Dealkenylative Thiylation of C(sp3)-C(sp2) Bonds

Article abstract of DOI:10.1021/acs.orglett.9b03186

Carbon-carbon bond fragmentations are useful methods for the functionalization of molecules. The value of such cleavage events is maximized when paired with subsequent bond formation. Herein we report a protocol for the cleavage of an alkene C(sp³)-C(sp²) bond, followed by the formation of a new C(sp³)-S bond. This reaction is performed in nonanhydrous solvent and open to the air, employs common starting materials, and can be used to rapidly diversify natural products.

Full text of DOI:10.1021/acs.orglett.9b03186

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Dealkenylative Thiylation of C(sp3)−C(sp2) Bonds
Andrew J. Smaligo and Ohyun Kwon*
Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California 90095-1569, United
States
S
* Supporting Information
ABSTRACT: Carbon−carbon bond fragmentations are
useful methods for the functionalization of molecules. The
value of such cleavage events is maximized when paired with
subsequent bond formation. Herein we report a protocol for
the cleavage of an alkene C(sp3)−C(sp2) bond, followed by
the formation of a new C(sp3)−S bond. This reaction is
performed in nonanhydrous solvent and open to the air,
employs common starting materials, and can be used to rapidly diversify natural products.
he formation of carbon−heteroatom bonds in organic
Tcompounds is an important step in the synthesis of many
drug molecules. After oxygen and nitrogen, sulfur is the
Figure 2. Substrate scope of the aryl disulfide coupling partner in the
dealkenylative thiylation of 1a. Experiments were performed on a 1.0
mmol scale. Isolated yields are after SiO2 chromatography. See the SI
for experimental details.
heteroatom found most frequently in FDA-approved drugs
(Figure 1A).1 Thioethers and their higher oxidation state
derivatives are also versatile and widely used synthetic
intermediates.2 Some of the most prevalent means of alkyl
aryl thioether synthesis are alkylation (e.g., SN2, Mitsunobu
reaction), addition to unsaturated bonds (e.g., Michael
Figure 1. (A) Pharmaceuticals featuring thioether and sulfone units.
(B) Timeline of aryl alkyl thiother formation via radical substitution.
(C) Mechanism of dealkenylative thiylation.
Received: September 7, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03186
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Figure 3. Substrate scope of alkene coupling partner. Experiments were performed on 1.0 mmol scale. Isolated yields are after SiO2
chromatography. See the SI for experimental details. aMajor diastereoisomer displayed. bInseparable mixture of diastereoisomers. c10.0 mmol scale.
addition, hydrothiylation), and cross-coupling.2 Less frequent
are reports of trapping of a carbon radical with an aryl disulfide
species (Figure 1B), a transformation that typically requires the
use of radical precursors (e.g., organometallic species, Barton
esters, trialkyl boranes), carboxylic acids, simple alkanes, or a
peroxide species.3−11 This approach is sometimes limited in its
applicability because of the syntheses of the requisite coupling
partners, the harsh reaction conditions (high temperatures,
long reaction times), or the low selectivity for C−H
abstraction (in the case of alkane starting materials).
Consequently, a method for the generation of carbon radicals
under mild reaction conditions from readily available starting
materials, including natural products, would be highly useful.
Recent methodological advancements in the area of C−C
bond activation have enabled a number of powerful trans-
formations.12 Specifically, C(sp3)−C(sp3) and C(sp3)−C(sp2)
bond fragmentations have proven to be effective methods for
functionalizing molecules with regard to both the total
synthesis and the preparation of pharmaceutically relevant
compounds.12,13 The value of such transformations can be
increased when paired with a subsequent bond-forming event.
Nevertheless, reports of alkene C(sp3)−C(sp2) bond cleavage,
followed by C(sp3)−heteroatom bond formation remain
uncommon13a,e,14 despite the ubiquity of alkenes in organic
molecules, especially within natural products.15 In this Letter,
we report a simple method for the dealkenylative thiylation of
alkenes (1, 4, and 6) to give alkyl aryl sulfides (3, 5, and 7)
under mild conditions (Figure 1C). We have found that alkyl
radicals generated through the single electron transfer (SET)-
based reductive cleavage of α-alkoxy hydroperoxides13,14,16
(generated during the ozonolysis of alkenes 1)17 can be
trapped with an aryl disulfide (2) to form a new C(sp3)−S
bond in 3. In contrast with previously reported carbon-radical-
based methods for C(sp3)−S bond formation, this trans-
formation is performed under mild reaction conditions (below
room temperature, within 1 min, open to air, nonanhydrous
solvent), employs common olefins as starting materials, and is
stereoselective when the starting materials contain stereo-
centers.
A survey of the reaction parameters revealed the optimal
conditions for the dealkenylative thiylation to be ozonolysis of
the alkene at −78 °C in methanol, followed by treatment with
3.0 equiv of the aryl disulfide and 1.2 equiv of ferrous sulfate
heptahydrate (added as a 5% w/v aqueous solution16f) at 0 °C.
(See Table S1 in the Supporting Information for details.)
