O-Heterocycle Synthesis via Intramolecular C-H Alkoxylation Catalyzed by Iron Acetylacetonate

Article abstract of DOI:10.1021/jacs.1c02074

Intramolecular alkoxylation of C-H bonds can rapidly introduce structural and functional group complexities into seemingly simple or inert precursors. The transformation is particularly important due to the ubiquitous presence of tetrahydrofuran (THF) motifs as fundamental building blocks in a wide range of pharmaceuticals, agrochemicals, and natural products. Despite the various synthetic methodologies known for generating functionalized THFs, most show limited functional group tolerance and lack demonstration for the preparation of spiro or fused bi- and tricyclic ether units prevalent in molecules for pharmacological purposes. Herein we report an intramolecular C-H alkoxylation to furnish oxacycles from easily prepared α-diazo-β-ketoesters using commercially available iron acetylacetonate (Fe(acac)2) as a catalyst. The reaction is proposed to proceed through the formation of a vinylic carboradical arising from N2 extrusion, which mediates a proximal H-atom abstraction followed by a rapid C-O bond forming radical recombination step. The radical mechanism is probed using an isotopic labeling study (vinyl C-D incorporation), ring opening of a radical clock substrate, and Hammett analysis and is further corroborated by density functional theory (DFT) calculations. Heightened reactivity is observed for electron-rich C-H bonds (tertiary, ethereal), while greater catalyst loadings or elevated reaction temperatures are required to fully convert substrates with benzylic, secondary, and primary C-H bonds. The transformation is highly functional group tolerant and operates under mild reaction conditions to provide rapid access to complex structures such as spiro and fused bi-/tricyclic O-heterocycles from readily available precursors.

Full text of DOI:10.1021/jacs.1c02074

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Article
O‑Heterocycle Synthesis via Intramolecular C−H Alkoxylation
Catalyzed by Iron Acetylacetonate
Yuyang Dong, Alexandra T. Wrobel, Gerard J. Porter, Jessica J. Kim, Jake Z. Essman, Shao-Liang Zheng,
and Theodore A. Betley*
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ABSTRACT: Intramolecular alkoxylation of C−H bonds can rapidly introduce structural and functional group complexities into
seemingly simple or inert precursors. The transformation is particularly important due to the ubiquitous presence of tetrahydrofuran
(THF) motifs as fundamental building blocks in a wide range of pharmaceuticals, agrochemicals, and natural products. Despite the
various synthetic methodologies known for generating functionalized THFs, most show limited functional group tolerance and lack
demonstration for the preparation of spiro or fused bi- and tricyclic ether units prevalent in molecules for pharmacological purposes.
Herein we report an intramolecular C−H alkoxylation to furnish oxacycles from easily prepared α-diazo-β-ketoesters using
commercially available iron acetylacetonate (Fe(acac)2) as a catalyst. The reaction is proposed to proceed through the formation of a
vinylic carboradical arising from N2 extrusion, which mediates a proximal H−atom abstraction followed by a rapid C−O bond
forming radical recombination step. The radical mechanism is probed using an isotopic labeling study (vinyl C−D incorporation),
ring opening of a radical clock substrate, and Hammett analysis and is further corroborated by density functional theory (DFT)
calculations. Heightened reactivity is observed for electron-rich C−H bonds (tertiary, ethereal), while greater catalyst loadings or
elevated reaction temperatures are required to fully convert substrates with benzylic, secondary, and primary C−H bonds. The
transformation is highly functional group tolerant and operates under mild reaction conditions to provide rapid access to complex
structures such as spiro and fused bi-/tricyclic O-heterocycles from readily available precursors.
