Iron-Nickel Dual-Catalysis: A New Engine for Olefin Functionalization and the Formation of Quaternary Centers

Article abstract of DOI:10.1021/jacs.8b05868

Alkene hydroarylation forms carbon-carbon bonds between two foundational building blocks of organic chemistry: olefins and aromatic rings. In the absence of electronic bias or directing groups, only the Friedel-Crafts reaction allows arenes to engage alkenes with Markovnikov selectivity to generate quaternary carbons. However, the intermediacy of carbocations precludes the use of electron-deficient arenes, including Lewis basic heterocycles. Here we report a highly Markovnikov-selective, dual-catalytic olefin hydroarylation that tolerates arenes and heteroarenes of any electronic character. Hydrogen atom transfer controls the formation of branched products and arene halogenation specifies attachment points on the aromatic ring. Mono-, di-, tri-, and tetra-substituted alkenes yield Markovnikov products including quaternary carbons within nonstrained rings.

Full text of DOI:10.1021/jacs.8b05868

Article
pubs.acs.org/JACS
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Iron−Nickel Dual-Catalysis: A New Engine for Olefin
Functionalization and the Formation of Quaternary Centers
́
́
Samantha A. Green, Suhelen Vasquez-Cespedes, and Ryan A. Shenvi*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S
* Supporting Information
ABSTRACT: Alkene hydroarylation forms carbon−carbon bonds
between two foundational building blocks of organic chemistry:
olefins and aromatic rings. In the absence of electronic bias or
directing groups, only the Friedel−Crafts reaction allows arenes to
engage alkenes with Markovnikov selectivity to generate quaternary
carbons. However, the intermediacy of carbocations precludes the
use of electron-deficient arenes, including Lewis basic heterocycles.
Here we report a highly Markovnikov-selective, dual-catalytic olefin
hydroarylation that tolerates arenes and heteroarenes of any
electronic character. Hydrogen atom transfer controls the formation
of branched products and arene halogenation specifies attachment
points on the aromatic ring. Mono-, di-, tri-, and tetra-substituted
alkenes yield Markovnikov products including quaternary carbons within nonstrained rings.
INTRODUCTION
■
Accelerating interest in high-fraction sp3 (Fsp3) scaffolds has
highlighted two major gaps in chemical methodology.1 First,
few metal-catalyzed cross-coupling reactions are competent to
generate quaternary ring carbons at a nonbridgehead position.2
The products are three-dimensional equivalents of biaryl
motifs and represent chemical space that is sparsely populated
by synthetic libraries and typically occupied by natural
products.3 Second, although nickel complexes have recently
Figure 1. Prior methods for the formation of arylated quaternary
centers using Ni-catalysis.
reigned supreme as alkyl cross-coupling catalysts, reaction
partners can suffer from a triple Achilles heel of low stability,
low synthetic efficiency, and low atom economy (high formula
weight loss).4 An ideal disconnection would obviate the need
for preinstallation of a functional group and open access to a
wide range of scaffolds or products inaccessible with other
cross-coupling methods. Here we report a cross-coupling
reaction with broad scope that forms quaternary carbons from
a simple, abundant feedstock: the olefin.
Pioneering nickel-catalyzed arylation methods have used
halides,5 organometaloids,6 carboxylic acids,7 and sulfones8 as
alkyl radical precursors9 (Figure 1). Olefins offer orthogonal
reactivity and the distinct advantage of relative inertness,
allowing them to be carried through multistep syntheses.
Furthermore, they are among the most prevalent functional
groups in natural products and commercially available building
blocks. Where Nature is not forthcoming, olefin synthesis or
metathesis can merge two building blocks, and the nascent
olefin itself can serve as the coupling point (Figure 2). Prior
methods for arylative quaternary centers synthesis first form a
functionalized tetrasubstituted carbon2a−c, in itself a challeng-
ing task; yet the functional group is next ablated during the
cross-coupling. A unique benefit of olefins is the ability to form
Figure 2. Current work combining HAT and Ni catalysis.
a quaternary center without starting from a preformed
tetrasubstituted carbon, circumventing the prefunctionalization
step and improving the atom economy of the transformation.
