylation on gram scale
Mechanistic Investigation
Having established the utility of pyridyl radical
intermediates in hydroarylation processes of functional
olefins, we were interested in gaining a deeper
mechanistic understanding of this system. Of particular
interest were the following two elements: (i) reductive
aIsolated yields, reactions were conducted as in Table 1. b4-
Bromopyridine•HCl was used as starting material. cReaction
performed on 0.5 mmol scale. dFormed as a (1.7:1) mixture of olefin
e
f
isomers. Reaction performed on 0.25 mmol scale. Formed as a
g
(3:1) mixture of olefin isomers. Isolated as a 1.2:1 mixture of
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activation of halopyridine substrates is efficient even in
cases where SET would appear to be endergonic (as
Figure 3. Mechanistic Proposal: Solvent dictated nature of pyridyl radical, imparting divergent chemoselectivity
indicated by thermodynamic reduction potentials), and
(ii) pyridyl radical
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species display remarkable chemoselectivity for different
olefin types depending on the reaction solvent.
rise to hydroarylation product 47 as a single regioisomer
(72% yield). In contrast, activation of the same radical
precursor with the same catalyst but in aqueous DMSO as
solvent (25% (v/v) H2O/DMSO) resulted in exclusive
radical conjugate addition to the Michael acceptor,
affording 48 as a single regioisomer (56% yield).
Regiochemical analysis in these experiments was
conducted by GC and, in both cases, <1% of the alternate
regioisomer was observed. Here, picoline production was
the major alternative pathway. These results, completely
consistent with a previously reported set of competition
experiments, indicate that pyridyl radical addition to
olefins operates through different reactive intermediates,
as dictated by solvent.11 Further evaluation of these
scenarios is presented in the following sections.
Shown in Figure 3 is a proposed mechanistic scenario
for the dual catalytic hydroarylation process that is
introduced above. Specifically, reductive quenching of
the photoexcited iridium catalyst (*[Ir]III) would give rise
0
to the reducing [Ir]II species (E1/2 = –1.51 V vs. SCE).
This mechanism would likely be initiated by oxidation of
a sacrificial amount of HEH, as supported by Stern-
Volmer quenching studies in agreement with previous
studies by Knowles.32 Reduction of the bromopyridine
substrate
3
via proton-coupled electron transfer
(involving TFE as proton source), followed by rapid
mesolytic cleavage would provide protonated pyridine
radical 44 and an equivalent of bromide. Regioselective
radical addition to the terminal carbon of vinyl acetate
(like other nucleophilic olefins) would furnish radical
species 45 that would undergo polarity-matched HAT
from the thiol catalyst, concurrently producing the
hydroarylation product and thiyl species. Regeneration of
the HAT catalyst with HEH would deliver the
corresponding dihydropyridine radical (HEH•), a mild
reductant that would close the photoredox catalytic cycle
delivering the corresponding pyridinium (HP).
Key to this electrophilic radical reactivity is the
notorious hydrogen-bond donating (but poorly hydrogen-
bond accepting) solvent TFE.33 Indeed, when the diene
compound vinylcrotonate 46 was reacted in
trifluoroethanol, the pyridyl radical derived from
bromopyridine 5 engaged the nucleophilic alkene, giving
Proton-coupled electron transfer (PCET)
As indicated above, we propose that pyridyl radical
formation occurs primarily through
a
reductive
quenching pathway of the iridium photocatalyst.
However, analysis of the salient reduction potentials in
this system is complicated. Accurate measurement of the
reduction potential of halogenated pyridines remains a
challenge because fragmentation of the resulting radical
anions is rapid and pyridyl radicals readily undergo
reduction to the corresponding anions. However, the
reduction potential of 2-bromopyridine has been reported
to be between –1.8034 and –2.29 V35 vs. SCE, which is
significantly beyond the reducing ability of the Ir-catalyst
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0
(E1/2 = –1.51 V vs. SCE). Although protonation of the
halopyridine substrate would significantly decrease
reduction potential (E01/2 = –1.10 V), a cursory analysis of
pKa values of TFE (pKa = 12 in DMSO) and 2-
(where both lines converge) was calculated to be 13
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kcal/mol at a N–H bond length of 1.55 Å, a reasonable
energetic barrier for the proposed PCET event. An
endergonic electron transfer of this is type is feasible from
a ground state reductant based on the highly exergonic
heterolytic cleavage event that occurs immediately post
reduction (i.e. Curtin-Hammett principle). While this
Scheme 2. Proposed Mechanism of Reduction: PCET
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principle
could
account
for
a
decoupled
protonation/electron transfer sequence, we posit that a
concerted mechanism is operative.