limited functional group tolerance and are ill-suited for
preparing spiro or fused bi- and tricyclic structural units
prevalent in most of the applications listed above.1,6 Recently,
Trost and co-workers published their Pd-catalyzed method to
drive a [3 + 2] cycloaddition employing an oxyallyl cation to
prepare a range of bi- and tricyclic fused structures (Figure
1a).16 However, the catalysis is limited by the necessity of a
conjugated diene, while it is also less effective toward the
1. INTRODUCTION
Tetrahydrofuran (THF) structures, among other oxygen-
containing heterocycles, are fundamental structural units
often encountered in a wide range of pharmaceuticals,
agrochemicals, and natural products.1−8 Indeed, THF-contain-
ing drugs such as darunavir are among the top 200
pharmaceuticals by retail sales in 2019,9 while thousands of
marine products such as macrolides with oxacyclic building
blocks are isolated each year, providing candidates for future
pharmacological developments.1 The high cation affinity and
potency as hydrogen bond acceptors make the cyclic ethers
potential candidates to alter membrane ion permeability to
function as antibiotics1 and to replace peptidic features of
protease inhibitors for antiviral HIV treatments, respectively.5
Although a variety of methodologies have been developed to
synthesize functionalized THF motifs,7,10−16 most show
Received: February 22, 2021
Published: May 5, 2021
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Figure 1. Synthesis of substituted tetrahydrofuran skeletons: (a) Pd-catalyzed [2 + 3] cycloaddition reported by Trost;16 (b) Fe-catalyzed C−H
bond alkoxylation in this report to generate polycyclic, substituted tetrahydrofuran cores; (c) natural products featuring polycyclic tetrahydrofuran
cores used as antimicrobial, anticancer, and antibiotic agents.
formation of spiro constructs. Direct C−H functionalization
provides an alternative route to rapidly introduce different
structural and functional group complexities into seemingly
simple or inert precursors. Thus, we were interested in the
direct alkoxylation of ubiquitous C−H bonds to synthesize
cyclic ethers.
likewise mediated by metalloradicals. In this report, we
describe the generation of a highly reactive vinylic radical via
dinitrogen extrusion from α-diazo-β-ketoester substrates by a
simple iron catalyst. The generated vinyl radical serves to
homolytically cleave intramolecular C−H bonds followed by
radical recombination with an open-shell iron alkoxide to
furnish tetrahydrofuran skeletons (Figure 1b,c).
Transition metal-mediated C−H bond functionalization has
greatly expanded our capabilities for the elaboration of simple
organic feedstocks. Traditional methods feature transition
metal stabilization of reactive intermediates which are, in turn,
inserted into C−H bonds.17−21 For example, Rh2-mediated
carbene insertion can be performed with exquisite regio- and
enantioselectivity wherein an electrophilic carbene unit inserts
into substrate E−H bonds in a concerted fashion.20−23 For
transition metal-stabilized reactive intermediates featuring
open-shell configurations, the multiply bonded functionality
can exhibit radicaloid character and alter the functionalization
trajectory. Indeed, hydroxylation in cytochrome P45024 occurs
via H−atom abstraction (HAA) by the ferryl unit followed by
radical recombination (RR) between the FeIV hydroxyl and
carboradical generated. The oxo-unit participation in the
electroactive orbitals allows the radical chemistry to proceed.
New abiological methodologies have emerged following this
precedent, wherein carbene and nitrene C−H insertion
catalyzed by a metal porphyrin or analogues25−34 and C−H
amination via dipyrrin-supported metal nitrenoids35−48 are
2. RESULTS AND DISCUSSION
2.1. O-Heterocycle Formation by Fe Catalyst. The
reaction of α-diazo-β-ketoesters with late transition metals
typically furnishes the carbocyclic product following carbene
generation.17,21,22,49,50 To study the effect of metalloradical
generation on the reactivity, we examined the reaction of
methyl 2-diazo-3-oxo-6-phenylhexanoate (1) with various iron
salts or complexes (Table S1) with accessible FeIII/FeII redox
couples for radical generation.51 We observed vigorous
effervescence at room temperature using a catalytic amount
(30 mol %) of inexpensive, commercially available Fe(acac)2
with 1, upon which the solution changed from dark to bright
orange. In contrast to the carbocyclic product observed with
Rh2 catalysis,49,52 the 1H NMR spectrum of the reaction
mixture showed full conversion of 1 into methyl (Z)-2-(5-
phenyldihydro-2(3H)-furanylidene)acetate (2; Figures 1b and
2a) after 3 h. The product 2 was further confirmed by
multinuclear NMR spectroscopy and single-crystal X-ray
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Figure 2. Mechanistic probes for the catalytic synthesis of substituted tetrahydrofurans: (a) establishing C−H bond strength accessible by vinylic
radical intermediate; (b) tracing the H−atom abstraction pathway via substrate isotopic labeling; (c) observing radical ring opening of the
cyclopropyl substituent; and (d) short-circuiting C−O bond formation via radical recombination with sacrificial 1,4-cyclohexadiene (CHD).