Received: June 6, 2018
© XXXX American Chemical Society
A
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Prior methods10 for the hydroarylation of olefins rely on the
innate reactivity of arenes. Friedel−Crafts alkylation, a
foundational reaction that adds a proton and arene across
unbiased α-olefins with high Markovnikov regioselectivity, is
generally limited to acid-stable, electron-rich aromatics,
whereas electron-deficient and Lewis-basic heteroarenes are
not tolerated.11 Similarly, the Minisci reaction is confined to
electron-deficient arenes and dependent on substrate bias for
its innate regiocontrol.12 In both methods, positional selectivity
is controlled by ring electronics and mixtures often result. In
contrast, cross-coupling takes advantage of regiospecific
reactivity of aryl halides, whereby a transition metal enables
absolute regiocontrol and the ability to use the full spectrum of
arene electronics.4
would require a complete reconstruction of the dual catalytic
cycles.
For the cycles to merge by unstabilized C-centered radical
interception, the rate of HAT should not exceed the rate
determining step of the nickel catalytic cycle. Whereas salen
ligands cause rapid alkene consumption,14 alternative ligands
decelerate the catalytic cycle.17 Mukaiyama’s pioneering work
in alkene radical hydrofunctionalization17,18 indicated that β-
diketonate ligands significantly changed reaction rates, but
subsequent interception of nickel catalytic cycles lacked
precedent. Co(acac)2 consumed the olefin within an hour
through hydrogenation and hydration, but yielded none of our
desired product (Table 1, entry 1). Mn(dpm)3 similarly
Here we demonstrate a Markovnikov-selective Fe/Ni dual-
catalytic alkene hydroarylation of mono-, di-, tri-, and
tetrasubstituted alkenes utilizing electronically diverse arenes
and heteroarenes. Furthermore, this cross-coupling embeds
quaternary carbons in oxetanes, pyrans, pyrrolidines, piper-
idines, and thianes in a single step from commercially available
materials. Application of this dual catalytic system allowed for
improved access to 3 drug leads and high-value building blocks
for biomedical application.
Table 1. Sec-alkyl Optimization
RESULTS AND DISCUSSION
■
Recently, we reported a proof-of-principle that olefins could
engage in highly branch-selective hydroarylation by merging
cobalt-catalyzed hydrogen atom transfer (HAT) and nickel
catalysis.13 This reaction was limited to monosubstituted
olefins, since substituted olefins (1a) yielded exclusively an
allylic isomer (1a′) (Figure 3). This limitation correlated with
a
0.1 mmol scale, yield determined by FID using dodecane as an
b
c
internal standard. 0.3 mmol scale, isolated yield. 3 equiv PhSiH3, 6
equiv i-PrOH (anhydrous) instead of Ph(i-PrO)SiH2.
yielded only traces of the desired product; however, there was
little consumption of either starting material (entry 2) and a
white heterogeneous slurry resulted. Iron, however, showed no
promiscuity with Ni and delivered the first evidence of
successful arylation, consistent with the initial cage escape
hypothesis.16c,18c,19
Investigation of olefin 3a and aryl iodide 4 using
16c,18c,19a,b
Fe(acac)3
(entry 3) yielded product 3b with low
catalyst turnover in the presence of metallic reductants.
Whereas Mukaiyama observed no difference between sterically
differentiated complexes of Fe,18c Baran and co-workers
correlated increased bulk with reaction efficiency, which they
proposed resulted from decreased catalyst decomposi-
tion.16c,19b Accordingly, bench stable catalyst, Fe(dpm)3,
proved ideal. A brief survey of nickel ligands identified 4,4-
di-tert-butylbipyridine (dtbbpy) as optimal, requiring only 2.5
mol% of Ni. The reaction was highly solvent dependent: 1,4-
dioxane led to high yields and outperformed similar ethereal
solvents (entry 4). Because of the limited solubility of Ni(II)
precatalysts in 1,4-dioxane, we observed that precomplexed
Figure 3. Comparison to our prior work with Co(salen) and our
current work with Fe(dpm)3: transmetalation vs free radical
mechanism.
the tendency for terminal alkenes to form stable organocobalt
complexes,14 implicating a transmetalation pathway. Tert-
alkylcobalt species have never been observed,15 and therefore
their participation in this dual catalysis was deemed unlikely, if
not mechanistically forbidden.
