Ring-Opening Diarylation of Siloxydifluorocyclopropanes by Ag(I) Catalysis: Stereoselective Construction of 2-Fluoroallylic Scaffold

Article abstract of DOI:10.1021/acs.orglett.7b03254

A silver-catalyzed, defluorination ring-opening diarylation of siloxy 2,2-difluorocyclopropanes, with two arenes, to directly prepare polysubstituted 2-fluoroallylic compounds, is described. This multicomponent reaction proceeds smoothly in good stereoselectivity, which is due to a chelation-controlled addition of arenes to α-fluorinated ketone intermediate.

Full text of DOI:10.1021/acs.orglett.7b03254

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ring-Opening Diarylation of Siloxydifluorocyclopropanes by Ag(I)
Catalysis: Stereoselective Construction of 2‑Fluoroallylic Scaffold
Xiaoning Song,† Cong Xu,† Dongxu Du,† Ziming Zhao,† Dongsheng Zhu,*,† and Mang Wang*,†,‡
†Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Faculty of Chemistry, Northeast Normal
University, Changchun 130024, China
‡State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China
S
* Supporting Information
ABSTRACT: A silver-catalyzed, defluorination ring-opening diary-
lation of siloxy 2,2-difluorocyclopropanes, with two arenes, to directly
prepare polysubstituted 2-fluoroallylic compounds, is described. This
multicomponent reaction proceeds smoothly in good stereoselectivity,
which is due to a chelation-controlled addition of arenes to α-
fluorinated ketone intermediate.
2-Fluoropropene is present as a privileged motif in a wide range
of medicinal and bioactive molecules.1,2 This substructure also
has relevance to material science.3 The striking features of these
compounds have encouraged many efforts for their prepara-
tion,4 among which dehalogenation ring-opening functionaliza-
tions of gem-halofluorocyclopropanes provide a general access
to 2-fluoroallylic scaffold (Scheme 1A).5 However, the
able examples still suffer from restricted substrate scope or
limited reaction mode. Reliable and facile methods for
stereoselective construction of the 2-fluoroallylic scaffold with
diverse substituents are highly desired.
gem-Difluorocyclopropanes are important fluoroorganics.11
Most research interests to date have focused on their
distinguished biological and physical properties as well as
their preparations.5a,12 However, their synthetic utilities have
hardly been explored, although they are expected to be readily
available fluorine-containing three-carbon synthons.13,14 Gen-
erally, simple gem-difluorocyclopropane derivatives undergo
thermodynamic ring-cleavage rearrangements at high temper-
ature.15 Catalytic ring-opening reaction provides an opportunity
for their applications.13,16 For instance, a new synthesis of 2-
fluoropropenes via Pd-catalyzed dehalogenation ring-opening
functionalization of gem-difluorocyclopropanes was recently
reported by Fu (Scheme 1B).16c The reactions proceeded in
stereoselectivity and could be extended to the nucleophilic trap
of Pd-intermediate with N-, O-, and C-nucleophiles.
Scheme 1. Metal-Catalyzed Dehalogenation Ring-Opening
Functionalizations of gem-Difluorocyclopropanes
In comparison, gem-difluorocyclopropanes bearing an O- or
N-based substituent on the three-numbered ring usually lack
stability.13 For example, the ring-opening of gem-difluorocyclo-
propanes derived from enol acetate easily occurred, affording
the homologous fluoroenones.17 This background reaction has
hampered practical applications of gem-difluorocyclopropanes
containing O- or N-substituents in synthesis.13 As part of our
ongoing interest in this field,18 we here report a preliminary
finding on stereoselectively Ag-catalyzed defluorination ring-
opening diarylations of gem-difluorocyclopropanes (Scheme
1C). The new chemistry of this work includes the following. (a)
First dehalogenation ring-opening difunctionalization of gem-
difluorocyclopropanes. The use of arenes expands the reaction
partners from heteroatom-based nucleophiles to carbon-based
ones. (b) This tandem process includes a chelation-controlled
processes generally lack satisfactory stereochemical control of
the olefin configuration. The reaction partners are limited to
heteroatom-based nucleophiles, such as amines or alcohols. In
addition, miscellaneous methods have also been used to
synthesize 2-fluoropropenes, for example, classical olefination
reactions of carbonyl compounds with a proper fluorine-
containing precursor,6 nucleophilic additions of fluoro-olefin
substrates with aldehydes,7 and hydrofluorination of alkynes.8
Current investigations have emphasized efficient and stereo-
selective routes to fluoroalkenes9 in which metal-catalyzed C−F
bond cleavage and allylic substitution of α,α-difluoroalkenes
with nucleophiles have been recognized as an alternative
representative to 2-fluoropropene target.9d,10 However, avail-
Received: October 18, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03254
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
addition of arenes to α-halo carbonyls which provides a
stereoselective method for the synthesis of monfluoroalkenes.