Different reaction conditions for full substrate conversion and corresponding NMR yields are given with alphabetical labels. Isolated product yields
using the higher-yielding conditions are given in italics at the end.
crystallography (see p 239 in the Supporting Information).
The E isomer was undetected in the 1H NMR spectrum of the
product mixture, suggesting a high level of stereoselectivity for
the reaction. We observed exclusive formation of the
substituted 2-alkylidene-dihydrofuran generated via cleavage
of the benzylic C−H bond along with the formation of new
benzylic C−O and vinyl C−H bonds. Similar C−O coupled
products both inter- and intramolecularly were previously
observed in precious metal-mediated carbene C−H insertion
catalysis.53−56 We hypothesized that the exclusive formation of
the Z isomer was due to chelation of both the ketone and ester
carbonyl O atoms to the Fe center, dictating the olefin
conformation. A similar β-ketoester substrate binding mode
was invoked in six-coordinate iron complexes in enantiose-
lective fluorination and hydroxylation reactions,57 while a
chelated carboradical has recently been proposed to account
for the Z selectivity in cobalt-mediated olefin isomerization
catalysis.58 Furthermore, theoretical calculations59 comparing
different substrate binding modes revealed the lowest barrier
toward N2 expulsion with the proposed coordination geometry
(see p 463 in the Supporting Information). To test for the
possibility that the transformation is carried out by colloidal
iron formed in situ, the catalysis was monitored by dynamic
light scattering spectroscopy (DLS), and no absorption was
observed for particle sizes between 0.1 and 104 nm.
to the dirhodium carbene catalysis,21−23,49,50,52 tertiary C−H
bonds (3) are the most reactive, achieving complete
conversion over 3 h at 25 °C with 5 mol % of Fe(acac)2
(70%). Despite the longer reaction time (3−12 h) and higher
catalyst loadings (30 mol %) required to fully consume
benzylic (2) and secondary substrates (4) at room temper-
ature, rapid reactions (20 min) were observed in both cases at
60 °C with 10 mol % Fe(acac)2, leading to overall comparable
results. Substrates featuring primary C−H bonds (5), on the
other hand, showed minimal conversion at 25 °C. An increased
reaction temperature (100 °C) with increased catalyst loading
(30 mol %), however, enabled the reaction to proceed. The
catalysis is stereospecific in every case. as indicated by crude
NMR spectra of the product mixture (see the Supporting
Information), while olefin isomerization often takes place
during product purification due to the relative thermodynamic
instability of the Z isomer in polar environments.61 Despite the
preference for tertiary C−H bonds observed here being similar
to the dirhodium-catalyzed carbene insertion chemoselectiv-
ity,22,49,50,52 the origins of the selectivity are distinctly different.
The dirhodium carbene insertion is proposed to arise from the
highly electrophilic dirhodium carbene intermediates, activat-
ing electron-rich C−H bonds in a concerted fashion.22,49,50,52
Although a similar concerted reaction trajectory is unlikely in
the present alkoxylation reaction, the ease with which tertiary
C−H bonds are broken suggests partial oxidation of the C−H
bond during the activation step.
To explore the range of C−H bond strengths activatable for
this cyclization reaction, we prepared a series of substrates
featuring different types of C−H bonds (2−5, Figure 2a). Akin
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2.2. Probing the Alkoxylation Mechanism. As multiple
bonds are cleaved (C−N2, C−H) and formed (vinyl C−H, C−
O) during the cyclization of 1, we sought to identify the
reactive intermediate that initiates the transformation. To
probe the reaction initiation, isotopically labeled 1′D2 was
prepared and subjected to the standard catalytic conditions to
trace the destination of the benzylic D atom initially abstracted
(Figure 2b). The corresponding product 2′D2 confirmed the
incorporation of deuterium atoms in both the vinylic and
benzylic positions (Figure S3), suggesting that the vinyl carbon
is indeed responsible for the initial C−H cleavage event.
