Radical Addition of SF5Cl to Cyclopropenes: Synthesis of (Pentafluorosulfanyl)cyclopropanes

Article abstract of DOI:10.1021/acs.orglett.1c01840

With the goal of accessing yet unknown SF5-cyclopropyl building blocks, the radical addition of SF5Cl to cyclopropenes was investigated. Addition of the SF5 radical occurs regioselectively at the less substituted carbon of cyclopropenes and trans to the m

Full text of DOI:10.1021/acs.orglett.1c01840

pubs.acs.org/OrgLett
Letter
Radical Addition of SF5Cl to Cyclopropenes: Synthesis of
(Pentafluorosulfanyl)cyclopropanes
Gauthier Lefebvre, Olivier Charron, Janine Cossy,* and Christophe Meyer*
Cite This: Org. Lett. 2021, 23, 5491−5495
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ABSTRACT: With the goal of accessing yet unknown SF5-
cyclopropyl building blocks, the radical addition of SF5Cl to
cyclopropenes was investigated. Addition of the SF5 radical occurs
regioselectively at the less substituted carbon of cyclopropenes and
trans to the most hindered substituent at C3, while chlorine atom
transfer proceeds with moderate to high levels of diastereocontrol.
The carbon−chlorine bond in the resulting adducts can undergo
subsequent radical reduction or be involved in a radical cyclization.
Scheme 1. Chloro(pentafluorosulfanylation) Reactions and
Radical Additions to Cyclopropenes
ppearing in the top 10 of the most encountered ring
1
Asystems in drugs, the cyclopropyl fragment is frequently
used to improve the potency, selectivity, and pharmacokinetic
properties of a lead compound and hence overcome bottle-
necks in drug discovery and development.2 Fluorine or
fluorinated groups can likewise address many roadblocks
during the development phases of a drug candidate and are
found in nearly one-third of marketed pharmaceuticals and
agrochemicals.3 As a logical consequence, the development of
synthetic methods toward cyclopropanes bearing fluorinated
groups, which combine both of these latter structural elements,
has elicited significant interest.4
The pentafluorosulfanyl group (SF5), which belongs to the
so-called “emerging fluorinated motifs” beyond the trifluoro-
methyl group (CF3),5 surpasses the latter substituent in terms
of electronegativity, lipophilicity, steric demand (with a unique
octahedral geometry), and hydrolytic stability.6 Not surpris-
ingly, pentafluorosulfanyl organic compounds have attracted
attention in medicinal chemistry, agrochemistry, and material
science.7 To date, (hetero)aromatic compounds incorporating
a SF5 group are undoubtedly the most represented
structures;6−8 hence, the development of new SF5-aliphatic
building blocks remains highly desirable.9 Despite the potential
interest in them, SF5-substituted cyclopropanes are still
unknown compounds to the best of our knowledge. To date,
the most general and practical entry to SF5-aliphatic
compounds remains the radical addition of SF5Cl to alkynes
or alkenes using Et3B as the initiator (Scheme 1A).10,11
Cyclopropenes are known to behave as radical acceptors, as
illustrated by the hydrostannylation of cyclopropenone
acetals,12 the addition of carbon-centered electrophilic radicals
generated from xanthates to similar substrates or cyclopropene
gem-dicarboxylates,13 the addition of the trichloromethyl
radical to cyclopropenoates,14 and the more recently disclosed
radical carbocyanation reaction15 (Scheme 1B).16
Herein, we report our results on the radical addition of
SF5Cl to cyclopropenes A and the investigation of the substrate
scope and subsequent manipulation of the carbon−chlorine
bond in the resulting adducts B, with the goal of accessing new
Received: June 2, 2021
Published: June 25, 2021
https://doi.org/10.1021/acs.orglett.1c01840
© 2021 American Chemical Society
Org. Lett. 2021, 23, 5491−5495
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Letter
diversely substituted SF5-cyclopropyl building blocks (Scheme
1C).