NiBr2(dtbbpy) allowed for more reproducible yields. Use of
17,20
Ph(i-PrO)SiH2
proved superior to a PhSiH3/i-PrOH21
Early examples of HAT catalysis observed similar collapse to
organometallics or rapidly reversible reactions that resulted in
inverse kinetic isotope effects.16a More recently, both
Carreira16b and Baran16c observed noninverse (normal) KIEs
in reactions where HAT has been implicated, which suggests
an irreversible atom transfer and cage escape. Successful
engagement of a tert-alkyl radical with a low valent nickel
might, therefore, occur with alternative catalyst systems, but
combination (entry 5) or PhSiH3 alone. Finally, the presence
of air was found to be critical for reactivity; no catalytic
turnover occurred in its absence (entry 6).16c
Optimal hydroarylation conditions transformed a variety of
feedstock olefins(5a−19a) to branched aromatics (5b−19b)
with exceptionally high regioselectivity.22 All olefins were
coupled in >20:1 regioselectivity, except where noted (Table
2). The reaction proved tolerant to many functional groups
B
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a
carbons and hindered attached ring motifs. Their reactivity
required interception of nickel with a tertiary carbon radical,
consistently a more difficult cross-coupling than sec-alkyl
counterparts.2,4 Consequently, the conditions described
above to couple secondary radicals for olefin 1a and aryl
iodide 2 yielded only arylation of the ethereal solvent (Table 3,
Table 2. Sec-alkyl Olefin Scope
Table 3. Formation of Quaternary Center Optimization
a
0.1 mmol scale, yield determined by FID using dodecane as an
b
c
internal standard. 0.3 mmol scale, isolated yield. Under an O2
balloon, the olefin was predominantly consumed to hydration via
Drago−Mukaiyama Hydration.
entry 1).2c An exhaustive ligand screen resulted in, at best, a
1:1 mixture of regioisomers, possibly due to background
reductive Heck reactivity of the nickel. Instead, the “ligandless”
nickel system developed by Fu provided superior results to
traditional conditions.25 NiBr2(diglyme) in a mixture of THF/
DMA produced the desired product 1b with high regiose-
lectivity (>20:1), although NMP (entry 2) eventually proved
superior and 1,2-DCE increased Fe(dpm)3 solubility. Even
though air was still critical for reactivity, the addition of MnO2
led to higher catalyst turnover (entry 3).
a
0.3 mmol scale, isolated yield, reaction time: 1248 h. 1 mL 1,4-
dioxane, N2 atmosphere for 2 h, then open to air. All substrates gave
>20:1 branched:linear ratio except where notated. NMR yield. 5
mol% NiBr2(dtbbpy), 800 μL 1,4-dioxane. 5 mol% NiBr2(dtbbpy).
b
c
d
The significance of this reaction was illustrated by the ease
with which quaternary carbons could be generated from simple
alkenes, many of which (20a−22a, 24a−30a, 32a−34a) were
in turn accessed via one-step olefination reactions from widely
available ketones (Table 4). We focused on cyclic coupling
partners, which led to high Fsp3 scaffolds that extend along
multiple vectors, yet are uncommon motifs in cross-coupling
reactions.3 Embedded in these unsaturated substrates are
Lewis basic functionality (20a−29a), carbamates (26a−29a),
esters (21a, 30a), silyl ethers (1a, 22a, 32a), phthalimides
(38a), carbocycles (30a−34a), and acid sensitive ring motifs
(22a, 26a−29a, 32a), all of which were tolerated and left the
high branch selectivity largely unaffected (>20:1 regioselectiv-
ity except where noted).