To the best of our knowledge, the stereoselective addition of C-
based nucleophiles to α-halo carbonyls under the chelation-
controlled conditions still challenges this field.19 (c) The
transformation broadens the application of gem-difluorocyclo-
propanes for general fluorine-containing three-carbon synthons
and provides a direct route to polysubstituted 2-fluoroallylic
compounds, which are expected to be used for the screening of
potential bio/pharmacological compounds.
Siloxy gem-difluorocyclopropane 1a was synthesized in situ
by the difluorocyclopropanation of 4-acetobiphenyl with
TMSCF2Br according to our previous work.18 Initially, we
investigated the defluorination ring-opening reaction of 1a with
1,2-dimethylindole 2a by the use of silver salt as the catalyst.
After 4 h of reaction at room temperature, α-fluoroketone 3a
was obtained in 59% yield under the catalysis of 10 mol %
AgBF4 in DCM (Table 1, entry 1). Interestingly, the reaction
the yield of 4a could be reached to 89% (entry 6). Notably, the
transformation proceeded with stereoselectivity delivering Z-4a
as major product (entry 6). However, further heightening
temperature resulted in low yield and poor stereoselectivity
(entry 8). We then turned to screen the silver catalysts,
including AgF, AgOTf, Ag2CO3, and AgNO3 (entries 9−12). It
was found that all the reaction could give desired 4a in 19% to
84% yields while AgBF4 was the best one. In addition, a screen
of other solvent revealed that the reactions also worked in THF
and MeCN (entries 13 and 14), but DMF was an ineffective
solvent. Fluoroenone was obtained via a background reaction17
in this case (entry 15).
With the optimized reaction conditions (Table 1, entry 6),
we then investigated the substrate scope of both 1 and 2. As
presented in Table 2, most tested conversions are efficient; for
example, the reactions of 1a with indoles 2 bearing different
substituents on the indole ring were well tolerated to provide a
set of 2-fluoroallylic compounds 4b−g in 63−91% yields
(entries 2−7). When 2,3-unsubstituted indole 1h was used as
a
Table 1. Survey of Reaction Conditions
a
Table 2. Substrate Scope of Both 1 and 2
a
Conditions: 1a which was synthesized in situ from 4-acetobiphenyl
b
(0.5 mmol), solvent (4 mL), in a sealed tube. Isolated yields based on
c
2a. The ratio of Z-4a and E-4a was determined by 19F NMR
d
spectroscopy of crude 4a. Yields were determined by 19F NMR
e
analysis using benzotrifluoride as an internal standard. Fluoro enone
was obtained.18c
also gave an unprecedented product, 2-fluoropropene 4a, likely
resulting from further nucleophilic addition and dehydration of
indole 2a with 3a. Considering that the addition of 2a to 3a
may involve a scarce chelation-controlled addition of arenes to
α-halo carbonyls19 and the 2-fluoropropene derivatives are
useful compounds,1,2 we systematically screened the reaction
conditions for the formation of 4a from 1a and 2a. As described
in Table 1, the efficiency of the conversion from 3a to 4a is
higher at 60 °C than at lower temperature (entries 1−7). With
the ratio of 1a to 2a as 1:2 at 60 °C, the reaction afforded 4a in
76% yield (entry 3). When the amount of AgBF4 was increased,
a
Conditions: 1 was synthesized in situ from corresponding ketones
(0.5 mmol), 2 (0.8 mmol), AgBF4 (0.08 mmol), DCM (4 mL), 60 °C,
b
c
4−6.5 h. Isolated yields based on 2. The ratio of Z- and E-isomer
was determined by 19F NMR spectroscopy of crude 4.
B
DOI: 10.1021/acs.orglett.7b03254
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Letter
the substrate, the reaction afforded 4h in 57% yield (entry 8).
The formation of this 2′,3-cross-substituted product 4h likely
resulted from a C3 to C2 migration of the alkenyl substituent of
the usual 3′,3-substituted product under the present reaction
conditions.20 On the other hand, a range of diverse gem-
difluorocyclopropanes, including those with electron-donating
or electron-deficient substituents at different positions of the
phenyl ring, were also found to be suitable to afford the desire
4i−q in 66−90% isolated yields (entries 9−17). In addition, 2-
naphthylated substrate 1r gave 4r in 83% yield (entry 18),
while 3-thienylated 1s furnished 4s in moderate yield (entry
19). In the case of 1t containing an alkylic R1 substituent, the
reaction had a complex results, in which product 4t was isolated
in 36% yield (entry 20). Furthermore, gem-difluorocyclopro-
pane 1u having two substituents on the three-membered ring
could also lead to the desired 2-fluoropropene product 4u in
moderate yield (entry 21). It is noteworthy that all the above
reactions produced 2-fluoroallylic compounds 4 in good to
excellent stereoselectivity.
carbocation with eletron-rich arenes in the ring-opening of gem-
difluorocyclopropanes and found a stereoselective addition of
arenes to α-fluoroketones for the first time by using Ag(I) as
chelating catalyst.
