Difluorohomologation of ketones

Article abstract of DOI:10.1021/acs.orglett.5b00097

A method for the homologation of ketones with the CF₂ fragment is described. The reaction involves silylation, room-temperature difluorocyclopropanation of silyl enol ethers, and selective ring opening of cyclopropanes under acidic conditions. The whole three-step sequence is conveniently performed in a one-pot mode.

Full text of DOI:10.1021/acs.orglett.5b00097

Letter
pubs.acs.org/OrgLett
Difluorohomologation of Ketones
Mikhail D. Kosobokov, Vitalij V. Levin, Marina I. Struchkova, and Alexander D. Dilman*
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Leninsky prosp. 47, Russian
Federation
S
* Supporting Information
ABSTRACT: A method for the homologation of ketones with the CF2
fragment is described. The reaction involves silylation, room-temperature
difluorocyclopropanation of silyl enol ethers, and selective ring opening of
cyclopropanes under acidic conditions. The whole three-step sequence is
conveniently performed in a one-pot mode.
rganofluorine compounds have attracted significant
Scheme 2. Concept for CF2-Homologation
O
attention in recent years, primarily because of their
widespread applications in medicinal chemistry.1 While many
approved drugs contain either the trifluoromethyl group or
the fluorine atom as a substituent, there are only a few
examples of medicines bearing a difluoromethylene fragment.1
At the same time, there is steadily growing interest toward
CF2-containing compounds that is not only associated with
their utility in drug design2 but also due to unique properties
imparted by the CF2 unit in various fields such as metal-free
click cycloadditions,3 conformation analysis,4 and carbohydrate
chemistry.5
cyclopropanation of 3 under milder conditions using a system
for difluorocarbene generation which was recently developed
in our group.15
α,α-Difluoroketones constitute a valuable class of com-
pounds for drug discovery. Indeed, two fluorine atoms favor
the formation of hydrates which can inhibit proteolytic
enzymes by mimicking tetrahedral intermediates involved in
peptide hydrolysis6 (Scheme 1). Current methodologies for
Silyl enol ether 3a derived from acetophenone was selected
as a model substrate, and it was treated with (bromodifluoro-
methyl)trimethylsilane (Me3SiCF2Br)16,17 and hexamethyl-
phosphoramide (HMPA) at room temperature within 2 h15
(Table 1). Analysis of the reaction mixture by 19F NMR
indicated clean formation of cyclopropane 4a as the sole
product. However, when the reaction was worked up in a
conventional manner using water/hexane extraction, the crude
product contained 4a along with ketones 2a and 5 (Table 1,
entry 1). Our attempts to isolate cyclopropane 4a using
nonaqueous workup followed by flash chromatography on
silica gel were unsuccessful, again pointing to its instability.
Fragmentation of difluorocyclopropanol derivatives to
fluoroenones of type 5 has been observed in the literature.10,18
At the same time, facile formation of ketone 2a by
protonation of the cyclopropane C−C bond was unexpected,
and this prompted us to perform a screening of conditions to
effect this process selectively. Thus, stirring of a dichloro-
methane solution of 4a with aqueous acid or base in a
biphasic system again gave mixtures (entries 2 and 3).
Surprisingly, addition of methanesulfonic or trifluoroacetic
acids did not affect cyclopropane 4a (entries 4 and 5).