Unsaturated heterocyclesoxetanes (20a−22a), tetrahy-
drofurans (23a), pyrans (24a), thianes (25a), pyrrolidines
(26a−28a), and piperidines (29a)all productively coupled.
Of particular note, the compatibility of thianes with this
method resulted in the first reported synthesis for this type of
attached ring motif. Previously, placement of a quaternary
center at C-3 of a pyrrolidine has required the intermediacy of
either 2-pyrrolidinone or succinimide, resulting in a 3−4 step
sequence that includes strong hydride reductants.26 Fe/Ni
dual-catalysis streamlined access via 3-pyrrolidinone olefination
(to 26a−28a) and high-yielding arylation (26b−28b).
such as carbamates (7b), strained cyclobutanes (8b), redox-
active esters (RAEs) (16b), amides (17b), vinyl thioethers
(18b), vinyl boronates (19b), and nitriles (5b−19b). Ring size
did not affect reactivity and the arylated products (9b−12b)
were obtained in high yield. Although this olefin cross-coupling
can be viewed as complementary to decarboxylative or
dehalogenative cross-electrophile coupling in some cases, in
others there are no options: olefins 8a and 13a are unavailable
as the corresponding carboxylate and unprecedented as the
halide. Interestingly, [2.2.0]-bicyclohexene 8a, an intermediate
in Burns’ ladderane synthesis23 could be hydroarylated in 70%
yield where the strained cyclobutyl arene predominated (3:1)
over the ring-opened product. Commercially available
perfluorinated olefin 13a and other fluorine-containing
substrates (14a, 15a) were successfully arylated, offering
unique access to these perfluoroalkane and -arene derivatives
in moderate to high yields. The propensity of RAEs to cross-
couple with iodoarenes or reduce in the presence of silanes is
established,24 yet RAEs (16b) emerged unscathed from our
reaction conditions: a 95:5 selectivity for cross-coupling via the
olefin vs the ester demonstrated the orthogonality of this
coupling to prior work.
More challenging 1,1-disubstituted and trisubstituted olefins
probed the capacity of this method to generate quaternary
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a
Table 4. Formation of Quaternary Centers: Olefin Scope
a
0.3 mmol scale, isolated yield, reaction time 16 h. 1.5 mL 1,2-DCE and 1.5 mL NMP. N2 atmosphere for 1.5 h then open to air. All substrates gave
b
c
d
>20:1 branched:linear (B:L) ratio except where notated. 0.1 mmol scale, isolated yield. Run under an air balloon. 0.3 mmol scale using reaction
conditions from Table 2. Isolated yield. 0.1 mmol scale, Fe(dibm)3 (50 mol%), NiBr2(diglyme) (30 mol%), 2.5 h, NMR yield.
e
Olefination via ylides can generate a variety of pyrrolidines for
which the corresponding tertiary bromides or boronic acids are
unknown, making this method the only viable cross-coupling
of these scaffolds.
derivative 47a offered access to a previously unexplored vector
of phenyltropane derivatives, cocaine receptor ligands that
have been pursued for the treatment of drug dependency,
Parkinson’s disease, and depression.29 1,3-diaxial interactions
across the tropane ring significantly challenged the arylation
and the product was obtained in low yield. For an additional
list of less reactive substrates, see the SI.
In contrast to traditional Markovnikov-selective arylation
reactions (Friedel−Crafts, Minisci), this dual-catalytic method
was compatible with a range of arene electronics. Under the
sec-alkyl conditions, the highest yields were obtained with
electron-deficient arenes (Table 5A, 49, 50, 53−61); however,
4-iodoanisole (52) and an aryl boronate ester (51) were also
successfully coupled. Heterocycles (57−61) served as effective
coupling partners, although pyridines required substitution at
C2.