Following the success in three-component reactions of 1 and
two identical indoles, we turned our attention to the reactions
between 1 and two different arenes. We found that mixed
products 4 were always obtained if two different indoles 2 were
added in one pot at 60 °C. Reactions could be controlled to
furnish 3 at room temperature in a shorter time. In the case of
N-methyl-2-(methoxycarbonyl)indole as the substrate, only 3
was obtained even when reacting at 60 °C. Thus, we hoped to
add two indoles step by step under different conditions. For
example, we carried out the reaction of 1a with indole 2e at
room temperature for generating α-fluoroketone 3 and then
added the second indole 2c to this reaction system for further
addition at 60 °C. As a result, cross-substituted 4v was isolated
in 79% yields (Scheme 3). Other tested reactions also afforded
a
On the basis of reports of both ring-opening of gem-
halofluorocyclopropanes5 and chelation-controlled additions of
nucleophiles to α-halo carbonyl derivatives,19 a plausible
mechanism is tentatively proposed as described in Scheme 2.
Scheme 3. Reactions of 1 with Two Different Arenes
Scheme 2. Plausible Reaction Mechanism
a
b
Isolated yields based on Ar1H. Reaction with Ar1H at rt and with
Ar2H at 60 °C.
Z-4w−z in good yields (Scheme 3 and SI). Additionally,
pyrrole and phenol were proved to be suitable trapping
reagents for intermediate A (Scheme 2) in the ring-opening of
At first, Ag(I)-mediated defluorination ring-opening of 1
furnishes allylic cations A, which undergo a sequential
Friedel−Crafts reaction with arenes and a desilylation to give
3 via monofluoroalkene intermediates B. Next, Ag(I) salt acts
as chelating agent to coordinate with the fluorine and oxygen
atoms of the 3 to form a highly ordered transition state R- and
S-[Ag]-3, respectively. Sequential nucleophilic additions of
arenes to carbonyl group of R/S-[Ag]-3 obey Cram’s rule to
deliver adducts C and D in high diastereoselectivity.21 Finally,
either C or D can afford Z-4 as main product via E2-elimination
of AgOH, which will be for the next catalytic cycle. To the best
of our knowledge, C-based nucleophiles are rarely utilized in
dehalogenation ring-opening functionalizations of gem-halo-
fluorocyclopropanes.5 Stereoselective addition of C-based
nucleophiles to α-halo carbonyls under the chelation-controlled
conditions has still a challenge compared to addition of hydride
nucleophile.19 By comparison, we realized a well trap of
1
1, delivering 3 which could be detected by H NMR. But they
were inefficient nucleophiles for further addtion to 3, while
indoles could be used for this Ag-chelation-controlled addition
procedure leading to 4aa−ac in good yields. Delightfully, all
reactions in Scheme 3 afforded Z-4 as main products.
In conclusion, a tandem Ag-catalyzed defluorination ring-
opening diarylation reaction of siloxy 2,2-difluorocyclopropanes
for the synthesis of 2-fluoroallylic compounds, which are of
interesting importance in medicines and materials, is described.
The transformations efficiently proceed with high stereo-
selectivity, which is consistent with the transition state being
under chelation control. Arenes proved to be extended to
alkenes as nucleophilic partners. To the best of our knowledge,
this work provides the first example of ring-opening
difunctionalization of gem-difluorinated cyclopropanes, which
C
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Organic Letters
Letter
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ASSOCIATED CONTENT
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■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03254.
Experimental procedures, analytical data for new
compounds, and crystallographic data for 4e (PDF)
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CCDC 1576220 contains 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.
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AUTHOR INFORMATION
■
(14) For recent selected examples for applications based on ring-
opening of difluorocyclopropanes, see: (a) Yang, T. − P.; Lin, J. − H.;
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(b) Yang, T. − P.; Li, Q.; Lin, J. − H.; Xiao, J. − C. Chem. Commun.
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Chem. Soc. 2017, 139, 9152. (d) Dolbier, W. R., Jr.; Cornett, E.;
Martinez, H.; Xu, W. J. Org. Chem. 2011, 76, 3450. (e) Nihei, T.;
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Corresponding Authors
*E-mail: zhuds206@nenu.edu.cn.
*E-mail: wangm452@nenu.edu.cn.
ORCID
Xiaoning Song: 0000-0001-5507-8073
Cong Xu: 0000-0001-9817-7186
Mang Wang: 0000-0001-8006-4626
(15) Dolbier, W. R., Jr. Acc. Chem. Res. 1981, 14, 195.
(16) Recent selected examples for the catalyzed ring-opening of
difluorocyclopropanes, see: (a) Cheng, Z.-L.; Xiao, J.-C.; Liu, C.;
Chen, Q.-Y. Eur. J. Org. Chem. 2006, 2006, 5581. (b) Wenz, J.;
Rettenmeier, C. A.; Wadepohl, H.; Gade, L. H. Chem. Commun. 2016,
52, 202. (c) Xu, J.; Ahmed, E. − A.; Xiao, B.; Lu, Q. − Q.; Wang, Y. −
L.; Yu, C. − G.; Fu, Y. Angew. Chem., Int. Ed. 2015, 54, 8231.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Sciences Foundation of China
(NNSFC-21372040 and 21672032) and the State Key
Laboratory of Fine Chemicals (KF1502) for funding support
of this research.
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