Metal-Free Synthesis of Indolopyrans and 2,3-Dihydrofurans Based on Tandem Oxidative Cycloaddition

Article abstract of DOI:10.1021/acs.orglett.0c01896

The synthesis of versatile scaffold indolopyrans based on C-C radical-radical cross-coupling under metal-free conditions is described. The reaction involving single electron transfer between coupling partners followed by cage collapse allows highly selective cross-coupling while employing only equimolar amounts of coupling partners. Moreover, the mechanistic manifold was expanded for the functionalization of enamines to give the stereoselective synthesis of 2,3-dihydrofurans. This iodine-mediated oxidative coupling features mild conditions and fast reaction kinetics.

Full text of DOI:10.1021/acs.orglett.0c01896

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Letter
Metal-Free Synthesis of Indolopyrans and 2,3-Dihydrofurans Based
on Tandem Oxidative Cycloaddition
Subin Choi, Hyeonji Oh, Jeongwoo Sim, Eunsoo Yu, Seunghoon Shin, and Cheol-Min Park*
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ABSTRACT: The synthesis of versatile scaffold indolopyrans
based on C−C radical−radical cross-coupling under metal-free
conditions is described. The reaction involving single electron
transfer between coupling partners followed by cage collapse allows
highly selective cross-coupling while employing only equimolar
amounts of coupling partners. Moreover, the mechanistic manifold
was expanded for the functionalization of enamines to give the
stereoselective synthesis of 2,3-dihydrofurans. This iodine-medi-
ated oxidative coupling features mild conditions and fast reaction kinetics.
inhibitory activities against various cancer cell lines and
hepatitis C NS5B have been reported to be associated with
indolopyran scaffolds.3 As such, intense efforts have been made
to develop expedient synthesis of polycyclic indoles.4 For
example, Pd- and Au-catalyzed intramolecular cyclization,5
ring-closing Friedel−Crafts alkylation,6 and Pictet−Spengler
reaction7 have been reported.
ndole derivatives have drawn a great deal of attention owing
1
Ito their broad biological activity, and numerous elegant
syntheses of indoles have been developed.2 Meanwhile,
elaboration of indoles by ring fusion would allow access to
unique scaffolds with new biological activities. Especially, the
C−C and C−X bond formation based on cross-dehydrogen-
ative coupling (CDC) has received considerable attention
owing to the advantage of obviating prefunctionalization of
reactants.8 While transition-metal-catalyzed reactions comprise
an important part of CDCs,9 metal-free reactions are desirable
in that the high cost of transition-metal catalysts and the
removal of residual toxic metals could be avoided. Owing to
the versatile reactivity and environmental friendliness, hyper-
valent iodines (λ3) have attracted great interest from the
synthetic community.10 However, the formation of iodoarenes
as the byproducts has been recognized as a drawback.
I2 is an inexpensive, readily available, inherently nontoxic,
and environmentally friendly reagent. In addition, I2-mediated
CDC reactions are operationally simple, and products can be
readily purified from residual I2. Thus, many efficient I2-
mediated reactions have been developed.11 Generally, I2 in
CDC reactions is used as a radical initiator12 or directly
involved in the formation of X−I (X = C, N, O, etc.).13
Bond formation based on radical−radical cross-coupling
(RRCC) is challenging owing to the very low activation barrier
Received: June 5, 2020
Figure 1. Strategy based on SET for radical−radical cross-coupling.
https://dx.doi.org/10.1021/acs.orglett.0c01896
© XXXX American Chemical Society
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A

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a
Scheme 1. Substrate Scope for Indolopyrans
a
Reaction conditions: reactions were performed with 1 (0.10 mmol) and 2 (0.11 mmol) in dry MeCN (1.0 mL) under N2. Isolated yield.
Reaction performed at −10 °C.
b
a
of radical couplings, which renders it difficult to control the
selectivity for cross-coupling over homocoupling.14 While I2-
mediated C−X bond formation via the RRCC mechanism has
been developed, to the best of our knowledge, the
corresponding C−C bond formation under such a mechanistic
realm has not been reported. Because of the two congeneric
carbon-centered radicals with intrinsically similar reactivity
derived from two coupling partners, the selective cross-
coupling poses even more challenges.