Under these optimized conditions and using 4-isopropenylte-
trahydropyran (1a) as our alkene substrate, we examined the
scope of the aryl disulfide reaction partner (Figure 2). Phenyl
disulfide (2a) gave the product 3aa in 80% yield, whereas
various tolyl and xylyl disulfides also produced their thiylation
products 3ab−af in yields of 62−77%. Electron-rich and -poor
aryl disulfides were competent partners, generating the
expected products 3ag−aj in yields of 50−75%. 1-Phenyl-
tetrazol-5-yl and 2-pyridyl disulfides, notable for the use of
B
DOI: 10.1021/acs.orglett.9b03186
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Figure 4. Dealkenylative thiylation of exo-methylene cycloalkanes.
Experiments were performed on 1.0 mmol scale. Isolated yields are
after SiO2 chromatography. See the SI for experimental details.
aInseparable mixture of regioisomers.
Figure 5. Dealkenylative thiylation of cyclic alkenes. Experiments
were performed on a 1.0 mmol scale. Isolated yields are after SiO2
a
chromatography. See the SI for experimental details. Solid FeSO4·
their thioether and sulfone derivatives in cross-coupling
reactions,18 were also compatible, providing the thioethers
3ak and 3al in yields of 51 and 75%, respectively. Attempts to
employ dialkyl disulfides as coupling partners were unfruitful,
presumably because of the side reactions resulting from the
generation of reactive alkylthiyl radical intermediates.3
7H2O was added at room temperature. bInseparable mixture of
diastereoisomers.
exception of 3na (12:1 d.r.), the diastereoisomeric ratios of the
products from the monoterpenoids were lower (in the range
from 1.5:1 to 4:1) than those of the decalinone substrates 1h−
k.
Subsequently, we investigated the substrate scope of the
alkene coupling partner (Figure 3). The primary radical
precursors 1b−d supplied the thioethers 3ba−da in yields of
58−80%. Secondary (1e, 1f) and tertiary (1g) radical
precursors were also compatible, furnishing the desired
products 3ea−ga in yields of 74−82%. The reaction was
tolerant to a range of functionalities, including alcohol, imide,
amide, carboxylic ester, and carbamate groups. A powerful
feature of the reaction is the ability to introduce heteroatom
functionality in terpenoid (e.g., (+)-nootkatone, 1i) and
terpenoid-derived starting materials. The bicyclic ketones
1h−k gave their corresponding products in yields of 67−
77% (5.9:1 to 7.5:1 d.r.). Notably, dealkenylative thiylation of
the diastereoisomeric enones 1j and 1k resulted in the same
distribution of product isomers. This observation is consistent
with stereoselectivity trends commonly observed in reactions
with cyclic radicals, in which the stereoselectivity of the
addition is dictated by a combination of torsional and steric
effects.19 The commonly available terpenoids (−)-isopulegol
(1l), trans-(+)-dihydrocarvone (1m), cis-(−)-limonene oxide
(1n), (−)-dihydrocarveol (1o), and (−)-limonene-1,2-diol
(1p) were also viable substrates, producing their products 3la−
pa, respectively, in yields of 60−84%. When run using 10
mmol of trans-(+)-dihydrocarvone (1m), the reaction
produced the thioethers 3ma/3ma′ in 66% yield. With the
Next, we found that alkenes containing exo-methylene
groups (4) were converted into the corresponding phenyl-
thiyl-containing methyl carboxylates (5) (Figure 4). The
simple cycloalkenes 4a and 4b generated their products 5aa
and 5ba cleanly in yields of 73 and 71%, respectively. 1-
Methylene-2-methylcyclohexane (4c) provided its product 5ca
in 75% yield, whereas the Boc-protected piperidine 4d also
cleanly supplied the thioether 5da in 80% yield. 1-
Methyleneindane (4e) furnished its product 5ea in 51%
yield, whereas 2-methylenetetralin (4f) displayed the poorest
efficiency, providing 5fa/5fa′ (1.6:1 r.r.) in only 35% yield.
The naturally occurring terpene ( )-sabinene (4g) produced a
single diastereoisomer of the trisubstituted cyclopropane 5ga
in 74% yield. The fragmentative coupling of methyleneada-
mantane (4h) also generated the exo-phenylthio ester 5ha
exclusively in 51% yield.