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Chemoselective C–C bond-formation
Among the most interesting features of this pyridyl
radical-based strategy is the highly-pronounced
chemoselectivity that is imparted by the chosen reaction
solvent. Shown in Scheme 3 are two electronically
diverse olefins, along with the optimal reaction solvent
for their intermolecular coupling with pyridyl radicals.
Because high chemoselectivity for either electron-rich or
-poor olefins has been observed (vide supra), we
hypothesize that these complementary systems differ in
the identity of the pertinent pyridyl radical species. More
specifically, we propose that protonated, electrophilic
radical species (e.g. 44) are active in TFE, while proton
dissociation in polar, H-bond accepting solvents favours
neutral, nucleophilc aryl radicals (e.g. 51).39
As an excellent H-bond donor and a weak H-bond
acceptor, TFE has the ability to form strong H-bonding
networks that effectively stabilize anions or protonate
very weak bases.33 As a result, the use of TFE as reaction
solvent has led to divergent selectivity profiles in other
systems that are reminiscent of our findings.33 To
investigate the relevance of this solvent property in our
systems, we attempted to overturn observed pyridyl
radical chemoselectivity through a series of competition
experiments. As indicated in Scheme 3, treatment of 5
with both the electron-rich propenyl acetate and electron-
poor dimethylethylidene malonate (3 equiv each) under
standard conditions in TFE led to exclusive production of
20. However, addition of various amounts of water was
accompanied by increasingly significant formation of the
radical conjugate addition product 52. With 150 equiv
H2O, the two products were formed in nearly equal
amounts, presumably resulting from increased
dissociation of proton from the pyridyl radical species by
the H-bond acceptor H2O.40 Addition of acids to the same
mixtures in DMSO did not have an impact on
chemoselectivity, which is also consistent with the
suggestion that protons are highly dissociated from the
pyridyl radical species in polar (aqueous) solvent.
aDFT calculations performed at the uB3LYP level of theory
using 6-311+G (d,p) CPCM = DMSO.
bromopyridinium (pKa = 0.5 in DMSO) does not support
formation of a discrete pyridinium salt. Thus, we reason
that reductive activation of pyridine substrates in TFE
occurs through a proton-coupled electron transfer (PCET)
mechanism.36
The effect of pyridine protonation on the energetics of
electron transfer has been well studied, particularly within
the context of CO2 reduction.37 However, reports
detailing the exact impact of protonation on pyridine
reduction potential remain disparate. Because the
complications associated with halopyridine reduction
potential measurements (vide supra) are compounded by
the fact that TFE has a narrow usable electrochemical
window, we turned to DFT calculations to further
interrogate this step (Scheme 2A). Using the uB3LYP
level of theory, the reduction potential of 2-
bromopyridine was calculated to be –2.61 V vs. SCE,38 as
0
were the potentials of H-bonded substrate 49 (E1/2 = –
2.29 V vs. SCE; N–H–O bond length 2 Å) and fully
protonated substrate 50 (E1/20 –1.1 V vs. SCE; 1.1 Å bond
length). Indeed, the measured reduction potential of the
0
An alternative set of reactive intermediates that could
potentially account for the observed solvent-based
complementary selectivity of this method could arise
from differential rates of radical anion fragmentation,
depending on solvent. In this scenario, an α-bromo, α-
amino radical (resulting directly from PCET) would
undergo C–C bond-formation prior to bromide
[Ir]II catalytic species (E1/2 = –1.51 V. vs. SCE) lies
squarely between these values.13 As shown in Scheme 2B,
protonation of the neutral species with TFE is endergonic
by 27 kcal/mol but is thermo-neutral after reduction.