Scheme 2. Substrate Scope for 2,3-Dihydrofurans
Our strategy involves the charge-accelerated single electron
transfer (SET) between coupling partners followed by cage
collapse (Figure 1a), which enables highly efficient coupling to
be completed at r.t. within 20 min in many cases, while
employing only equimolar amounts of coupling partners. The
pair of corresponding radical species formed by SET between
the reactants undergoes rapid cross-coupling via cage collapse
to give A or B depending on the substrate type (Figure 1b).
Indole-derived A undergoes a second oxidation followed by
6π-electrocyclization to give indolopyrans, whereas direct oxa-
Michael addition occurs for enamine-derived B, resulting in the
formation of 2,3-dihydrofurans in a stereoselective manner.
To realize the coupling of indolomalonate 1a with
acetylacetone 2a under oxidative conditions, we commenced
with the examination of several oxidants and bases (see S2).
Ultimately, the use of I2 and K3PO4 afforded 3aa in excellent
yield with fast kinetics. Examination of solvent effects revealed
acetonitrile as an optimal solvent. Under the optimized
a
Reaction conditions: Reactions were performed with 4 (0.10 mmol)
and 2 (0.11 mmol) in dry MeCN (1.0 mL) under N2. Isolated yield.
b
Acetoacetate (1.5 equiv), iodine (2 equiv), K3PO4 (5 equiv).
B
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ketones to provide indolopyrans in good yields (3ab−3ae). To
examine the regioselectivity of the cyclization, diketone 2f
bearing two electronically disparate carbonyl groups was
subjected to the reaction. A moderate selectivity of 2:1 was
observed with the electron-deficient carbonyl group participat-
ing in the cyclization (X-ray structure of 3af). Aliphatic cyclic
diketone 2g and aryl alkylketone 2h reacted smoothly with 1a
to produce the corresponding products 3ag and 3ah in high
yields (78% and 75%, respectively). Notably, complete
regiocontrol was observed with 2h.
To investigate the feasibility for introducing various
functional groups on the pyran ring, we performed the
reaction with various active methylene compounds (AMCs)
including ketoesters 2i and 2j, ketoamide 2k, ketonitrile 2l,
ketosulfone 2m, and ketophosphonate 2n (3ai−3an). In all the
cases, coupling successfully proceeded in excellent yields.
Moreover, the introduction of vinyl groups on diketones (2o−
2t) as functional handles was tolerated to afford the
corresponding products in good yields (3ap, 3aq, and 3io−
3it).
To broaden the scope of the method, we investigated the
cross-coupling of enamines and AMCs (Scheme 2). Under the
standard reaction conditions, 2,3-dihydrofuran 5aa was
obtained in 75% yield as a single diastereomer (NOESY
experiment, SI Figure 4). Examination of the electronic effect
of the aryl groups revealed that the reaction with the enamines
bearing both electron-rich and -deficient aryl groups proceeded
smoothly to give good to excellent yields of 2,3-dihydrofurans
(5aa−5ga). Also, various AMCs smoothly participated in the
reaction to give 5ai, 5au, and 5an.
Next, we explored the synthetic application of the method
(Figure 2a). The reaction could be performed as a two-step
one-pot reaction by combining the carbene- and iodine-
mediated steps (89% overall). Also, a gram-scale reaction
proceeded without loss of efficiency (Figure 2b).
Figure 2. Synthetic tractability and applications.
We demonstrated that the indolopyrans are a versatile
scaffold, which can be elaborated into complex polycyclic
compounds. Thus, additional 7- and 8-membered rings could
be readily introduced by ring-closing metathesis (RCM) to
give 6a and 6b in good yields by employing N-allyl or N-
butenyl (Figure 2c). Thermal rearrangement can be promoted
to produce highly complex architectures with cyclobutane
formation when pendant vinyl groups are introduced on the
substrates (Figure 2d). The reaction appears to involve the
interconversion of the two regioisomers under the reaction
conditions since identical products were obtained from both
isomers (7a−7c).
As part of our mechanistic studies, we first focused on the
identification of reaction intermediates along the reaction
pathway. It was established that 3′aa is an intermediate in the
pyran formation based on the observation that a nearly
quantitative amount of pyran 3aa was obtained when 3′aa was
treated with 1.1 equiv of iodine (Figure 3a-i). With the
speculation that the conversion of 3′aa to 3aa might involve
the formation of oxa-triene 3″aa, we performed an alternative
oxidation of 3′aa with MnO2 to afford 3aa (Figure 3a-ii). This
led us to conclude that 6π-electrocyclization of 3″aa is
responsible for the formation of 3aa. Next, the intermediacy of
8a was confirmed by the formation of 3ab in 91% yield when
8a was reacted with 1a in the presence of 1.1 equiv of iodine
(Figure 3a-iii).
conditions employing equimolar amounts of 1a and 2a, the
reaction proceeded to completion in 20 min with a quantitative
yield.
