Controlled Ring-Opening of Siloxydifluorocyclopropanes for Carbocyclization: Synthesis of Difluorocyclopentenones

Article abstract of DOI:10.1021/acs.orglett.6b01567

A highly controlled ring opening of siloxydifluorocyclopropanes, formed by nBuN₄Br-catalyzed difluorocyclopropanation of methyl vinyl ketones bearing a β-alkylthio group by using TMSCF₂Br as a unique difluorocarbene source, results in metal difluorohomoenolates with assistance of copper or silver followed by an intramolecular addition and elimination reaction leading to α-gem-difluorocyclopentenones efficiently.

Full text of DOI:10.1021/acs.orglett.6b01567

Letter
pubs.acs.org/OrgLett
Controlled Ring-Opening of Siloxydifluorocyclopropanes for
Carbocyclization: Synthesis of Difluorocyclopentenones
Xiaoning Song,† Shuangquan Tian,† 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 highly controlled ring opening of siloxydifluorocyclo-
propanes, formed by nBuN4Br-catalyzed difluorocyclopropanation of methyl
vinyl ketones bearing a β-alkylthio group by using TMSCF2Br as a unique
difluorocarbene source, results in metal difluorohomoenolates with assistance
of copper or silver followed by an intramolecular addition and elimination
reaction leading to α-gem-difluorocyclopentenones efficiently.
yclopropanols and their derivatives are widely used as
homoenolate equivalents (Scheme 1A).1,2 However,
corresponding siloxy, acyloxy, or alkoxyl derivatives were
reported to be isolable, their reactivity toward electrophiles
has been proven to be difficult to control. Competitive
dehalogenations often predominated the process leading to α-
halogenated enones.8−10 Although metal-mediated/catalyzed
ring-opening cross-couplings of cyclopropanols have been also
developed,11,12 no reports have appeared of a similar C−C
coupling based on siloxydihalocyclopropanes. In fact, besides a
report on thermal rearrangement cyclization of difluorovinyl-
cyclopropanol silyl ethers delivering siloxydifluorocyclo-
pentenes via a homolytic pathway (Scheme 1B),13,14 Ag-
initiated ring openings of these compounds underwent an
alternative cationic process to give siloxymonochlorocyclo-
pentadienes (Scheme 1C).15 To the best of our knowledge,
controlled ring openings of siloxy- or acyloxy-difluorocyclopro-
panes are limited in the use for further protonation9b,16,17a or
halogenation to date.17 The corresponding anion process via
metal difluorohomoenolate for C−C formation is unknown.
In the course of our research on the applications of
fluoroalkylsilanes,8,18 we recently reported a catalytic difluoro-
cyclopropanation of enolizable ketones8 by using TMSCF2Br as
a unique difluorocarbene source.19 The in situ generated
siloxydifluorocyclopropanes were used for the synthesis of α-
fluorinated enones8a and naphthols.8b Considering the
importance of developing siloxydifluorocyclopropanes into
difluorohomoenolate equivalents along with our interest in
ketene dithioacetal chemistry,20,21 we envisioned a domino
cyclization of α-acyl ketene dithioacetals and TMSCF2Br by
taking difluorohomoenolates as the key intermediates. To our
delight, tandem difluorocyclopropanation, ring opening, and
intramolecular addition and elimination reactions proceeded in
a controllable manner. gem-Difluorocyclopentenones, which
may be of particular interest for developing new bioactive
compound candidates,22 were obtained (Scheme 1D).
C
Scheme 1. Ring Opening of Siloxydihalocyclopropanes for
C−C Bond Formation
applications of their difluorinated analogs have met a
substantial challenge. Organofluorides often possess remarkably
enhanced chemical, physical, and bioactive properties. In view
of the fact that rapid assembly of a fluorine atom into organic
molecules can be achieved from fluorine-containing synthons,3
the development of difluorocyclopropanols into the control-
lable difluoro-homoenol equivalents is expected to bring new
opportunities to organofluorine chemistry and pharmacy.
Cyclopropanols can participate in many C−C bond forming
reactions2 via metal homoenolates, for example, in nucleophilic
addition onto carbonyls,4 conjugate addition,5 SN2′ alkylation,6
or acetylation.7 By comparison, gem-dihalogenated cyclo-
propanols are thermodynamically unstable. Although the
Received: May 31, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01567
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
We initially investigated the difluorocyclopropanation
reaction of α-acetyl ketene dithioacetal 1a with TMSCF2Br.
