Radical-Mediated Distal Ipso-Migration of O/S-Containing Heteroaryls and DFT Studies for Migratory Aptitude

Article abstract of DOI:10.1021/acs.orglett.0c02030

Herein we describe an efficient distal ipso-migration of O- and S-containing heteroaryls and the radical heteroarylation of unactivated alkenes. The migration is triggered by various fluoroalkyl radicals, leading to valuable multifunctionalized ketones. The comparisons of migratory aptitude for O-/S-containing heteroaryls are comprehensively investigated. The origin of the chemoselective migration could be partially attributed to the discrepancy in the energy level of the LUMO of each heteroaryl group.

Full text of DOI:10.1021/acs.orglett.0c02030

pubs.acs.org/OrgLett
Letter
Radical-Mediated Distal Ipso-Migration of O/S-Containing
Heteroaryls and DFT Studies for Migratory Aptitude
Huihui Zhang, Luyao Kou, Dong Chen, Meishan Ji, Xiaoguang Bao,* Xinxin Wu, and Chen Zhu*
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ABSTRACT: Herein we describe an efficient distal ipso-migration
of O- and S-containing heteroaryls and the radical heteroarylation
of unactivated alkenes. The migration is triggered by various
fluoroalkyl radicals, leading to valuable multifunctionalized ketones.
The comparisons of migratory aptitude for O-/S-containing
heteroaryls are comprehensively investigated. The origin of the
chemoselective migration could be partially attributed to the
discrepancy in the energy level of the LUMO of each heteroaryl
group.
Scheme 1. Distal Functional Group Migration for Radical
Difunctionalization of Unactivated Alkenes
imultaneous incorporation of two different functional
Sgroups to alkenes supplies an effective utilization
technique of alkenes. Upon consideration of the broad
availability of alkenes, the radical-mediated difunctionalization
of alkenes is of highly synthetic importance, which has
attracted extensive attention.1 Despite the great progress over
the past few decades, the reaction substrates are largely limited
to activated alkenes, in which the olefinic moiety is adjacent to
π-conjugated system, e.g., aryl, carbonyl, or heteroatom. As a
consequence, the transient alkyl radical intermediate can be
stabilized by p−π conjugation, thus allowing the subsequent
functionalization to proceed readily due to increased lifetime.
In contrast, unactivated alkenes are commonly regarded as
challenging substrates in this transformation due to the
absence of such stabilizing effect.
Recently, remote functional group migration (FGM) has
proven to be a robust tactic for elusive radical-mediated
difunctionalization of unactivated alkenes.2 In this context, a
portfolio of groups including (hetero)aryl,3,4 cyano,5 oximi-
no,4e,6 carbonyl,6a,7 alkynyl,8 and alkenyl9 have displayed
migratory aptitude (Scheme 1A), leading to various syntheti-
cally useful functionalization of unactivated alkenes.
In 2017, we disclosed the radical-mediated heteroarylation
of unactivated alkenes by means of remote heteroaryl
migration for the first time.4a The utility of this protocol has
been comprehensively explored in the later accomplish-
ments.4b−i Among these efforts, N-containing heteroaryls
(e.g., benzothiazolyl, benzoxazolyl, benzimidazolyl, pyridyl,
quinolyl, etc.) were mostly engaged in the radical-induced
migration. However, little attention has been paid to migration
of O- or S-containing heteroaryls, which are also a class of
important structural motifs widely found in nature and play key
roles in numerous bioactive compounds. If the migration of O-
or S-containing heteroaryls could take place, it could lead to a
novel alkene difunctionalization. Herein, we provide concrete
support for the hypothesis (Scheme 1B). A set of O- or S-
containing heteroaryls such as benzofuryl, benzothienyl, furyl,
and thienyl readily migrate under mild conditions. The distal
migration is triggered by fluoroalkyl radicals (CF3, CF2R,
Received: June 18, 2020
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CHFR), affording a vast array of multifunctionalized ketones.
The comparison of migratory aptitude is comprehensively
studied between O-, S-, or N-containing heteroaryls, offering a
significant complement to the current knowledge of heteroaryl
migration. DFT studies provide insight into the driving force of
the radical-mediated heteroaryl migration and the origin of the
chemoselectivity.