With the optimized conditions in hand, we examined the
scope of the reaction (Scheme 1). It turned out that the
electronic effect of the indole ring was insignificant, as
observed by the highly efficient conversions regardless of the
electronic nature of the substituents (3aa−3ha, X-ray strucure
of 3da). The examination of several N-substitutions on the
indole revealed that while the N−H indole substrate 1i
produced 3ia with a good yield those containing benzyl and
aryl groups 3ja and 3ka afforded diminished yields. In addition
to the malonate, various electron-withdrawing groups includ-
ing ketoester, diketone, and ketophosphonate were well
tolerated to yield the corresponding products in good to
excellent yields (3ma−3oa). Notably, 1p bearing ketoester at
position C2 of indole, in which the corresponding enolate
anion is in cross-conjugation with the indole nitrogen atom,
afforded 3pa in poor yield. We speculated that the cross-
conjugation results in attenuation of the ability for electron
transfer. Likewise, the reaction of C2-substituted pyrrole 1q
produced 3qa in moderate yield. In a similar context, the
heterocycles lacking a nitrogen atom, benzofuran 1r and
benzothiophene 1s, afforded either low or no conversion (3ra
and 3sa).
Next, we investigated the scope of the coupling partner 2.
The reaction tolerated well both electron-rich and -deficient
To probe the reaction mechanism, we performed a series of
control experiments. The ability of the intermediate 8a to form
C
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Figure 3. (a) Identification of the intermediates along the reaction pathway. (b) Probing the presence of radical species derived from the reactants.
(c) HRMS analysis by direct injection of the reaction mixtures of 1a and 8a compared to 1a alone sampled at 10 min. (d) RRCC vs SRN
1
mechanism: effect of reaction concentration and radical scavenger; ΔG for SRN1 pathway. (e) Gibbs free energy changes for the SET calculated at
a
the B3LYP-D3/6-31+G(d,p)/LANL2DZdp level in MeCN (SMD) and the corresponding yields. NMR yield.
radical species has been confirmed by the formation of the
tricarbonyl compound 8b when iododiketone 8a was treated
with nBu4NI in the presence of air, which may form via the
corresponding peroxy intermediate (Figure 3b-i). The
formation of a radical species on the indolomalonate was
evidenced by reacting indolomalonate anion 9a with Togni
reagent II, a well-known electron acceptor (Figure 3b-ii).15
The reaction was completed at −40 °C in 10 min to produce
trifluoromethylated 8c and dimer 8d in 27% and 22% yield,
respectively, both of which strongly suggest the presence of
indolomalonate radical 9b.
To further examine the presence of the radical species
derived from indolomalonate 1a, high-resolution mass
spectrometry (HRMS) was obtained by direct sampling from
the reaction of 1a with 8a (Figure 3c). The HRMS analysis
indicated a peak corresponding to iminium ion 9c (m/z =
260.0917). To identify the source of the iminium ion 9c, we
performed a control experiment. When the mixture lacking 8a
was subjected to HRMS, a peak corresponding to the
protonated 9d was detected (m/z = 262.1073), thus indicating
that the species corresponding to the peak of m/z = 260.0917
is a unique species forming only when both reactants are
present. Based on the observation, we reasoned that the
oxidation of radical species 9b in the mass spectrometer is
responsible for the species at m/z = 260.0917.
We performed several control experiments to distinguish the
mechanism in operation between solvent-caged RRCC and
SRN1. First, the cross-coupling proceeded with similar
efficiency even under 10-fold dilution (Figure 3d−i, 92%, 0.1
M vs 81%, 0.01 M, see S14). Second, the effect of a radical
scavenger was examined (Figure 3d-ii, see S14), in which the
presence of TEMPO did not interrupt the cross-coupling,
affording a similar combined yield (73%) of 3′ab and 3ab
compared to that without the scavenger (70%). This
observation led us to examine the intrinsic reactivity of the
radical species derived from 8a toward TEMPO (Figure 3d-
iii);16 the trapping turned out to be highly efficient (91%).
