Nucleophilic Vinylic Substitution (SNV) of Trisubstituted Monofluoroalkenes for the Synthesis of Stereodefined Trisubstituted Alkenes and Divinyl Ethers

Article abstract of DOI:10.1021/acs.orglett.1c02359

We herein describe a nucleophilic vinylic substitution (SNV) of trisubstituted monofluoroalkenes with excellent stereocontrol (d.r. > 99:1). Starting from (E)-β-monofluoroacrylates, various trisubstituted (E)-alkenes containing O/N/S-substituent groups at the vinylic position can be obtained under simple conditions. Furthermore, (E,E)-divinyl ethers can be generated through dimerization of the monofluoroalkenes, triggered by adventitious water in the reaction mixture.

Full text of DOI:10.1021/acs.orglett.1c02359

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Letter
Nucleophilic Vinylic Substitution (SNV) of Trisubstituted
Monofluoroalkenes for the Synthesis of Stereodefined
Trisubstituted Alkenes and Divinyl Ethers
Yuwei Zong, Qiao Ma, and Gavin Chit Tsui*
Cite This: Org. Lett. 2021, 23, 6169−6173
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ABSTRACT: We herein describe a nucleophilic vinylic substitution (SNV) of
trisubstituted monofluoroalkenes with excellent stereocontrol (d.r. > 99:1). Starting
from (E)-β-monofluoroacrylates, various trisubstituted (E)-alkenes containing O/N/
S-substituent groups at the vinylic position can be obtained under simple conditions.
Furthermore, (E,E)-divinyl ethers can be generated through dimerization of the
monofluoroalkenes, triggered by adventitious water in the reaction mixture.
ucleophilic vinylic substitution (SNV) is a useful
synthetic tool for directly generating compounds with
multisubstituted C−C double bonds including vinyl ethers and
enamines.1 In SNV, a leaving group (X) such as halogen is
replaced by a nitrogen, oxygen, sulfur, or carbon nucleophile
(Nuc) (Scheme 1a). The stereochemical outcome of the
cyclizations (Scheme 1b).4 Cao and co-workers more recently
contributed to the intermolecular version using various
nucleophiles (Scheme 1c).5 Mixtures of E/Z products were
often obtained and the ratios depended on the substrate and
nucleophile. The susceptibility of fluoroalkenes to nucleophilic
substitution can be reasoned by the following:3 (1) activation
of the double bond by the electron-withdrawing inductive
effect of fluorine; (2) β-anion stabilizing effect of fluorine
through negative hyperconjugation; (3) repulsive interaction
between fluorine lone pairs and π-electrons; (4) leaving group
ability of the fluoride ion.
N
Scheme 1. Nucleophilic Vinylic Substitution (SNV) of
Fluoroalkenes
In comparison with difluoroalkenes, the SNV reaction of
monofluoroalkenes 2 has been much less studied.5 The
conversion of a vinylic carbon−fluorine bond into a carbon−
heteroatom bond under simple conditions would be highly
attractive for obtaining multisubstituted alkenes 3 (Scheme
1d), which is especially applicable because of various available
stereoselective methods for preparing monofluoroalkenes 2.3,6
Moreover, this approach is complementary to conventional
methods such as nucleophilic conjugate additions to activated
alkynes7a−c and transition metal-catalyzed cross-couplings of
vinyl halides.7d,e
One major challenge remains that monofluoroalkenes are
intrinsically less reactive than difluoroalkenes toward nucleo-
philic substitution.8 Also, the E/Z selectivity is unpredictable,
alkene product is of significance and the subject of much
debate. Nucleophilic substitution of perfluorinated alkenes is a
well-known process in organofluorine chemistry.2 In particular,
gem-difluoroalkenes 1 are susceptible to nucleophilic sub-
stitution of the vinylic F via an addition−elimination
mechanism.3 Ichikawa and co-workers pioneered the intra-
molecular SNV of gem-difluoroalkenes through 5-endo-trig
Received: July 15, 2021
Published: July 27, 2021
https://doi.org/10.1021/acs.orglett.1c02359
© 2021 American Chemical Society
Org. Lett. 2021, 23, 6169−6173
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which can be influenced by the nature of nucleophiles,
substrates, and reaction conditions.1 For the method to be
synthetically practical and useful, the reaction ought to be
completely selective for generating stereodefined alkene
product 3.9 We herein introduce a novel SNV reaction of
trisubstituted monofluoroalkenes using oxygen-, nitrogen-, or
sulfur-containing nucleophiles to synthesize multifunctional
trisubstituted alkenes with excellent diastereoselectivities.