Furthermore, incorporation of a cyclopropyl radical clock into
substrate 6 (Figure 2c) and subjecting it to catalytic conditions
led to ring opening of the cyclopropyl unit (Figure S7).62 As a
result, we propose two potential mechanisms for the initial C−
H activation while accounting for the heightened reactivity
toward electron-rich tertiary C−H bonds: (1) a radical type
H−atom abstraction with predominantly electron transfer
(ET) character during the transition state63−65 or (2) C−H
bond heterolysis via a hydride abstraction pathway.66
Following the proposed chelation binding mode of the
substrate to Fe(acac)2,57 a radical mechanism (mechanism 1)
is initiated by single-electron transfer from iron to the substrate
carbonyl to arrive at an open-shell, Fe(acac)3-like intermediate.
In the alternative pathway (mechanism 2), the catalyst remains
in a ferrous state and merely stabilizes the vinyl carbocation via
substrate chelation. The in situ generated vinyl carbocation
then undergoes a hydride abstraction mechanism (see Figure
S1 for the proposed hydride transfer pathway). Since the
transition metal center is not involved in any redox event in a
hydride transfer mechanism, we examined the catalytic efficacy
of Zn(acac)2 to test this proposal where Zn is a redox-inactive,
similarly sized71 Lewis acid surrogate for Fe(acac)2 for the
transformation of 1 to 2. We observed no cyclized product
after prolonged (12 h) heating (100 °C) with stoichiometric
Zn(acac)2 (Table S1), arguing against this proposed hydride
transfer mechanism. An examination of the kinetic profiles for
a range of para-substituted benzylic substrates permitted a
Hammett analysis (16−19), which shows a small, negative
slope (ρ = −0.30, Figure 3) in contrast to the large correlation
expected (i.e., ρ ≈ −2 for benzylic SN1 substitution)60,72,73 for
the formation of a benzylic carbocation in the hydride
abstraction pathway. To shed light on the reactive
intermediate, we performed structural optimization in silico,
and unpaired electron distribution of the proposed active
species were derived using density functional theoretical
calculations.59 The resulting spin-density plot (Figure 4)
indeed showed a significant amount of spin delocalized onto
the vinyl carbon rather than fully residing on the Fe center,
further supporting the single-electron oxidation of iron
following dinitrogen extrusion, priming the vinyl radical for a
subsequent radical-mediated H−atom abstraction.
Figure 3. Hammett analysis using an excess amount of substrate to
generate products 16−19 in competition with an equimolar amount
of proteo substrate 2 (ρ = −0.30).60
Figure 4. Proposed catalytic mechanism for the synthesis of
substituted tetrahydrofurans.
1
compound as detected by H NMR spectroscopy. We note
that a significant amount of product 3 (∼10%) was already
found at the first time point taken (1 s), consistent with a high
reaction rate at the beginning of the transformation. The
turnover frequency dropped significantly upon lowering the
amount of Fe(acac)2 with almost no further conversion (<5%)
after its disappearance, suggesting that Fe(acac)2 was directly
involved in the cyclization. Unfortunately, due to facile catalyst
deactivation, a detailed rate law cannot be derived.
We propose the ferric species results from (1) the
disproportionation of Fe(acac)2 with concomitant production
of a reduced Fe species or (2) the coordination of enolates (9,
Figure 2d) generated from reduced α-diazo-β-ketoesters via
To further elucidate the mechanism enabling this trans-
formation, the concentration profiles of substrate, product, and
1
identifiable Fe-containing species were monitored using H
NMR spectroscopy over the course of the reaction. The
catalytic formation of 3 in C6D6 was examined at room
temperature with 5 mol % of Fe(acac)2 (Figure S6). Two Fe-
containing species were identified in the paramagnetic region
of the 1H NMR spectrum during the reaction: Fe(acac)2 and a
ferric species that has features similar to those of Fe(acac)3.