Addition of solutions of HCl in dioxane or HBr in acetic acid
Scheme 1. Hydrate Formation
their synthesis rely either on modification of existing α,α-
difluorocarbonyl functionality7 or on direct difluorination of
ketones which frequently require prior functionalization.8
Herein we report a practical protocol for the one-pot
conversion of readily available carbonyl compounds 1 into
their difluorinated homologues 2 (Scheme 2). Our concept is
based on facile room-temperature difluorocyclopropanation of
silyl enol ethers 3 and a discovery that cyclopropanes 4 may
undergo selective ring opening.9,10
While conventional cyclopropanols are well studied,11 their
gem-difluorinated derivatives have remained virtually unex-
plored despite the fact that numerous methods for the
addition of difluorocarbene to alkenes are known.12 In
particular, it has previously been described that silyl enol
ethers 3 can be converted to difluorocyclopropanes 4 at
elevated temperatures (using either PhHgCF3/NaI at 80 °C13
or BrCF2CO2Na at 150 °C14). We decided to perform
Received: January 12, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00097
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Letter
problem, and its reaction with 4 M HCl in dioxane was slow
even on heating! Switching to a more acidic system, HBr in
acetic acid, provided noticeable acceleration in the conversion
of 4o, but the reaction rate was not reproducible. Based on
the latter phenomenon, we conjectured that the reaction is
limited by desilylation of silyl ether, with the cyclopropanol
Table 1. Reaction of Enol Ether 3a
being the true intermediate undergoing the ring opening.21
A
hydroxyl group can engage in hydrogen bonding with a
molecule of solvent or adventitious water thereby fostering
cyclopropane fragmentation. Rewardingly, the addition of
about 10 equiv of water (100 μL per 0.5 mmol of substrate)
and heating with HBr/AcOH within 1 h gave difluoroketone
2o in excellent yield (Scheme 3). Finally, the whole sequence
involving silylation, cyclopropanation, and ring opening was
performed in a one-pot manner. In this case, evaporation of
dioxane was necessary before the addition of HBr/AcOH, and
this procedure afforded ketone 2o in 92% yield based on
tetralone.22
Under the optimized conditions, a variety of ketones were
subjected to the one-pot CF2-homologation (Table 2). Acyclic
and cyclic ketones provided products 2 in good yields. Even
isopropyl-substituted ketone 1n reacted nicely despite the fact
that intermediate cyclorpopane has to be attacked by the
proton at the quaternary carbon (entry 14). In the reaction of
α,β-unsaturated substrate 1j, analysis of the final reaction
mixture indicated partial addition of HBr to the CC double
bond, but typical basic workup (aq Na2CO3) caused
elimination of HBr leading to product 2j in excellent yield
(entry 10). In reactions of ketones 1e−g, the products were
unstable to HBr/AcOH (partial demethylation for 2e;
deallylation for 2f; decomposition for 2g), but switching to
a milder HCl/dioxane system afforded good yields of ketones
2e−g (entries 5−7).
In the reaction of p-nitroacetophenone 1q, expected
difluoroketone 2q was difficult to purify by chromatography,
likely, because of the addition of water at the CO group,
which is typical for fluorinated carbonyl compounds. In this
case, the crude product was reduced with sodium borohydride
affording alcohol 6 in 78% yield based on ketone 1q (Scheme
4).The reaction of acetophenone 1r bearing an ortho-
methoxycarbonyl group led to spirocyclic product 7, which
may form by lactonization of intermediate cyclopropanol.
When a typical one-pot procedure was applied to 1,1-
diphenylacetone (1s) and 1-adamantyl methyl ketone (1t),
a
b
no.
conditions
4a:2a:5a
1
2
3
4
5
6
7
workup with water/hexane
50:25:25
50:0:50
9:69:26
100:−:−
100:−:−
22:78:−
6:94:−
stirring with sat. aq Na2CO3, rt, 1 h
stirring with conc aq HCl, rt, 1 h
MsOH (5 equiv), rt, 1 h
TFA (5 equiv), rt, 1 h
4 M HCl (in dioxane) [8 equiv], rt, 18 h
33% HBr in AcOH [11 equiv], rt, 1 h
4 M HCl in dioxane [8 equiv], 65 °C, 1 h
c
8
−:100:−
a
Ratio was determined by 19F NMR for reaction mixtures.
b
c
Determined by 19F NMR of crude product. Transformation of 3a
to 4a was performed in dioxane.
to a dichloromethane solution of 4a provided homogeneous
systems. This effected the desired transformation of 4a to 2a,
though incomplete conversions were frequently observed
(entries 6 and 7). It should be pointed out that formation of
fluoroenone 5a was completely suppressed under these
strongly acidic conditions. Finally, use of dioxane as a solvent
for the difluorocarbene generation step and treatment of the
cyclopropane with 4 M HCl/dioxane at 65 °C during 1 h
provided difluoroketone 2a as the sole product (entry 8).