Scheme 3. Scope of the Addition of SF5Cl to Disubstituted
Cyclopropenes
a
Cyclopropenyl ester 1a, possessing a 2-(tert-butyldiphenyl-
silyloxy)ethyl group (TBDPS = Si-t-BuPh2),17 was treated with
SF5Cl (2 equiv), and the reaction was initiated by addition of
Et3B (10 mol %) and air (CH2Cl2, −40 °C, 1.5 h; then rt, 0.5
h). Under these conditions, the radical chain addition of SF5Cl
across the double bond of 1a proceeded smoothly, with perfect
control of the regioselectivity, and delivered a diastereomeric
mixture of β-chloro(pentafluorosulfanyl)cyclopropanes 2a and
2′a in a 90:10 ratio (78%, 5 mmol scale experiment). Analysis
1
of the H NMR spectrum of 2a and 2′a indicated a similar
vicinal coupling constant between cyclopropyl protons H1 and
H3 in both diastereomers,18 thereby confirming that addition
of the SF5 radical occurred at the less substituted carbon (C1)
of cyclopropene 1a on the face opposite to the ester moiety at
C3, as observed in other radical additions to cyclopropen-
oates.14,15 The resulting rapidly interconverting cyclopropyl
radical intermediates19 3a and 3′a suffer from a steric
interaction between the (CH2)2OTBDPS substituent and the
SF5 group (at C1) or the ester moiety (at C3), respectively.
However, the less stable invertomer 3a should undergo a faster
chlorine atom transfer from SF5Cl (trans to the sterically
demanding SF5 substituent at C1) compared to that of 3′a.
This would account for the formation of 2a as the major
diastereomer, the relative stereochemistry of which was
assigned by NMR spectroscopy (NOESY) (Scheme 2).20
a
The structure of the major diastereomer is shown. Indicated dr
values refer to the ratio of the two observed diastereomers (among the
four possible). Experiments on a 1−15 mmol scale for 1b−1j.
(72%, dr = 85:15). Substrate 1g, having the silyl ether located
at a more remote position compared to cyclopropene 1a, led to
similar results in terms of yield and diastereoselectivity and
afforded adducts 2g and 2′g (66%, dr = 87:13). By contrast,
substrate 1h, in which the TBDPS ether is separated from the
three-membered ring by a single methylene unit, provided
adducts 2h and 2′h with a decrease in diastereoselectivity (dr
= 70:30) and yield (45%) compared to those of 1a. The steric
hindrance of the silyloxy substituent may decrease the
efficiency of the chlorine atom transfer from SF5Cl at C2
and hence of the whole radical chain mechanism.21
Replacement of the TBDPS protecting group by the less
sterically hindered benzyl ether in substrate 1i improved the
yield of the corresponding adducts 2i and 2′i (60%, dr =
78:22) compared to that of 2h and 2′h. The scope is not
restricted to cyclopropenoates, as illustrated with the addition
of SF5Cl to cyclopropenes 1j and 1k possessing a moderately
electron-donating (acetyloxy)methyl group at C3, which
delivered the corresponding adducts 2j and 2′j (57%, dr =
90:10) and 2k and 2′k (72%, dr = 83:17), respectively
(Scheme 3). A competition experiment indicated that 1j
undergoes addition of the SF5 radical 3 times faster than
cyclopropenoate 1a. Indeed, the presence of a carboethoxy
group at C3 in substrate 1a, which is known to withdraw
electron density from the HOMO of the cyclopropene CC
bond,22 would slow down the addition of the electrophilic
pentafluorosulfanyl radical compared to that of 1j.