Cycloalkenes bearing endocyclic olefins (6) were also
competent substrates, providing phenylthio-aldehydes (7) as
products (Figure 5). Simple hydrocarbon substrates (6a−c)
supplied the expected products 7aa−ca, respectively, in yields
from 63 to 75%. (+)-2-Carene (6d) furnished a single
diastereoisomer of the tetrasubstituted cyclopropane 7da in
65% yield. α-Terpineol (6e) gave the cyclic ketals 7ea/7ea′ in
C
DOI: 10.1021/acs.orglett.9b03186
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Letter
d.r.). The subsequent oxidation of the major diastereoisomer
(3ql) gave the sulfone 8 (see ORTEP of the solid-state
structure in Figure 6) in 43% overall yield from betulin,
providing facile access to previously inaccessible derivatives of
this natural product. Sulfones and sulfides are also useful
functional group handles that are widely used in organic
synthesis. When dealkenylative thiylation is combined with
terpenoid precursors, enantiopure synthetic intermediates are
readily generated. Oxidation, mesylation, and intramolecular
alkylation of the dihydrocarveol-derived thioether 3oa
produced the enantiomerically pure bicyclo[3.1.0]hexane 9
in 85% overall yield. Vinyl sulfides and sulfones are also useful
synthetic precursors.24 A sequence of oxidation, mesylation,
and elimination generated a single enantiomer of the vinyl
sulfone 10 in 96% yield from the thioether 3la. When
employing the dihydrocarvone-derived thioether 3ma′, we
found that the protected sulfone underwent iron-catalyzed
cross-coupling18a to provide the arylated products 11/11′ in
47% overall yield (4.3:1 d.r.). Finally, the oxidation of the
thioether 3ma to the sulfone, followed by Baeyer−Villiger
oxidation, gave the lactone 12 in 70% yield. Caprolactones are
employed widely as monomers for polymer synthesis,25 and
this approach establishes a route toward biorenewable
terpenoid-based caprolactones that are both diastereomerically
and enantiomerically pure.
In summary, we have demonstrated that alkene C(sp3)−
C(sp2) bond fragmentation and C(sp3)−S bond formation can
be combined under mild operating conditions when employing
abundantly available starting materials.26 This transformation,
which occurs upon ozonolysis and the subsequent FeII-
mediated SET-based reduction, is a facile means for the
diversification of natural products. We have also demonstrated
that the thiylated adducts could be elaborated for use in
organic synthesis and in the preparation of biologically relevant
materials. On a fundamental level, we have established a
deconstructive strategy of using olefins for the introduction of
heteroatoms in organic compounds. Further efforts directed
toward the application of this technology in the preparation of
pharmaceutically and synthetically useful adducts are under-
way.
Figure 6. Synthetic transformations of the thioether products.
Experiments were performed on ≥0.5 mmol scale. Isolated yields
after SiO2 chromatography. See the SI for experimental details.
42% yield (1.2:1 d.r.), the result of intramolecular trapping of
the aldehyde; in contrast, the corresponding acetate 6f
produced the uncyclized product 7fa in 61% yield. Upon
fragmentation, norbornylene (6g) generated the products 7ga
and 7ga′ (1.2:1 d.r.) in 50% yield. Intriguingly, attempts to
extend this transformation to generate benzaldehydes resulted
in the cyclization of the intermediate radical rather than
trapping with the disulfide species. 6-Methyl-5,6-didehydro-
benzocycloheptane (6h) provided the desired product 7ha in
only 5% yield while generating α-tetralone (7ha′) in 90%
yield.20
Figure 6 presents several examples of synthetic applications
in which we have employed this transformation. With regard to
medicinal agents, this process can be a tool for the
functionalization of biologically active compounds. We
examined the reaction of betulin (1q), which has wide
biological activities (in particular, anticancer and anti-HIV
properties)21 yet few functional group handles on the skeleton.
Notably, the cleavage of the C-19 C(sp3)−C(sp2) bond,
followed by the introduction of a heteroatom at this position is
rare,22 with most modifications occurring at the C-3 or C-28
positions.23 Dealkenylative thiylation of betulin readily
furnished the thioethers 3ql and 3ql′ in 78% yield (1.2:1
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03186.
■
S
Experimental procedures, detailed discussions, com-
pound characterization, and NMR spectra (PDF)
Accession Codes
CCDC 1913869 and 1917888 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 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ohyun@chem.ucla.edu.
ORCID
Ohyun Kwon: 0000-0002-5405-3971
D
DOI: 10.1021/acs.orglett.9b03186
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Letter
functionalization of C(sp3)−H bond. Org. Lett. 2014, 16, 3032−
Notes
3035. (c) Sahoo, S. K. A comparative study of Cu(II)-assisted vs
The authors declare no competing financial interest.
̊
̊
Cu(II)-free chalcogenation on benzyl and 2/3-cycloalkyl moieties. J.
Chem. Sci. 2015, 127, 2151−2157.
ACKNOWLEDGMENTS
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Merging C−H and C−C bond cleavage in organic synthesis. Nat. Rev.
Chem. 2017, 1, 1−16. (c) Morcillo, S. P. Radical-promoted C−C
bond cleavage: A deconstructive approach for selective functionaliza-
tion. Angew. Chem. 2019, 58, 2−13.
■
Financial support for this study was provided by the NIH
(R01GM071779). A.J.S. thanks the Majeti−Alapati fellowship
for funding. We thank the UCLA Molecular Instrumentation
Center for the NMR spectroscopy and mass spectrometry
instrumentation and for the X-ray diffraction studies (S. I.
Khan).
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NOTE ADDED AFTER ASAP PUBLICATION
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This paper was published on the Web on October 1, 2019.
Figures 1, 3, 4, and 6 were replaced, and the corrected version
was reposted on October 3, 2019.
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DOI: 10.1021/acs.orglett.9b03186
Org. Lett. XXXX, XXX, XXX−XXX