Electron-deficient, -neutral, and -rich arenes successfully
coupled in moderate to good yield, providing a library of C3-
quaternary oxetanes (Table 5B, 62−75). Iodopyridines (68,
69) and bromopyrimidines (70, 71) were successful coupling
partners independent of electronic character, as was electron-
rich 2-iodo-5-furan-dioxolane, which coupled in high yield with
the acid-labile acetal fully intact. Other electron-rich hetero-
cycles, such as benzothiophene proved to be more difficult, yet
still were compatible, crucial for structure−activity inter-
rogation campaigns. As proof-of-principle for the broader
generality of this reaction engine, we found that a vinyl
bromide could replace the haloarene and engage in cross-
Acylic olefins have a greater potential to engage in
background reductive Heck (anti-Markovnikov) reactivity
than their more-hindered cyclic counterparts.2d We never-
theless observed complete regioselectivity; no isomers were
detected (1b, 35b−37b, 39b). Allylic substitution was well
tolerated yielding branched diols (37b) and phthalimides
(38b) in moderate to high yield. The increased steric bulk on
tetrasubstituted olefins impedes accessibility by a metal
catalyst, making them less reactive than disubstituted olefins.27
Despite this, tetramethylethylene (39b) still served as a
compatible olefin, albeit in modest yield. Notably, arylation
of 1a could be performed on gram scale without a significant
deterioration in yield (52%).
Natural products and their derivatives (40a−46a) could also
serve as successful coupling partners (Figure 2). Allyl glycine
(40a) was arylated in high yield, opening the door to a range of
unnatural amino acids. The terpenes caryophyllene oxide
(42a) and β-pinene (43a) were arylated as their ring-opened
products; however, no evidence of epoxide opening was
observed for 42b, a demonstration of the mild, nonacidic
conditions.
Although this method was compatible with a broad array of
olefins, sterically hindered or unstable olefins were low yielding
and returned starting materials.28 Arylation of tropinone
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their breadth of commercial availability compared to
iodoarenes (ca. 78 000 (hetero)aryl bromides versus ca.
17 000 (hetero)aryl iodides).30
Table 5. Aryl Halide Scope*
During the assessment of the haloarene scope (Table 5), we
focused on arenes in which Friedel−Crafts or Minisci reactions
would be unsuccessful.11,12 The position of aryl halide
substitution perfectly translated to alkylated product, whereas
Friedel−Crafts alkylations (e.g., with anisole) generate
mixtures of o- and p- regioisomers. Friedel−Crafts reactions
are also unfavorable with electron-rich heterocycles such as
furan and benzothiophene due to catalyst-induced polymer-
ization or polyalkylation;31 dihydrofuran 6a has never been
reported in a Friedel−Crafts, presumably due to decom-
position. Minisci-type reaction with 2-chloropyridine would
yield a mixture of 58 and its C6 isomer. Furthermore, radical
addition into C3 of pyridine and C5 of a pyrimidine is
unfavorable, and products 57, 59, and 68−71 are not viable
using Minisci chemistry.
A survey of compounds containing arylated quaternary
centers identified the importance of oxetanes, a small ring that
alters scaffold lipophilicity and acts as a ketone bioisostere with
increased metabolic stability.32 Oxetanes may be prepared via
transition metal-catalyzed conjugate addition, requiring extra-
neous functional groups (cyano, ester, sulfonates) that are
often excised in the desired target.32 Alternatively, oxetanes can
be prepared through ring closing dehydration that requires 3 or
more steps and varies dramatically in yield (19−81%).33
A
Vertex patent detailing the use of small molecules for the
modulation of ATP-binding cassette transporters investigated
oxetane 80 (Figure 4),33c whose aryl bromide precursor (79)
has been employed in 9 patents33b−j and one discovery
article.33k Oxetane 79 is commercially available at $368/g34 or
can be prepared in 4 steps (8% overall yield) through
Mitsunobu dehydration of the corresponding diol (77).33c
Employment of our Fe/Ni dual catalysis allowed for the
cross-coupling of olefin 20a with 1,4-dibromobenzene,
resulting in a 3 step synthesis of 79 from the inexpensive
ketone 20′ in an overall yield of 27%. Furthermore, no
dialkylation of the dihaloarene was observed. This method
bypasses designer diol intermediates and cyclodehydration,
and obviates the need for potentially explosive diazo reagents,
providing a route that is more amenable to intermediate
diversification.