Scheme 2. Scope of Benzofuryl-, Furyl-, Benzothienyl-, and
Thienyl-Substituted Tertiary Bishomoallylic Alcohols
a
The presence of a fluoroalkyl group in biologically active
molecules usually leads to significant improvement in
metabolic stability, lipophilicity, and selectivity.10 Simultaneous
incorporation of a fluoroalkyl and a heteroaryl group holding
pharmaceutical values provides an efficient approach to the
diverse synthesis of fluorine-containing compounds. The
trifluoromethylheteroarylation of unactivated alkenes via the
distal migration of O/S-containing heteroaryls was imple-
mented by using the benzofuryl-substituted tertiary alcohol 1
as model substrate and the Togni’s reagent II as
trifluoromethylating reagent under visible-light irradiation.11
A set of photosensitizers were examined, indicating that Mes-
Acr-ClO4 (9-mesityl-10-methylacridinium perchlorate) offered
the best catalytic efficiency under 14 W blue LED irradiation
(see Table S1). Solvent screening revealed that the highest
yield of desired product was delivered by using DMA (N,N-
dimethylacetamide) as solvent. Control experiments demon-
strated that the use of photocatalyst was indispensable to the
reaction, which also did not proceed without photoirradiation.
With the optimized reaction conditions in hand, we set
about assessing the generality of the method and defining the
substrate scope (Scheme 2). The transformation displayed a
good functional group tolerance; a variety of electron-rich and
deficient groups were compatible with the mild conditions.
The positional change of the ortho-, meta-, or para-substituents
on benzene did not have much impact on the reaction
outcome. The 1,4-migration of the benzofuryl group occurred
exclusively in the presence of phenyl or naphthyl groups (2a−
2l) and was even preferential over other migratory group such
as pyridyl (2m). In addition to benzofuryl, other O-/S-
containing heteroaryls such as benzothienyl, furyl, and thienyl
also exhibited good migratory aptitude, affording the
corresponding heteroaryl-migrated products with unique
chemo- and regioselectivity (2n−2aa). Remarkably, the
reaction of 1a could be performed on a 1.5 mmol scale
without compromising the outcome, affording 2a with 73%
yield (see SI).
a
Reaction conditions: 1 (0.2 mmol, 1.0 equiv), Togni’s reagent (II)
(0.4 mmol, 2.0 equiv), and Mes-Acr-ClO4 (0.008 mmol, 4 mol %) in
DMA (3.0 mL) at rt, 14 W blue LED irradiation. Yields of isolated
products are given.
Subsequently, the formed alkyl radical (spin density mainly
locates on C2) could undergo radical addition to either C3 of
benzofuryl (path a) or C4 of furyl (path b), leading to 1ab-
INT2a and 1ab-INT2b, respectively. Computational results
show that the free energy barriers for path a and path b are
10.2 and 10.9 kcal/mol, respectively, indicating that the
intramolecular radical addition to C3 of benzofuryl is more
favorable than to C4 of furyl moiety (Figure 1). It should be
noted that the spin density of the formed 1ab-INT2a is more
delocalized than 1ab-INT2b due to the presence of the
annelated benzo group (Figure S1). Therefore, the formed
1ab-INT2a is thermodynamically more stable than 1ab-
INT2b. In addition, frontier molecular orbital (FMO) analysis
can provide an insight into the discrepancy in the energy level
for the two heteroaryls in 1ab. The LUMO of 1ab′13 is
essentially the same as the LUMO of benzofuryl group, while
the LUMO+1 of 1ab′ mainly locates in the furyl group (Figure
2). The radical addition is more likely to occur with LUMO
and consequently C3 of benzofuryl is more facile to be attacked
than C4 of furyl in 1ab. Next, the yielded radical intermediate
1ab-INT2a could undergo C3−C5 bond cleavage to afford the
benzofuryl migration intermediate 1ab-INT3a. It is note-
worthy that the generated 1ab-INT3a is thermodynamically
more stable than 1ab-INT2a. Due to the connection of both
In order to gain deeper insight into the migratory aptitude,
the comparison of migration rate between different heteroaryls
was systematically performed (Scheme 3). Because it has been
proven that migration of the five-membered N-containing
heteroaryls (benzothiazolyl, benzoxazolyl, and benzimidazolyl)
was prior to the six-membered ones (pyridyl, quinolyl),4a the
competitive experiments herein were focused on the favorable
five-membered heteroaryl migration. The cases of 1ab−1af
explicitly illustrated that the migration rate of benzofuryl was
superior to others. The following comparisons in 1ag−1an
were carried out in the same manner. Finally, the order of
migratory aptitude was in line with benzofuryl > benzothiazolyl
> furyl ≈ thiazolyl > benzothienyl > thienyl.