As we expected, siloxydifluorocyclopropane 2a was obtained in
almost quantitative yield under the catalysis of 5 mol %
nBuN4Br (TBAB) in toluene at 110 °C for 4 h (Table 1, step
Scheme 2. Scope of Ketene Dithioacetals 1
a
Table 1. Screening of Reaction Conditions
temp
time
(h)
yield (%) of
b
entry
catalyst
nBuN4F
(°C)
solvent
4a (3a)
1
rt
4
4
6
3
3
3
3
2
10
4
8
4
2
2
2
5
5
3
toluene
MeCN
MeCN
DCM
DCM
DCM
DCM
DCE
− (91)
− (89)
− (87)
− (83)
2
KF
rt
3
NaOAc
FeCl3
rt
4
rt
c
5
TiCl4
rt
trace
c
6
ZnI2
rt
− (49)
7
Cu(OAc)2
Cu(BF4)2·6H2O
CuCl
rt
− (94)
15 (53)
55 (40)
89
8
60
60
60
60
60
60
60
60
60
60
70
9
toluene
DCE
a
Conditions: Step 1: TMSCF2Br (2.5 equiv), TBAB (5 mol %),
10
11
12
13
14
15
16
17
18
CuCl
toluene (2.5 mL), 110 °C, 4 h; Step 2: CuCl (1.1 equiv), DCE (5
d
CuCl
DCE
39 (48)
trace
b
c
mL), 70 °C, 4 h. Isolated yields. Step 2: 10 h. Step 2: 80 °C, 10 h.
CuI
DCE
d
CuOTf was used.
CuBF4(MeCN)4
AgOTf
DCE
32 (61)
14 (69)
40 (18)
22 (50)
27 (47)
93
DCE
e
diethylthioacetals 1a−h, bearing either an electron-donating
or -withdrawing group at a different position of the phenyl ring,
could afford the desired 4a−h in excellent yields. By
comparison, bulky α-alkyl substituents of 1 have a deleterious
effect on the reaction.23 4i and 4j were isolated in 71% and 43%
yield, respectively. 1 containing α-ester, acyl, amide, and cyano
substituents also worked leading to 4k−n and 4o′ in good
yields under identical reaction conditions. Among them, 1o
with cyano as the R1 substituent furnished amide 4o′, which
resulted from further hydrolysis of the α-cyano group of 4o. In
addition, α-propionyl ketene dithioacetals 1p and 1q (R2 = Me)
could also provide 4p and 4q in satisfactory yields. Finally, both
the methylthio and benzylthio functional group were proven to
be tolerated in these reactions. Corresponding 3-methylthio-/3-
benzylthio-2-cyclopentenones 4r−z were obtained in 69−93%
yields.
On the basis of our knowledge on the reactivity of metal
homoenolates2,4−7 and the chemistry of ketene dithioace-
tals,20,21 as well as the use of TMSCF2Br in catalytic
difluorocyclopropanations of ketones,8 it was reasonable to
propose a domino mechanism as described in Scheme 3. First,
the reaction of 1 with Br−-activated TMSCF2Br afforded 2 via
catalytic enolization and difluorocyclopropanation. Then, upon
treatment of 2 with CuCl with assistance of a halogen anion,
copper alkoxide II was formed and converted to copper
difluorohomoenolate III by a β-carbon elimination. Next,
transfer of the coordination of copper from oxygen onto sulfur
in III gave IV which allowed an addition−elimination (IV to 4
via V) leading to gem-difluorocyclopentenones 4 as the
products. Some control experiments were then performed.
The presence of a radical scavenger could not decrease the
reaction efficiency (Scheme 3A), thereby excluding the free
radical process. To obtain information on the sulfur-
AgBF4
DCE
CuCl
CuCl
CuCl
MeCN
THF
DCE
a
Conditions: Step 1: 1a (0.5 mmol), TMSCF2Br (2.5 equiv), TBAB
(5 mol %), toluene (2.5 mL), 4 h, in sealed tube; Step 2: catalyst (1.1
b
c
equiv), solvent (5 mL). Isolated yields based on 1a. Along with a
d
e
complex mixture. With 0.5 equiv of CuCl. 4-FPhCC(SEt)2 was
obtained in 30% yield.
1).8a Then, the reaction conditions for ring opening and
recyclization of 2a were screened systematically. It was found
that a high temperature and long reaction time resulted in the
reaction complex. However, the use of a fluoride or a base as
the deprotecting reagent at room temperature led to α-
fluorinated enone 3a (entries 1−3). Considering the formation
of metal difluorohomoenolate2c for cyclization, we focused on
screening the metal catalysts, including Fe, Ti, Zn, Cu, and Ag
for ring opening of 2a (entries 4−15). Delightfully, the reaction
could give the desired gem-difluorocyclopentenone 4a in 15%
yield along with 3a in 53% yield in the presence of Cu(BF4)2·
6H2O in DCE at 60 °C (entry 8). Gratifyingly, CuCl afforded
4a in 89% yield (entry 10). By comparison, both CuI and
CuBF4(MeCN)4 were ineffective (entries 12 and 13). In the
case of silver salts as the catalyst, the reaction worked but gave
4a in low yield (entries 14 and 15). A screen of other solvents
revealed that DCE at 70 °C could provide somewhat better
efficiency (entry 18).