*
(A) Aryl halide scope for sec-alkyl conditions starting from olefin 6a.
a0.3 mmol scale, isolated yield, reaction time: 1248 h. 1 mL 1,4-
dioxane, N2 atmosphere for 2 h, then open to air. All substrates gave
>20:1 branched:linear ratio except where notated b2:1 ratio of
arylation at C3 vs C2. (B) Aryl halide scope for tert-alkyl conditions
using olefin 21a. 0.3 mmol scale, isolated yield, reaction time 16 h.
1.5 mL 1,2-DCE and 1.5 mL NMP. N2 atmosphere for 1.5 h then
open to air.
c
coupling with no subsequent hydrogenation of the styrene
product (75). Interestingly, bromoarenes coupled effectively
with tert-alkyl partners, but were significantly less efficient with
sec-alkyl reactants (62 vs Table 1, entry 7). The capacity of
bromoarenes to cross-couple offers a significant benefit due to
Figure 4. Application of Fe/Ni Dual catalysis to various biological intermediates containing oxetanes and piperidines.
E
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A 2014 Allergan patent documented a library of tert-alkyl
substituted arylthioethers for treatment of sphingosine-1
phosphate-related ocular diseases.35 The patent identifies 82
as an intermediate en route to 84; however, there is no
reported synthesis in the patent or elsewhere. Access may be
attained through esterification of acid 83, which is priced at
$3990/100 mg from the sole commercial vendor.36 Alter-
natively, olefin hydroarylation simplifies access to 82 through
oxetane olefination (Figure 4) and cross-coupling with 4-
fluoro-iodobenzene (51% yield).
JDTic and its analogs (87) are potent κ-opioid receptor
antagonists that contain arylated quaternary carbons embed-
ded in a piperidine.37 Prior access to 86 required a 5-step
sequence for the construction of the quaternary center.37
Olefin cross-coupling, however, retrosynthetically signals the
Wittig olefination of N-Boc 4-piperidone (85b′) followed by
arylation/deprotection to yield intermediate 86, resulting in an
883% improvement in overall yield (53% versus 6%) and a
40% reduction in step count compared to the prior route. As
the olefin coupling partner is prepared by a Wittig olefination
of N-Boc 4-piperidone, this sequence offers the ability to
expansively derivatize similar heterocyclic ketonesoxeta-
nones, piperidones, pyrrolidinones, pyranonesall of which
are inexpensive.
Mechanistic analysis of this hydroarylation is complicated by
the number of reaction components, but a thumbnail sketch is
suggested in Figure 5A. A metal hydride formed from the iron
precatalyst and silane has been proposed to undergo hydrogen
atom transfer (HAT) with alkenes to generate carbon-centered
radicals, consistent with the ring opening observed in 42b and
43b.16c,17 To further probe the intermediacy of a carbon-
centered radical, a competition between our hydroarylation
reaction and previously reported Fe-catalyzed Giese reaction
(which has been postulated to occur via a radical
mechanism)15 was conducted (Figure 5B). In the absence of
nickel, only Giese product was observed in a moderate yield. In
the presence of nickel, our desired product and Giese product
were formed in comparable yields. Additionally, in the
presence of TEMPO, the reaction was completely inhibited
and the TEMPO-adduct of the olefin starting material was
isolated (Figure 5c).
Figure 5. (A) Potential mechanism for sec- and tert- alkyl arylation.
(B) Competition experiment to probe for intermediacy of radical
reaction. (C) Radical trapping experiment with TEMPO.