Computational studies12 were performed to shed light on
the migratory activity for these O-/S-containing heteroaryls.
First, the comparisons between benzoannelated heteroaryls
and their parent aryls were carried out. Take 1ab, for example;
the generated CF3 radical is ready to attack the terminal carbon
(C1) of alkenyl moiety to afford intermediate 1ab-INT1.
B
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Scheme 3. Comparison of Migratory Aptitude between
a
Different Heteroaryls
Figure 1. Energy profile (in kcal/mol) for the migration of
heterocycles of 1ab. Bond lengths are shown in angstroms.
Figure 2. LUMO and LUMO+1 of 1ab′.
more ready to migrate than benzothiazolyl group. Likewise, the
substrate 1ah was studied computationally, suggesting that the
benzothiazolyl group is more favorable to migrate than
benzothienyl group. Therefore, the order of migratory activity
is benzofuryl > benzothiazolyl > benzothienyl. Similarly, the
order of migratory activity for the parent heteroaryls is also
obtained computationally, which is furyl ≈ thiazolyl > thienyl
(Figures S5 and S6). Third, the migratory activities between
benzothiazolyl and furyl and between thiazolyl and benzo-
thienyl were examined. Computational studies for the substrate
1ag show that the migration of benzothiazolyl is easier than
that of furyl group (Figure S7). For substrate 1am,
computational results suggest that the migration of thiazolyl
is more favorable than that of benzothienyl group (Figure S8).
Overall, the order of migratory ability can be concluded as
benzofuryl > benzothiazolyl > furyl ≈ thiazolyl > benzothienyl
> thienyl, which is consistent with the experimental results
well. Additionally, the calculated ΔΔG⧧ values for the two
chemoselective pathways are qualitatively consistent with the
experimental ratios of migrated products (see Table S2).
Then we focused attention toward incorporating di- and
monofluoroalkyl into unactivated alkenes through the afore-
mentioned olefin difunctionalization approach. Di-/mono-
fluoromethylheteroarylation both readily proceeded with the
similar visible-light photoredox catalysis via cascade radical
addition. First, the desired products (4a−4e) of difluoroalkyl-
heteroarylation were furnished in moderate to excellent yields,
a
Reaction conditions: 1 (0.2 mmol, 1.0 equiv), Togni’s reagent (II)
(0.4 mmol, 2.0 equiv), and Mes-Acr-ClO4 (0.008 mmol, 4 mol %) in
DMA (3.0 mL) at rt, 14 W blue LED irradiation. Yields of isolated
products are given.
furyl and hydroxyl groups for C5, the formed radical
intermediate 1ab-INT3a is well stabilized. The calculated
energy profile shows that transformation from 1ab-INT1 to
1ab-INT3a is downhill, which is the driving force for the
migration of heteroaryls and could be rationalized by the
relative stability of the formed radical intermediates. Similarly,
it is not difficult to deduce that the benzothienyl group is more
ready to migrate than the thienyl group (Figure S2).
Second, the order of migratory activity for benzofuryl,
benzothiazolyl, and benzothienyl was investigated (Figures S3
and S4). Computational studies for the substrate 1ae
demonstrate that the generated alkyl radical is more ready to
attack C3 of benzofuryl, indicating that benzofuryl group is
C
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regardless of the electronic characteristics of substrates
(Scheme 4, top). The monofluoroalkylation also generated
ical stability of the sequentially formed radical intermediates. In
addition, the discrepancy in the energy level of the LUMO of
each heteroaryl might partially account for the origin of the
chemoselective migration. After the formation of alkyl radical
via an external radical addition, the following intramolecular
radical cyclization prefers to attack the heteroaryl with LUMO
in lower energy level, subsequently leading to the chemo-
selective migration of the attacked heteroaryl group. The
comprehensive comparisons of the migration rates between
different heteroaryls and mechanistic insights may provide a
guide for subsequent efforts in the design of selective
migrations.