Our group has recently reported a series of protocols for the
synthesis of (E)-β-monofluoroacrylates 2 from tetrasubstituted
β,β-difluoroacrylates 1a via stereoselective Pd(0)-catalyzed C−
F bond activation (Scheme 2).10 We surmised that such type
Scheme 3. SNV Reaction of Monofluoroalkenes (E)-2 with
O/N/S-Containing Nucleophiles for the Synthesis of
a
Stereodefined Trisubstituted Alkenes (E)-4/5
Scheme 2. Reactivity and Diastereoselectivity of (E)-β-
Monofluoroacrylates in SNV Reaction with 4-
Methoxyphenol
of monofluoroalkenes could overcome the challenge of low
reactivity in SNV because of the activation of double bond by
the ester substituent group. However, the diastereoselectivity
in the product was not clear at the outset. Three representative
monofluoroalkenes (E)-2 bearing different substituent groups
R, including aryl,10c alkynyl,10a and hydrogen,10b were prepared
according to known procedures. They were subjected to the
SNV reaction using 4-methoxyphenol as a nucleophile and
K3PO4 as a base in DMF at 80 °C.5a Reactions indeed took
place with the isolation of the vinyl ether products 3a, 3b, and
4a in moderate to good yields. The diastereoselectivities, on
the other hand, depended heavily on the substituent group R.
Whereas tetrasubstituted monofluoroalkenes yielded mixtures
of diastereomers 3a and 3b in 74:26 to 85.5:14.5 ratios, the
trisubstituted monofluoroalkene afforded product (E)-4a, β-
phenoxyacrylate, as a single diastereomer. Its reactivity was also
the highest, with complete conversion only after 2 h.
β-Aryloxy-/alkoxyacrylates and vinyl ethers in general are
important structural motifs in natural products and versatile
synthons in organic synthesis.11 However, available methods
for the synthesis of trisubstituted β-aryloxyacrylates resembling
the structure of 4a with well-defined alkene geometry are very
limited.12 The SNV reaction of (E)-β-monofluoroacrylates 2
thus could offer a straightforward route to such class of
compounds. The scope of the reaction was subsequently
investigated (Scheme 3). Various substituted phenols afforded
the β-aryloxyacrylates 4b−e in good yields (90−95%),
tolerating electron-donating and -withdrawing groups at
different positions of the benzene ring. The reaction yield
was consistent at a larger scale (1.0 mmol, 88% 4a). Using
salicylaldehyde as a nucleophile led to decreased yield (4f),
whereas 2-naphthol was an effective nucleophile (4g). The
human hormone estrone generated compound 4h smoothly,
demonstrating the feasibility of late-stage modification by
a
General conditions: (E)-2 (0.1 mmol, E/Z > 99:1), nucleophile (1.5
equiv.), K3PO4 (2.0 equiv.), DMF (0.2 M). Isolated yields. Unless
specified otherwise, diastereomeric ratios (d.r.) of (E)-4/5 were
>99:1, determined by GC-MS and 1H NMR analyses. b80 °C, c23 °C,
d1.0 mmol scale, ed.r. = 97:3 and 89% yield at 80 °C, fd.r. = 96:4 and
g
62% yield at 80 °C, d.r. = 97:3.
installing a tethered acrylate functionality onto a natural
product core. Excellent diastereoselectivities were obtained
(d.r. > 99:1) in these products, however, for some compounds
(4e and 4f), we observed the deterioration of d.r. (96:4 to
97:3) at 80 °C. The E configuration of the alkene was verified
through the X-ray crystal structure of compound 4d (CCDC
2074407).13 Aliphatic alcohols including benzyl alcohol,
methanol, allyl alcohol, neopentyl alcohol, and cyclohexanol
were employed to synthesize β-alkoxyacrylates 4i−m.14 Full
conversions and excellent diastereoselectivities were observed;
however, the products were prone to decomposition by
column chromatography, thus resulting in lower isolated yields.
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Using isopropanol and diethyl malonate failed to give the
desired products because of byproduct formation at 80 °C.
Even a carboxylic acid could be used as nucleophile leading to
the vinyl acetate product 4n, albeit in a lower d.r. (97:3).