More than 90% of substrate conversion to 3 took place within
the first 30 min, with the conversion of Fe(acac)2 into a ferric
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HAT from adventitious H−atom sources. The lack of
observable colloidal particles by DLS spectroscopy argues
against the generation of insoluble reduced iron species. To
provide evidence on the second proposed pathway, the
transformation from 8 to 3 was carried out with 30 mol %
of Fe(acac)2 in both the absence and presence of 1,4-
cyclohexadiene (CHD) (Figure 2d). Vigorous effervescence
was observed in both reactions, and the 1H NMR spectra taken
after the bubbling ceased showed partial and full conversion of
Fe(acac)2 into the ferric species in the absence and presence of
CHD, respectively. Following an acidic workup, near-
quantitative conversion of 8 to 3 was observed in the absence
of CHD, while a significant quantity of 9 (23%) diminished the
amount of product 3 (18%), and the remaining starting
material 8 (59%) was found with the exogenous H−atom
source added (Figure S4). The result supports our second
hypothesis that catalyst deactivation is caused by HAT from
adventitious H−atom sources.
On the basis of the foregoing results, we propose the
following catalytic cycle shown in Figure 4. Substrate binding
to Fe(acac)2 occurs through the ketoester functionalities.
Electron transfer from the Fe center reduces the keto
functionality and triggers dinitrogen loss, resulting in a stable,
high-spin S = 5/2 Fe(III) center and a vinyl carboradical. The
vinyl carboradical undergoes 1,5-HAT with predominant ET
character during the transition state. The alkyl carboradical
generated in situ from the HAT step combines with the keto
oxygen bound to iron to furnish the (Z)-2-alkylidene
dihydrofuran. Theoretical calculations59 simulating the reac-
tion of substrates with benzylic (2), tertiary (3), and secondary
C−H bonds (4) revealed a rate-determining N2 loss step
(RDS) with an activation barrier of ca. 21.4 kcal/mol (Figure
6), consistent with the reaction taking place at room
temperature. The subsequent HAA step is computed to be
the most favorable for tertiary C−H activation (2.9 kcal/mol
for 3 vs 6.0 and 6.8 kcal/mol for 2 and 4, respectively),
followed by barrierless radical recombination processes35 to
yield the final (Z)-2-alkylidene dihydrofuran product. Despite
the similar calculated rate-determining N2 loss barriers for 2−4
(Figure 6), we propose that the differences in reactivities
observed experimentally were due to the post-RDS catalyst
deactivation in competition with the productive HAA barrier.
For substrates that are harder to activate, a relatively higher
rate for catalyst deactivation is expected, leading to the overall
lower reactivity observed, while for substrates with more
reactive C−H bonds, the HAA step is more kinetically
competitive against the catalyst deactivation, resulting in more
rapid catalytic turnovers and lower catalyst loadings.
2.3. Examining the Alkoxylation Selectivity. Remark-
ably, only products corresponding to activation of the ketone
substituents from the α-diazo-β-ketoesters were observed.
Substrates (Figure 5a, 10 and 11) featuring benzylic C−H
bonds on the ester group (phenethyl ester) and benzylic or
tertiary C−H bonds on the ketone substituents were prepared
and examined under standard catalytic conditions. Products
resulting from C−O bond formation with the ester carbonyl O
atom were undetected in the 1H NMR spectrum of the
product mixture in both cases. Furthermore, cyclization using
α-diazo malonate derivatives (12) does not proceed at all after
heating to 100 °C for 36 h with stoichiometric amounts of
Fe(acac)2, whereas a α-diazo-β-diketone substrate (13)
undergoes the cyclization at room temperature with 30 mol
% catalyst loading. We rationalized the reactivity discrepancy
Figure 5. Exploration of C−H bond alkoxylation cyclization reaction
examining the chemoselectivity (a) and oxacycle ring-size selectivity
(b). Different reaction conditions for full substrate conversion and
corresponding NMR yields are given with alphabetical labels. Isolated
product yields using the higher-yielding conditions are given in italics
at the end.
between cyclization with the ketone versus the ester carbonyl
oxygen as the result of differences in their corresponding redox
potentials or, alternatively, the electrophilicities between these
two functional groups,74 where the ester carbonyl is more
electron rich due to π-donation from the alkoxyl substituent
and thus is harder to reduce. Indeed, DFT simulations using
the α-diazo malonate derivative 12 showed a much higher
barrier for both the N2 extrusion and HAT steps (Figure 6),
corroborating the experimental observation.