Underscored by similarity in reaction conditions, coupling
with sec-alkyl fragments may overlap in mechanism with Weix’s
reductive electrophile coupling, i.e., capture of the alkyl radical
by an aryl−Ni(II) complex.5a However, a 50% reduction in
yield occurs when a bromoarene replaces an iodoarene under
sec-alkyl coupling conditions, whereas tert-alkyl coupling
conditions can use these haloarenes interchangeably with
only slight variation in yield. Such insensitivity by the tert-alkyl
conditions may indicate a reordering of steps, where an
electron-rich alkyl Ni(I) species engages the haloarene, as
suggested by Molander and Kozlowski.38 Even though both
tert- and sec-alkyl coupling reactions derive from identical
transition metal nuclei, differences in optimal ligand, co-
oxidant, solvent and rate indicate significant mechanistic
disparities between both dual-catalytic cycles.
transfer and interception of traditional nickel catalytic cycles;
two cycles that, to the best of our knowledge, have not been
combined previously. These dual catalytic cycles enable cross-
coupling of chemical feedstocks in a fundamentally new way,
connecting unsaturated building blocks and arenes to generate
privileged medicinal chemistry scaffolds and validated drug
leads. Hydroarylation of partly saturated rings resembles an sp3
equivalent of biaryl coupling, replacing one aromatic “hub”
with a high Fsp3 motif. Such cross-couplings hasten synthetic,
ideally combinatorial, approaches to natural product space and
answer the call to escape from flatland.1
ASSOCIATED CONTENT
■
S
* Supporting Information
CONCLUSION
■
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b05868.
Olefins may now be considered viable and broadly applicable
cross-coupling partners for branch-selective hydroarylation,
without the regioselectivity and chemoselectivity restrictions of
Minisci and Friedel−Crafts reactions. Arylations of polysub-
stituted alkenes are enabled by iron-catalyzed hydrogen atom
Detailed experimental procedures, compound character-
ization, and spectral data (PDF)
F
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́
Gui, J.; Qin, T.; Gutierrez, S.; Giacoboni, J.; Smith, M. W.; Holland,
P. L.; Baran, P. S. J. Am. Chem. Soc. 2017, 139, 2484.
(17) Crossley, S. W. M.; Obradors, C. L.; Martinez, R. M.; Shenvi, R.
A. Chem. Rev. 2016, 116, 8912.
AUTHOR INFORMATION
Corresponding Author
*rshenvi@scripps.edu
■
(18) (a) Mukaiyama, T.; Isayama, S.; Inoki, S.; Kato, K.; Yamada, T.;
Takai, T. Chem. Lett. 1989, 18, 449. (b) Inoki, S.; Kato, K.; Isayama,
S.; Mukaiyama, T. Chem. Lett. 1990, 19, 1869. (c) Kato, K.;
Mukaiyama, T. Chem. Lett. 1992, 21, 1137.
(19) (a) Lo, J. C.; Yabe, Y.; Baran, P. S. J. Am. Chem. Soc. 2014, 136,
1304. (b) Lo, J. C.; Gui, J.; Yabe, Y.; Pan, C. − M.; Baran, P. S. Nature
2014, 516, 343. (c) Leggans, E. K.; Barker, T. J.; Duncan, K. K.;
Boger, D. L. Org. Lett. 2012, 14, 1428.
ORCID
Ryan A. Shenvi: 0000-0001-8353-6449
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the following individuals for graciously providing the
following starting materials: N. Z. Burns (8a), J. C. Lo (29a),
R. M. Martinez (33a), and C. L. Obradors (36a). Generous
support was provided by the National Science Foundation
(GRFP to S.A.G.) and the National Institutes of Health (R35
GM122606).
(20) Obradors, C. L.; Martinez, R. M.; Shenvi, R. A. J. Am. Chem.
Soc. 2016, 138, 4962.
(21) PhSiH3/EtOH at 60 °C is commonly employed in Fe-HAT
reactions and has been proposed to form Ph(OEt)SiH2 under the
reaction conditions (ref 15c). In our reaction, this combination yields
the product in 31% yield. Instead, PhSiH3/i-PrOH could be used at
room temperature to provide 41% of the desired coupling product
(Table 1). A significant amount of protodehalogenation of the aryl
iodide was seen with PhSiH3/i-PrOH, which is likely the cause for the
deterioration in yield. For a further discussion on silanes, please see
the SI.
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