Next, the effects of the substituent groups R1 and R2 of
substrate 2 were investigated using 4-methoxyphenol. Electon-
rich or -deficient α-aryl groups were tolerated (4o−q).
Changing the ethyl ester group to bulkier isopropyl group
did not affect the reaction (4p vs. 4r). Heteroaromatic group
such as 3-thienyl was tolerated (4s). Benzyl derivatives were
high-yielding tolerating ortho substituent (4t−u). The
structure of 4t was verified by NOESY NMR experiments.
Varying the ester group from ethyl to benzyl and tert-butyl
decreased the yields (4t vs. 4v−w). A long-chain alkyl group at
α-position was also compatible (4x). Therefore, a modular
synthesis of (E)-4 was demonstrated where the nucleophile, α-
substituent and ester group can be easily varied, which
provides the advantage for SAR studies in drug discovery.
More importantly, single diastereomers (E) were obtained for
almost all of the products despite the steric and electronic
differences in the nucleophiles and substrates. The reaction
was not only limited to alcohols, various nitrogen- and sulfur-
containing nucleophiles were also effective furnishing the SNV
products 5 in good yields and excellent diastereoselectivities.
Morpholine afforded product 5a, which belongs to the family
of β-enamino esters that are versatile building blocks in organic
synthesis.15 Aromatic N-heterocycles are pharmaceutically
important, they were suitable nucleophiles for generating
indole (5b), benzimidazole (5c), imidazole (5d), and pyrazole
(5e) derivatives. A vinyl sulfide compound 5f was also
obtained in high yield by using 2-naphthalenethiol as the
nucleophile.
Interestingly, when subjecting monofluoroalkene 2a to
K3PO4 in DMF at room temperature without any nucleophile,
an unexpected dimeric product divinyl ether 6a was obtained
in 84% yield (1H NMR).16 The yield was improved in DMSO
and (E,E)-6a was isolated cleanly in good yields (89%, 92% at
1.0 mmol scale) as a single diastereomer (Scheme 4). Only a
few reports have observed the formation of bis(trans-2-
ethoxycarbonylvinyl)ether (i.e., compound 6, R1 = H, R2 =
Et),17 to the best of our knowledge, synthesis of multi-
substituted divinyl ethers such as 6a was unprecedented. The
reaction tolerated various aryl α-substituent group (R1)
containing electron-donating/-withdrawing groups and halo-
gens (6b−g). The structure of the product was unambiguously
confirmed through 6b (CCDC 2074399) by X-ray crystallog-
raphy.13 Replacing the ethyl ester group by isopropyl did not
affect the yield (compare 6e and 6h). Naphthyl and 3-thienyl
groups were also compatible (6i−j). With the benzyl-
substituted product 6k, the conversion was poor using
K3PO4.16 A stronger base NaOEt was necessary to provide
good yields of the benzylic compounds 6k−n bearing different
functional groups. The reaction yield decreased somewhat as
the steric bulk of the ester group was increased (compare 6k,
6o, and 6p). The compound containing a long-chain alkyl
group (6q) was also furnished. In all cases, excellent
diastereomeric ratios (>99:1) were obtained in the products.
The modular synthesis of novel divinyl ethers 6 with well-
defined alkene geometries (E,E) and tunable α-substituent
group (R1) and ester group (R2) was therefore achieved
through the base-mediated dimerization of monofluoroalkenes
2.
Scheme 4. Synthesis of Stereodefined Divinyl Ether (E,E)-6
from Monofluoroalkenes (E)-2
a
a
General conditions: (E)-2 (0.2 mmol, E/Z > 99:1), base, DMSO
(0.2 M), 12−48 h. Isolated yields. Diastereomeric ratios (d.r.) of 6
1
b
c
were determined by H NMR analysis. K3PO4 (3.0 equiv.), NaOEt
d
(2.0 equiv.), 1.0 mmol scale.
Furthermore, a convenient two-step sequence to prepare the
divinyl ether 6a directly from gem-difluoroalkene 1a without
the isolation of 2a was shown (eq 1). Following the Pd-
catalyzed hydrodefluorination step,10b simply switching sol-
vents and adding base allowed the isolation of (E,E)-6a in 68%
yield over two steps.