Similarly, reduction of bromopyridine at 2 Å is
endergonic by 18.1 kcal/mol but exergonic by 9.4
kcal/mol after protonation. The lowest energetic barrier
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dissociation, presumably as an intermediate in radical
conjugate addition (i.e. aq. DMSO). Indeed, Weaver has
Scheme 3. Proposal for Observed Solvent-Dependent Chemoselectivity of Pyridyl Radicals
proposed that rate of radical anion fragmentation is
responsible for altered selectivity in reductive photoredox
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aPerformed with Ir(ppy)2(dtbbpy)•PF6 (1 mol%), Hantzsch ester (1.3 equiv), 2-bromo-6-methylpyridine (1 equiv),
dimethylalkylidine malonate (3 equiv), isopropenyl acetate (3 equiv) in 2,2,2-trifluoroethanol (0.1 M) at 23 °C for 16 h.
processes of 2-haloazoles (where differential reactivity
resulted from different halogens).41 Along the same lines,
it has been shown that the rate of 2-halopyridine (2-X-
pyr) radical anion fragmentation decreases significantly
in the series X = I > Br > Cl >>F.35a While the
fluoropyridine-based radical anion persists long enough
to observe reversible redox by CV, bromopyridine radical
anion fragmentation is exceedingly rapid, as measured by
Savéant and others.42 Solvent polarity has also been
shown to alter fragmentation rate to a lesser extent, but
unimolecular fragmentation rates remain significantly
higher than the relevant bimolecular addition rates for
aryl radical addition to olefins.43
by Buchwald, a similar α-oxy radical, generated from
Meerwein addition to an enol acetate, is efficiently
Figure 4. Mechanisms of Radical Termination
Radical termination after alkene addition
During our investigations into addition of pyridyl
radicals to olefins, we have observed different radical
termination mechanisms that are highly dependent on the
employed alkene subtype. While different reaction modes
often lead to identical outcomes (e.g. Giese termination
via HAT44 or a reduction/enolate protonation sequence45),
they could be expected to have discrete implications for
photocatalyst turnover or, more importantly, the
structural nature of the product. Using combinations of
deuterium-labelled HEH and solvents, we have shown
that dehydroalanine-derived 53 undergoes essentially
exclusive reduction and enolate protonation to give the
desired amino acid products.10b In contrast, radicals 54
and 55, receive α-protons or deuterons primarily from
HEH, indicating HAT as the primary termination events
(>80% incorporation of the label from HEH, rather than
solvent).10a,11 When coupling to more nucleophilic vinyl
heteroatoms is considered, both oxidation and HAT
processes of the intermediate radical (e.g. 56, derived
from vinyl acetate) are relevant as they would likely be
product determining. For example, in a method described
oxidized by ferrocinium to provide an aldehyde product.46
However, the conditions that are introduced here appear
to enforce termination via HAT, even though single
electron oxidation of 56 would be facile (E1/2 = 0.21 V
vs. SCE).
0
Evidence for product formation via terminal HAT is
offered in Figure 4, where both potentially competing
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pathways involving radical intermediate 57 are
Page 8 of 11
30 W blue LED array
focused single LED
OAc
Me
illustrated. Work by Moeller,47 and Horner and
Newcomb48 indicates that oxidation to the corresponding
cation would be followed by exceedingly rapid
cyclization to dioxolane 58. However, hydroarylation
product 19 was delivered in 72% yield, without any
indication of 58 by NMR or GCMS analysis. Further,
isotopic labelling experiments involving deuterated HEH
and/or solvent were consistent with this proposal (see SI
for details). The discrepancy between these results and
the system reported by Buchwald46 arises from effective
concentration of the putative oxidant; 10 mol% Cp2Fe+
(generated through highly exergonic reduction of
arenediazonium salts) vs minute concentration of
photooxidant.
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+
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N
Br
standard conditions
Me
Me
N
OAc
0
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Time (min)
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low quantum yield
without Ir catalyst: 10% conversion (16 h)
with 1 mol% [Ir]: 100% conversion (10 min)
� = 0.31
major reaction pathway: proposed photoredox mechanism
Alternative redox pathways
h vs. 72% yield after 10 min, see supporting information
for details). We suggest that the catalyst–free reaction
arises from the HEH excited state reducing the
halopyridine.51 Charge transfer complexes between HEH
and bromopyridine were not observed in either the ground
state via 1H NMR analysis or the excited state via UV/Vis
spectroscopy (See SI for further details). Moreover,
alteration of the catalyst properties had a noticeable
impact on overall reaction efficiency (see SI for full
details).50 Taken in aggregate, these findings implicate
the outlined catalytic manifold as the major contributor to
product formation in this system.50
Although the mechanistic analyses that we present are
consistent with experimental data, the observed results
likely arise from an ensemble of related mechanistic
pathways. For example, the proposed role of the
stroichiometric reductant (HEH) is highly consistent with
previous reports, facilitating product formation through
sequential HAT and SET steps. However, the order of
these events is experimentally ambiguous, as HEH
consumption via the same steps in reverse order (SET
then HAT) would reasonably lead to the same
experimental results.