Scheme 4. Di-/Monofluoromethylheteroarylation of
a
Unactivated Alkenes
ASSOCIATED CONTENT
■
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02030.
Experimental details, compound characterization data,
NMR spectra (PDF), DFT studies, and mechanism
studies (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Xiaoguang Bao − Key Laboratory of Organic Synthesis of
Jiangsu Province, College of Chemistry, Chemical Engineering
and Materials Science, Soochow University, Suzhou, Jiangsu
215123, China; orcid.org/0000-0001-7190-8866;
Email: xgbao@suda.edu.cn
Chen Zhu − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science, Soochow University, Suzhou, Jiangsu 215123,
China; orcid.org/0000-0002-4548-047X; Email: chzhu@
suda.edu.cn
a
Reaction conditions A: 1 (0.2 mmol, 1.0 equiv), BrCF2CO2Et (0.4
mmol, 2.0 equiv), and fac-Ir(ppy)3 (0.008 mmol, 4 mol %) in DMF
(2 mL) at rt, 14 W blue LED irradiation. Reaction conditions B: 1
(0.2 mmol, 1.0 equiv), BrCFHCO2Et (0.3 mmol, 1.5 equiv), fac-
Ir(ppy)3 (0.006 mmol, 3 mol %), and K2HPO4 (0.3 mmol, 1.5 equiv)
in EtOAc (2 mL) at rt, 30 W blue LED irradiation. Yields of isolated
products are given.
Authors
Huihui Zhang − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science, Soochow University, Suzhou, Jiangsu 215123,
China
the products in useful yields and good selectivities (Scheme 4,
bottom). The example of 4c and 5c also indicated that the
migration of benzofuryl was prior to other heteroaryls in the
reaction. The example of 5d again verified the similar
migration rate between furyl and thiazolyl groups. Remarkably,
the addition of electrophilic fluoroalkyl radicals to the electron-
rich O-/S-containing heteroaryls was not detected, manifesting
the exclusive chemoselectivity.
Luyao Kou − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science, Soochow University, Suzhou, Jiangsu 215123,
China
Dong Chen − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science, Soochow University, Suzhou, Jiangsu 215123,
China
In summary, we have disclosed the radical-mediated
heteroarylfunctionalization of unactivated alkenes via the distal
migration of O-/S-containing heteroaryls. In this protocol,
benzofuryl, furyl, benzthienyl, and thienyl showcase the remote
migratory aptitude for the first time, complementary to the
current knowledge of heteroaryl migration mainly involving N-
containing heteroaryls. Fluoroalkyl radicals, such as CF3,
CF2COOEt, and CHFCOOEt, trigger the migration process
and are readily incorporated into alkenes alongside the
construction of C−C bonds. The transformation features
good chemo-/regioselectivities, mild reaction conditions, and
broad functional group compatibility. DFT studies shed light
on the driving force for the radical-mediated migration of
heteroaryls, which could be rationalized by the thermodynam-
Meishan Ji − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science, Soochow University, Suzhou, Jiangsu 215123,
China
Xinxin Wu − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science, Soochow University, Suzhou, Jiangsu 215123,
China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02030
Notes
The authors declare no competing financial interest.
D
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Dicarbofunctionalization of Olefin with Aldehyde. J. Org. Chem.
2018, 83, 5629.
ACKNOWLEDGMENTS
■
C.Z. is grateful for the financial support from the National
Natural Science Foundation of China (21722205, 21971173,
21973068), the Project of Scientific and Technologic Infra-
structure of Suzhou (SZS201708), and the Priority Academic
Program Development of Jiangsu Higher Education Institu-
tions (PAPD).
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Copper-Catalyzed Heteroarylsilylation of Unactivated Olefins
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Organic Letters
pubs.acs.org/OrgLett
Letter
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(12) See the SI for computational details.
(13) A truncated model of 1ab was used to show the LUMO and
LUMO+1.
F
https://dx.doi.org/10.1021/acs.orglett.0c02030
Org. Lett. XXXX, XXX, XXX−XXX