By using the optimized reaction conditions (Table 1, entry
18), the scope of this one-pot reaction was evaluated next. A
variety of α-oxo ketene dithioacetals were prepared for this
cyclization strategy. As described in Scheme 2, ketene
B
DOI: 10.1021/acs.orglett.6b01567
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
75−83% yields, while pure 6g could not be obtained due to its
instability toward chromatographic purification (for details, see
Supporting Information (SI)). Additional experiments with a
radical scavenger (TEMPO or BHT, 1.5 equiv) also excluded
the free radical process.
Scheme 3. Proposed Mechanism
As described above, a new route to functionalized
difluorocyclopentenones has been provided. Further trans-
formations of 4 are presented in Scheme 4 for highlighting the
Scheme 4. Transformations of Compound 4
synthetic potential. We first carried out a substitution24 of 4a by
benzylamine. 3-Aminodifluoro-cyclopentenone 7 was obtained
in 97% yield. Then, Pd-catalyzed cross-coupling of 4a with
PhB(OH)221a,25 gave 3-phenyldifluorocyclopentenone 8 in 61%
yield. Finally, condensation of 4v with hydrazine afforded
pyrimidodifluorocyclopentenone 9 efficiently.
In conclusion, we have developed a highly controlled ring
opening of siloxydifluorocyclopropanes which permits gen-
eration of metal difluorohomoenolates for carbocyclization. By
using TMSCF2Br as the unique difluorocarbene source, TBAB-
catalyzed difluorocyclopropanations of α-acyl ketene dithioa-
cetals produced siloxydifluorocyclopropanes. Copper
difluorohomoenolates were then formed which allows an
intramolecular SNV type reaction for the construction of α-
gem-difluorocyclopentenones. The one-pot process can be
extended to the transformation of vinylogous thioesters via a
silver difluorohomoenolate. The easy construction of densely
functionalized building blocks from readily available starting
materials makes the method well-suited for broad applications
in organic synthesis and drug design.
coordination stabilization of copper homoenolate IV for an SNV
type reaction, we also extended the reaction to vinylogous
thioesters 5. It was found that Z-5a reacted with TMSCF2Br to
afford gem-difluorocyclopentenone 6a in 78% yield (Scheme
3B). By contrast, no reaction was detected in the case of E-5a as
the substrate (Scheme 3C).
Interestingly, when we used AgBF4, instead of CuCl, for the
reactions of both E-5a and Z-5a, the cyclizations could furnish
6a efficiently. In fact, silver salts showed reactivity in the ring
opening and recyclization of 2a, but less efficiently than in the
case of CuCl (Table 1, entries 14 and 15). Compared with a
required coordination between copper and the cis-sulfur atom
for stabilization of IV, silver difluorohomoenolate VI likely
contained a coordination of silver with the C−C double bond
for further SNV reaction (Table 2). Thus, we focused on
extending the scope of vinylogous thioesters E-5 for the
cyclization strategy by the use of AgBF4 as the catalyst. As we
expected, all tested reactions worked well leading to 6b−6g in
ASSOCIATED CONTENT
* Supporting Information
■
S
a
Table 2. Domino Cyclizations of Vinylogous Thioesters
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01567.
Experimental procedures, analytical data for new
compounds (PDF)
Crystallographic data for 4a (CIF)
b
entry
R1
product 6
yield (%) of 6
1
2
3
4
5
6
7
4-OMePh
3-OMe, 4-OMePh
4-FPh
6a
6b
6c
6d
6e
6f
81
82
83
79
75
76
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: wangm452@nenu.edu.cn.
*E-mail: zhuds206@nenu.edu.cn.
Notes
4-ClPh
4-BrPh
2-FPh
c
nBu
6g
76
The authors declare no competing financial interest.
a
Conditions: TMSCF2Br (2.5 equiv), TBAB (5 mol %), toluene (2.5
mL), 100 °C, 4 h, then AgBF4 (1.1 equiv), DCE (5 mL), 60 °C, 2 h.
ACKNOWLEDGMENTS
We thank National Natural Sciences Foundation of China
(NNSFC-21372040), National Natural Science Foundation of
■
b
c
Isolated yields. Yield based on 1H NMR. Substrates with methylthio
functional group.
C
DOI: 10.1021/acs.orglett.6b01567
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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