To further evaluate the validity of the proposed
photoredox pathway, we conducted a series of temporal
studies. Under these conditions, propenyl acetate
hydroarylation (to give 20) exhibited zero order kinetics
(with respect to starting materials and catalyst) in a
manner that was highly dependent on the light source,49
as shown in Figure 5. In conjunction with the finding that
the benchmark reaction reached completion within 10
min, these results led us to question the degree of radical
chain character of this processes.50 However, the
relatively low quantum yield (Φ = 0.31) of this process
indicates that photosensitized processes are dominant.
Control experiments showed that formation of 20 can
occur in the absence of the iridium catalyst, but the
reaction rate is considerably slower (~10% yield after 16
Conclusions
In summary, a general and efficient method for the
hydroarylation of electron rich olefins has been
developed. Addition of a thiol polarity-reversal catalyst
promotes a rapid intermolecular HAT step that prevents
side reactions such as olefin polymerization and single
electron oxidation to provide the anti-Markovnikov
products exclusively. Investigation of the reaction
mechanism revealed a solvent dependent mechanistic
divergence. Use of the highly coordinating solvent TFE,
leads to a protonated, electrophilic pyridyl radical which
is polarity matched for alkene addition with electron rich
olefins. Use of a H-bond accepting medium such as
DMSO(aq) leads to a dissociated, neutral pyridyl radical
that is polarity matched for electron-poor olefins. We
believe these data will provide a greater rationale for
chemistries utilizing heteroaryl radicals and expand the
scope and understanding of related radical-olefin
couplings.
Figure 5. Temporal Evaluation of Reaction Profile
ASSOCIATED CONTENT
Supporting Information.
Experimental procedures and spectral data are available free
of charge on the ACS Publications website.
AUTHOR INFORMATION
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(9) (a) Duncton, M. A. J. Minisci reactions: Versatile CH-
Corresponding Author
functionalizations for medicinal chemists. Med. Chem. Commun. 2011,
2, 1135–1161. (b) Minisci, F.; Citterio, A.; Giordano, C. Electron-
transfer processes: peroxydisulfate, a useful and versatile reagent in
organic chemistry. Acc. Chem. Res. 1983, 16, 27–32.
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njui@emory.edu
Notes
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7
8
9
The authors declare no competing financial interests.
(10) (a) Aycock, R. A.; Wang, H.; Jui, N. T. A mild catalytic system
for radical conjugate addition of nitrogen heterocycles. Chem. Sci.
2017, 8, 3121–3125. (b) Aycock, R. A.; Vogt, D. B.; Jui, N. T. A
practical and scalable system for heteroaryl amino acid synthesis.
Chem. Sci. 2017, 8, 7998–8003.
(11) Boyington, A. J.; Riu, M.-L.; Jui, N. T. Anti-Markovnikov
Hydroarylation of Unactivated Olefins via Pyridyl Radical
Intermediates. J. Am. Chem. Soc. 2017, 139, 6582–6585.
ACKNOWLEDGMENT
This project was supported by funds from the National
Institutes of Health (R01 GM129495), and NMR spectra
were obtained under the support of the National Science
Foundation (CHE-1531620). The authors would like to
thank Savannah Post (Emory) for preliminary experiments,
Professors R. Brian Dyer and Tianquan Lian (Emory) for
generous access to instrumentation, and Professor Zachary
Wickens (University of Wisconsin) for helpful discussions.
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(12) Heinrich, M. R. Intermolecular Olefin Functionalisation
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redox catalyst, light
H
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N
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HetAr– Br
olefin
X = O, S, P, B, Br, Cl, F
hydroarylation
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