Further studies were carried out to shed light on the reaction
mechanisms (Scheme 5). Temperature effects on the
diastereoselectiviy were investigated using 2-naphthol as a
nucleophile with substrate 2a (Scheme 5a). The reactions gave
full conversions and were very selective at lower temperatures
(60 °C and below), but showed decreased selectivity at higher
temperatures. This effect was also observed with certain
nucleophiles such as 4-fluorophenol and salicylaldehyde (cf.
Scheme 3, 4e and 4f). Disubstituted monofluoroalkene (Z)-7
was prepared according to literature procedures18 and
subjected to the standard conditions with 4-methoxyphenol
(Scheme 5b). No SNV reaction occurred, indicating the
importance of the ester group for activating the double bond
(compare with 4o, Scheme 3). Tetrasubstituted monofluor-
oalkene 2t with (Z)-configuration was employed in the
standard SNV conditions leading to a mixture of (E/Z)-
products 3c (Scheme 5c). This result was analogous to that
using (E)-alkene as the substrate (compare with 3a, Scheme
2), thus showing that the SNV reaction of tetrasubstituted
monofluoroalkenes was unselective regardless of the (E)- or
(Z)-configuration. Substrate 2r was unreactive in the standard
conditions for generating divinyl ether products (Scheme 5d),
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divinyl ether intermediate 6. To probe the mechanism for the
formation of divinyl ethers 6, we added H2O18 to the standard
conditions using 2a (Scheme 5g). The O18-labeled product 6a′
was obtained in significant amounts. On the basis of this
evidence and literature report,17a the source of oxygen in 6 is
likely from adventitious water in the reaction mixture, in which
case, water acted as an effective nucleophile in the SNV with 2.
In summary, a nucleophilic vinylic substitution (SNV)
reaction has been developed for the synthesis of trisubstituted
alkenes containing vinylic O/N/S-substituents from (E)-β-
monofluoroacrylates. The stereocontrol of the alkene geometry
is complete, affording (E)-products exclusively. Moreover, by
omitting the nucleophile, novel (E,E)-divinyl ethers can be
generated from the same substrates in high yields and >99:1
diastereomeric ratios. A plausible explanation for the excellent
stereocontrol in the addition−elimination pathway is that the
incipient ester enolate could participate in intramolecular
hydrogen bonding with the β-hydrogen. As a result, the bond
rotation is restricted until β-F elimination takes place affording
the (E)-products.
Scheme 5. Mechanistic Studies
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02359.
Experimental procedures and spectral data (PDF)
Accession Codes
CCDC 2074399 and 2074407 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
■
Gavin Chit Tsui − Department of Chemistry, The Chinese
University of Hong Kong, New Territories, Hong Kong SAR,
China; orcid.org/0000-0003-4824-8745;
Email: gctsui@cuhk.edu.hk
despite its high yield in SNV with a phenol (cf. Scheme 2),
thereby demonstrating the superior reactivity of trisubstituted
monofluoroalkenes for dimerization.
Authors
It is intriguing that the SNV product 4a could also be
obtained from divinyl ether 6a, instead of monofluoroalkene
2a, in comparable yield and excellent diastereoselectivity
(Scheme 5e). This implied the possible intermediacy of
dimer 6, although not exclusively, for product 4, as similar
conditions were employed for the SNV reaction and
dimerization (cf. Schemes 3 and 4).16 Competition studies
were carried out by mixing divinyl ether 6a with mono-
fluoroalkenes 2c or 2b bearing different α-aryl substituent
groups, in the presence of the nucleophile (Scheme 5f). The
results revealed an interesting distribution of the SNV products
(4a vs. 4p or 4o) depending on the substituent X. With an
electron-withdrawing group (X = F), product 4p predomi-
nated. With an electron-donating group (X = OMe), almost
equal amounts of products 4a and 4o were obtained.
Therefore, monofluoroalkenes 2 containing different α-
substituent groups R1 may have different reactivities in the
SNV reactions, and thus their mechanistic pathways may also
differ, i.e., direct addition−elimination with 2 or through the
Yuwei Zong − Department of Chemistry, The Chinese
University of Hong Kong, New Territories, Hong Kong SAR,
China
Qiao Ma − Department of Chemistry, The Chinese University
of Hong Kong, New Territories, Hong Kong SAR, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02359
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Research Grants Council of
Hong Kong (CUHK 14301820) and the Chinese University of
Hong Kong (Faculty of Science Direct Grant for Research).
We also thank the Key Laboratory of Organofluorine
Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, for funding.
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