Two factors dictate the observed chemoselectivity toward
the ring size of the O-heterocycle formed: (1) the relative
bond dissociation energy (BDE) differences of the target C−H
bonds (enthalpic) and (2) the entropic preference among
different ring-forming transition states. To compare these two
contributions, 14 was prepared, where secondary C−H bonds
were positioned to form either five- or six-membered rings
1
(Figure 5b). H NMR spectroscopy of the product mixture
showed exclusive formation of the five-membered-ring-
containing product, suggesting an entropic preference toward
furan ring formation. To evaluate the strength of this entropic
preference, 15 was synthesized in which the weaker, benzylic
C−H bond was positioned to form a tetrahydropyran
derivative, while the formation of a five-membered cycle
necessitates the activation of a stronger, secondary C−H bond.
Gratifyingly, a high level of selectivity was similarly observed
by 1H NMR spectroscopy with the sole formation of
tetrahydrofuran-containing product 15, as further verified by
single-crystal X-ray diffraction (see p 279 in the Supporting
Information). This result suggests that the entropic preference
outcompetes enthalpic BDE differences between benzylic and
secondary C−H bonds (ca. 8 kcal/mol),75 further demonstrat-
ing the importance of the entropic factor in the product
selectivity of this catalytic transformation.
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Figure 6. DFT (B3LYP/def2-SVP(C,H),def2-TZVP(Fe,O))67−70 free energy diagram (in kcal/mol) calculated using the Orca software package59
for the proposed C−H alkoxylation mechanism for the cyclization of substrates featuring benzylic (2) (optimized structures shown), tertiary (3),
and secondary (4) C−H bonds as well as a malonate core structure (12) mediated by Fe(acac)2 with energies labeled in blue, red, green, and
maroon, respectively.
Figure 7. Scope and exploration of C−H bond alkoxylation cyclization reactions examining the substrate functional group tolerance. Different
reaction conditions for full substrate conversion and corresponding NMR yields are given with alphabetical labels. Isolated product yields using the
higher-yielding conditions are given in italics at the end.
2.4. Expanding the Substrate Scope. The alkoxylation
tolerates a wide scope of functional groups (Figure 7, 16−30),
while it provides rapid access to a range of complex spiro and
fused structures (Figure 8, 32−47). Given the ubiquity of
heterocycles in pharmaceuticals, particularly N-containing
compounds,76 the cyclization was probed with a variety of
aromatics present, such as furan (20), thiophene (21), pyridine
(22), benzothiazine (23), and indole (24). We note that
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Figure 8. Scope and exploration of C−H bond alkoxylation cyclization reactions examining the efficacy for the generation of spiro bi- and tricyclic
systems (a) as well as fused bi- and tricyclic products (b). Different reaction conditions for full substrate conversion and corresponding NMR yields
are given with alphabetical labels. Isolated product yields using the higher yielding conditions are given in italics at the end.
increased reaction temperatures (100 °C) were required to
drive substrate conversions with electron-deficient heterocycles
to completion (22 and 23) relative to the electron-rich
heterocycles, potentially due to (1) higher C−H bond
oxidation potentials due to adjacent electron-withdrawing
aryl groups or (2) competing binding of the coordinating N
atoms versus substrate ketoester functionalities toward the Fe
center. Interestingly, the N-methylindole-containing substrate
cleanly afforded a product with distinct 1H NMR features after
workup, which was further identified by single-crystal X-ray
diffraction as the cyclopentanone derivative (24) commonly
synthesized by rhodium-catalyzed carbene insertion cataly-
suggests a slower rate of radical recombination with the
carbonyl O atom in comparison to carboradical rotation prior
to ring closure.
Due to the electron richness of tertiary and ethereal C−H
bonds, spiro bicyclic rings can be readily prepared using
substrates featuring four- (32), five- (33, 36, 38, 39), and six-
membered cyclic motifs (34, 35, 37). The cyclopropyl variant
(31), however, showed no conversion even under forcing
conditions, potentially due to the high s character in the target
C−H bond.77 The dioxaspiro building blocks (36−39)
synthesized here are widely present in pharmaceuticals for
HIV treatment,5 in polyether antibiotics, and in a range of
natural products.78 Moreover, to demonstrate the ability of
rapidly introducing structural and functional group complexity
into simple hydrocarbons, a substrate with multiple diazo units
was employed to directly arrive at a biologically relevant spiro
bicyclic structure via double activation of the same methylene
unit (39). Remarkably, fused rings were also readily prepared,
providing quick access to a range of bi- and tricyclic structures
(40−47). Notably, excellent stereoselectivity toward the syn
isomer was observed in every case, with no anti isomer
detected in the product NMR spectra. Furthermore, high
selectivity toward ethereal over secondary C−H bond
activation resulted in exclusive formation of the fused bicyclic
acetal (45), again showcasing the heightened reactivity for
alkoxylation of electron-rich C−H bonds.