Investigation of the scope was pursued with cyclopropenes
gem-dicarboxylates 1l−1n (Scheme 4). Cyclopropenes 1l and
1m bearing two electron-withdrawing groups at C3 did not
react with SF5Cl, and only traces of adducts 2l and 2m were
detected by analysis of the crude reaction mixture by 19F NMR
spectroscopy. The presence of an electron-donating alkyl
substituent at C2 [R2 = (CH2)2OTBDPS] in cyclopropene 1n
enabled the radical addition of SF5Cl that provided cyclo-
propane 2n (26%) as a single diastereomer (trans addition of
SF5Cl). However, partial cleavage of the silyl ether in 2n,
presumably triggered by a fluoride source, also took place and
led to crystalline alcohol 4n (15%), the relative stereo-
Scheme 2. Addition of SF5Cl to Cyclopropene 1a
The reactivity of cyclopropane 1a was also compared to that
of the terminal alkyne and alkene possessing the same
(CH2)2OTBDPS substituent. A competition experiment
revealed that the radical addition of SF5Cl to cyclopropene
1a and to the terminal alkyne occurred at comparable rates
whereas the alkene reacted faster.20
The substrate scope was then investigated with cyclo-
propenes 1b−1k bearing one substituent at C3 and C2
(Scheme 3). Benzyl cyclopropenoate 1b led to similar results
compared to those for ethyl ester 1a, and the radical addition
of SF5Cl afforded cyclopropanes 2b and 2′b in 74% yield (dr =
87:13). Cyclopropene 1c, in which the alcohol was protected
as a benzoate, exhibited a reactivity comparable to that of silyl
ether 1a and provided cyclopropanes 2c and 2′c (83%, dr =
85:15). By contrast, benzyl ether 1d led to a complex mixture
of products from which the desired cyclopropane 2d was
isolated in low yield (<10%).20 Cyclopropene 1e bearing an
n‑pentyl chain at C2 cleanly led to cyclopropanes 2e and 2′e
(53%, dr = 85:15) without formation of a secondary alkyl
chloride resulting from a putative 1,5-hydrogen atom transfer
triggered by the cyclopropyl radical intermediate.15 Cyclo-
propene 1f possessing a 3-chloropropyl chain underwent an
efficient addition of SF5Cl and was converted to 2f and 2′f
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Scheme 4. Scope of the Addition of SF5Cl to
Scheme 5. Access to SF5-Cyclopropyl Building Blocks
gem‑Disubstituted or Trisubstituted Cyclopropenes
a
SF5Cl (2 × 1.5 equiv) and Et3B (2 × 10 mol %) were used for
substrates 1l−1o.
chemistry of which was unambiguously assigned by X-ray
diffraction analysis.23 A phenyl group at C3 also altered the
efficiency of the addition of SF5Cl to di- and trisubstituted
cyclopropenes 1o and 1p, respectively, and led to incomplete
conversions despite the presence of the electron-donating
CH2OAc substituent at the same position. Adducts 2o and 2′o
were isolated in low yield (17%, dr = 77:23), whereas 2p was
generated as a single detectable diastereomer (20%). In both
cases, addition of the SF5 radical occurred preferentially trans
to the more hindered phenyl group.20 By contrast, cyclo-
propenes 1q−1t with gem-di(acetoxymethyl) substitution
reacted smoothly with SF5Cl. After reduction of initial adduct
2q with DIBAL-H, tetrasubstitued cyclopropane 5q was
obtained as a single detectable diastereomer in 58% yield
(two steps from 1q). Cyclopropenes 1r−1t led to pentasub-
stituted cyclopropanes 2r−2t (53−77%), respectively. The
radical addition of SF5Cl was more efficient for cyclopropenes
1s and 1t having the TBDPS located at a more remote position
on the chain compared to substrate 1r (Scheme 4).
Having evaluated the scope of the radical addition of SF5Cl
to cyclopropenes, the subsequent transformation of the
carbon−chlorine bond in the resulting adducts was inves-
tigated.24 The implementation of a hydrodechlorination
process was considered, and this operation was achieved
under radical conditions by treating 2a and 2′a (dr = 90:10)
with (Me3Si)3SiH in the presence of AIBN as an initiator (10
mol %) (toluene, 80 °C, 6 h). Although reduction of the C−Cl
bond occurred efficiently, hydrogen atom transfer from
(Me3Si)3SiH to the cyclopropyl radical intermediate, generated
at C2, proceeded with little stereocontrol and led to epimeric
SF5-cyclopropanes 6a and 6′a in a 60:40 ratio (80%).
Reduction of chlorocyclopropanes 2g and 2′g, and 2h and
2′h, was likewise accomplished to afford the corresponding
SF5-cyclopropanes 6g and 6′g (73%) and 6h and 6′h (71%),
respectively, although partial separation of 6g (41%), 6′g
(32%), and 6h (43%) could be achieved. The structure of
crystalline 6h was unambiguously confirmed by X-ray
diffraction analysis (Scheme 5A). Reduction of the previously
obtained mixture of 6a and 6′a with DIBAL-H afforded the
corresponding cyclopropylcarbinols 7a (30%, dr = 95:5) and
7′a (30%) after purification by flash chromatography on silica
gel. After oxidation of 7a with Dess-Martin periodinane
(DMP), the resulting aldehyde 8 was involved in a reductive
a
b
Isolated yield of dechlorinated products. Diastereomeric ratio
c
(crude product). Isolated yield of the separated diastereomer.
amination with p-methoxybenzylamine to afford cyclopropyl-
methyl amine 9 (44%, two steps from 7a) (Scheme 5B).