Based on the two experiments (Figure 3d-ii and -iii), the SRN
1
mechanism could be ruled out, the chain nature of which
would have been interrupted by TEMPO (Figure 3d-ii). The
D
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Figure 4. Proposed reaction mechanism. (a) Formation of 3′aa via cage-collapse radical−radical cross-coupling followed by a second oxidation and
electrocyclization to provide 3aa. Gibbs free energy changes were calculated at the B3LYP-D3/6-31+G(d,p)/LANL2DZdp level in MeCN (SMD).
(b) Mechanism for the formation of 2,3-dihydrofurans.
mechanistic rationale was further corroborated by the DFT
calculations, where the SRN1 pathway turned out to be
endergonic in contrast to the highly exergonic RRCC pathway
(Figures 3d-iv vs 4a-i).
Of note is the crucial role of the nitrogen-conjugated
unsaturation in the reaction (Figure 3e). We reasoned that the
stability of the radical species resulting from SET accounts for
the efficiency of the reaction, in which the formation of 9a is
highly favorable as opposed to those for 9f and 9g. The Gibbs
free energy changes calculated by DFT calculations are
consistent with the experimental results (Scheme 1, 3ra and
3sa).
The proposed mechanism for indolopyrans based on the
mechanistic studies and DFT calculations is shown in Figure
4a. The SET between 8f and 9a results in the formation of 9b
and 9e with a Gibbs free energy change of −11.7 kcal/mol
(Figure 4a-i; see SI Figure 3). Subsequently, the resulting
radical species 9b and 9e undergo RRCC via cage collapse to
afford 3′aa with a free energy change of −18.2 kcal/mol,
indicating an overall highly exergonic process. Moreover, the
delocalized negative charge in 9a is shown to be crucial in SET
as suggested by the unfavorably high free energy change in
SET between the neutral 1a and 8f (23.4 kcal/mol, Figure 4a-
ii). Finally, oxidation of 3′aa provides 3″aa, which sponta-
neously undergoes 6π-electrocyclization to give 3aa.
On the other hand, the formation of 2,3-dihydrofuran
proceeds through RRCC to afford 5′aa via the SET between 8f
and 9i, and subsequent oxa-Michael addition of the enolate
TS-5′aa affords 5aa (Figure 4b). The formation of single
diastereomers could be rationalized by the chairlike transition
state (TS).
In conclusion, we have developed an efficient synthesis of
indolopyrans and 2,3-dihydrofurans based on radical−radical
cross-coupling. Extensive mechanistic studies allowed us to
conclude that the coupling proceeds through solvent-caged
radical−radical cross-coupling mediated by charge-accelerated
SET, in which cage collapse plays an important role to achieve
high selectivity for cross-coupling over homocoupling.
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Full experimental details, characterization data, and
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copies of H and 13C spectra and HRMS data (PDF)
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AUTHOR INFORMATION
Corresponding Author
■
Cheol-Min Park − Department of Chemistry, UNIST (Ulsan
National Institute of Science & Technology), Ulsan 44919,
Korea; orcid.org/0000-0002-2675-1414; Email: cmpark@
unist.ac.kr
Authors
Subin Choi − Department of Chemistry, UNIST (Ulsan
National Institute of Science & Technology), Ulsan 44919,
Korea
Hyeonji Oh − Department of Chemistry, UNIST (Ulsan
National Institute of Science & Technology), Ulsan 44919,
Korea
Jeongwoo Sim − Department of Chemistry, UNIST (Ulsan
National Institute of Science & Technology), Ulsan 44919,
Korea
Eunsoo Yu − Department of Chemistry, UNIST (Ulsan
National Institute of Science & Technology), Ulsan 44919,
Korea
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Seunghoon Shin − Department of Chemistry, Hanyang
University, Seoul 04763, Korea; orcid.org/0000-0003-
1702-8918
Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Research
Foundation of Korea (NRF) grants (2014R1A5A1011165
Center for New Directions in Organic Synthesis (CNOS),
NRF 2017R1A2B2012946, and NRF 2017M3A9E4078558)
funded by the Korean government.
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Organic Letters
pubs.acs.org/OrgLett
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https://dx.doi.org/10.1021/acs.orglett.0c01896
Org. Lett. XXXX, XXX, XXX−XXX