sis.21−23,49,50 Closer inspection of the H NMR spectra during
1
catalysis revealed the kinetic formation of the anticipated (Z)-
2-alkylidene dihydrofuran product (24′) that gradually
converted into cyclopentanone 24 entirely as its trans isomer
at 25 °C in CDCl3 (see p 330 in the Supporting Information
for the proposed mechanism). Similar transformations have
been demonstrated with palladium catalysis via the formation
of a π-allyl cation16 or simple Lewis acid catalysis for 2-
alkylidene-4-aryl-4-alkyldihydrofurans with similar stereospeci-
ficity.10 To showcase the ability of functionalization of complex
structures and tolerance toward protic functional groups, a
substrate featuring a steroid core derived from lithocholic acid
(30) was prepared and subjected to catalytic conditions at
room temperature, affording product 30 in a 3.08:1 mixture of
the two diastereomers resulting from alkoxylation of the
corresponding tertiary C−H bond. The partial epimerization
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3. CONCLUSION
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Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c02074
The foregoing data describe a methodology for the preparation
of structurally complex furan heterocycles employing easily
prepared diazo substrates catalyzed by commercially available
Fe(acac)2 under mild conditions. Our mechanistic inves-
tigation suggested a novel, stereospecific C−H functionaliza-
tion pathway via the in situ formation of a vinyl C-based radical
to generate the kinetically stable (Z)-2-alkylidene dihydrofur-
ans with high entropic selectivity for five-membered rings and
heightened reactivity toward electron-rich C−H bonds. The
catalysis is particularly effective in the synthesis of spiro and
fused bi- and tricyclic ethers commonly found in agrochemical,
pharmaceutical, and natural products.1−6,9 With the wide
functional group tolerance and the generation of enolester
motifs,16 we envision the methodology presented here would
provide rapid access to a variety of highly functionalized cyclic,
structurally complex ether precursors for elaborated down-
stream organic synthesis.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was generously supported by a grant from the NIH
(GM-115815), the Dreyfus Foundation (Teacher-Scholar
Award to T.A.B.), and Harvard University. A.T.W. is grateful
for a predoctoral fellowship from the NSF.
ABBREVIATIONS
■
CCR2, CC chemokine receptor 2; CCL2, CC chemokine
ligand 2; CCR5, CC chemokine receptor 5; TLC, thin-layer
chromatography
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c02074.
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REFERENCES
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Accession Codes
CCDC 2003790−2003793 and 2031360−2031365 contain
the supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
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AUTHOR INFORMATION
Corresponding Author
Theodore A. Betley − Department of Chemistry and
Chemical Biology, Harvard University, Cambridge,
Massachusetts 02138, United States; orcid.org/0000-
0001-5946-9629; Email: betley@chemistry.harvard.edu
■
Authors
Yuyang Dong − Department of Chemistry and Chemical
Biology, Harvard University, Cambridge, Massachusetts
02138, United States; orcid.org/0000-0002-4533-4798
Alexandra T. Wrobel − Department of Chemistry and
Chemical Biology, Harvard University, Cambridge,
Massachusetts 02138, United States
Gerard J. Porter − Department of Chemistry and Chemical
Biology, Harvard University, Cambridge, Massachusetts
02138, United States; orcid.org/0000-0003-3969-548X
Jessica J. Kim − Department of Chemistry and Chemical
Biology, Harvard University, Cambridge, Massachusetts
02138, United States
Jake Z. Essman − Department of Chemistry and Chemical
Biology, Harvard University, Cambridge, Massachusetts
02138, United States; orcid.org/0000-0003-2000-2196
Shao-Liang Zheng − Department of Chemistry and Chemical
Biology, Harvard University, Cambridge, Massachusetts
02138, United States; orcid.org/0000-0002-6432-9943
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