Another complementary route to SF5-cyclopropylmethyl
amine derivatives25 was devised from cyclopropene 1u,
which was involved in a radical addition of SF5Cl. After
dechlorination under radical conditions, a mixture of the
epimeric N-(phthaloyl)cyclopropylmethyl amines 6u and 6′u
was obtained (46%, dr = 80:20) (Scheme 5C). The presence
of a carbon−chlorine bond in β-chloro SF5-cyclopropanes
could also be exploited to construct a new ring by a radical
cyclization, and this strategy was illustrated in the case of
substrate 2j. After reductive cleavage of the acetyl group, the
resulting alcohol 10 was involved in a conjugate addition to
ethyl propiolate to afford the corresponding β-alkoxy acrylate
11 (79%, two steps from 2j). The 5-exo-trig radical cyclization
was triggered by treatment of 11 with (Me3Si)3SiH.
Subsequent treatment with n-Bu4NF under buffered conditions
(AcOH, THF, rt) induced the cleavage of the silyl ether and
facilitated product isolation. Oxabicyclic compound 12 bearing
a controlled quaternary stereocenter was formed as a single
diastereomer and isolated in 49% yield (two steps from 11).
The relative stereochemistry of 12 was assigned by NMR
(NOESY) (Scheme 5D).20
In summary, we have demonstrated that cyclopropenes
constitute an interesting class of substrates in radical
chloro(pentafluorosulfanylation) reactions. Addition of the
electrophilic SF5 radical occurs regioselectively and with high
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01840.
Experimental procedures, 1H, 13C, and 19F NMR spectra,
and characterization data of new compounds (PDF)
Accession Codes
CCDC 2081921−2081922 contain the supplementary crys-
tallographic 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 Authors
■
Christophe Meyer − Molecular, Macromolecular Chemistry,
and Materials, ESPCI Paris-PSL, CNRS, 75005 Paris,
France; orcid.org/0000-0003-3420-5584;
Email: christophe.meyer@espci.fr
Janine Cossy − Molecular, Macromolecular Chemistry, and
Materials, ESPCI Paris-PSL, CNRS, 75005 Paris, France;
orcid.org/0000-0001-8746-9239; Email: janine.cossy@
espci.fr
Authors
Gauthier Lefebvre − Molecular, Macromolecular Chemistry,
and Materials, ESPCI Paris-PSL, CNRS, 75005 Paris,
France
Olivier Charron − Molecular, Macromolecular Chemistry, and
Materials, ESPCI Paris-PSL, CNRS, 75005 Paris, France
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01840
Notes
The authors declare no competing financial interest.
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contributions, see: (b) Cloutier, M.; Roudias, M.; Paquin, J.-F.
Regioselective Gold-Catalyzed Hydration of CF3- and SF5-alkynes.
Org. Lett. 2019, 21, 3866−3870. (c) Savoie, P. R.; von Hahmann, C.
N.; Penger, A.; Wei, Z.; Welch, J. T. The control of stereochemistry
by the pentafluorosulfanyl group. Org. Biomol. Chem. 2018, 16, 3151−
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SF5-Enolate Enables Preparation of 3-SF5-Quinolin-2-ones, 3-SF5-
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ACKNOWLEDGMENTS
Financial support from the ANR (DEFIS project, ANR-17-
CE07-0008) is gratefully acknowledged.
■
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LiHMDS, or LDA) have so far been unsuccessful.
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Yamasihita, K.; Matsuda, A. Conformational Restriction by Repulsion
between Adjacent Substituents on a Cyclopropane Ring: Design and
Enantioselective Synthesis of 1-Phenyl-2-(1-aminoalkyl)-N,N-diethyl-
5495
https://doi.org/10.1021/acs.orglett.1c01840
Org. Lett. 2021, 23, 5491−5495