Then we decided to perform CF2-insertion into a cyclic
substrate. Since transformation of ketones into silyl enol
ethers using a silyltriflate/triethylamine combination is an
efficient process,19 we tried to perform difluorocyclo-
propanation in the same flask, simply by adding Me3SiCF2Br
and HMPA to a solution of formed silyl enol ether. This
concept was verified starting from α-tetralone 1o, which led to
clean formation of cyclopropane 4o (Scheme 3). Unexpect-
edly, product 4o turned out to be quite stable and reluctant
to undergo fragmentation on workup. However, this
compound undergoes partial decomposition on silica gel,
and after chromatography it was isolated in 43% yield as a
stable liquid.20 The enhanced stability of 4o proved to be a
Scheme 4. Reactions of Substrates 1p,q
Scheme 3. Reaction of Tetralone 1n
B
DOI: 10.1021/acs.orglett.5b00097
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Letter
hindrance slowing down either silylation or cyclopropanation
steps. For these substrates, a different one-pot protocol was
developed (Scheme 5). Ketones were silylated with LDA/
Table 2. CF2-Homologation of Ketones
Scheme 5. Reactions of Substrates 1r,s
Me3SiCl in THF under conventional conditions,23 followed by
solvent exchange to acetonitrile and addition of Me3SiCF2Br
and heating at 80 °C.24 Subsequent treatment of intermediate
cyclopropanes with HBr/AcOH furnished products 2s,t in
high yields.
It was also interesting to perform homologation of esters.
Thus, esters 8a,b were first treated with LDA and Me3SiCl in
THF to generate silyl ketene acetals 9 (Scheme 6). The latter
Scheme 6. Reactions of Esters
substances were not isolated but, after solvent exchange to
acetonitrile, were treated with Me3SiCF2Br/HMPA. As a
result, products 11a,b were isolated in reasonable yields,
formally corresponding to the alkylation of starting esters
8a,b.25 Presumably, initially formed cyclopropanes 10 are
unstable at room temperature, owing to the strong donating
effect of two oxygen atoms, and undergo rearrangement into
products 11.
In summary, a convenient protocol for the CF2-
homologation of ketones is described. The key feature of
the method is the selective protonation of difluorocyclo-
propane at the nonfluorinated fragment. At the same time, the
opportunity to effect difluorocyclopropantion of silyl enol
ethers under very mild conditions allows the three-step
sequence to be performed in a one-pot fashion.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, compound characterization data,
copies of NMR spectra for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
a
b
Isolated yield. The decrease in isolated yield is due to volatility of
c
d
the product. Determined by 19F NMR with internal standard. Ring
opening was performed using 4 M HCl in dioxane, 65 °C, 1 h.
AUTHOR INFORMATION
Corresponding Author
■
moderate yields of homologation products were obtained
(22% for 2s, 43% for 2t), which may be associated with steric
*E-mail: adil25@mail.ru.
C
DOI: 10.1021/acs.orglett.5b00097
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Letter
(13) Wu, S.-H.; Yu, Q. Acta Chim. Sinica 1989, 7, 253−257.
Notes
(14) Oshiro, K.; Morimoto, Y.; Amii, H. Synthesis 2010, 2080−
The authors declare no competing financial interest.
2084.
(15) Tsymbal, A. V.; Kosobokov, M. D.; Levin, V. V.; Struchkova,
M. I.; Dilman, A. D. J. Org. Chem. 2014, 79, 7831−7835.
(16) (a) Li, L.; Wang, F.; Ni, C.; Hu, J. Angew. Chem., Int. Ed.
2013, 52, 12390−12394. (b) Kosobokov, M. D.; Dilman, A. D.;
Levin, V. V.; Struchkova, M. I. J. Org. Chem. 2012, 77, 5850−5855.
(17) For miscellaneous applications of Me3SiCF2Br, see: (a) Levin,
V. V.; Zemtsov, A. A.; Struchkova, M. I.; Dilman, A. D. Org. Lett.
2013, 15, 917−919. (b) Kosobokov, M. D.; Levin, V. V.; Zemtsov,
A. A.; Struchkova, M. I.; Korlyukov, A. A.; Arkhipov, D. E.; Dilman,
A. D. Org. Lett. 2014, 16, 1438−1441. (c) Kosobokov, M. D.; Levin,
V. V.; Struchkova, M. I.; Dilman, A. D. Org. Lett. 2014, 16, 3784−
3787. (d) Zemtsov, A. A.; Kondratyev, N. S.; Levin, V. V.;
Struchkova, M. I.; Dilman, A. D. J. Org. Chem. 2014, 79, 818−822.
(e) Smirnov, V. O.; Struchkova, M. I.; Arkhipov, D. E.; Korlyukov, A.
A.; Dilman, A. D. J. Org. Chem. 2014, 79, 11819−11823.
(18) It was also reported that even silyl-protected difluorocyclo-
propanol 4a upon heating at 160 °C may eliminate Me3SiF with the
formation of enone 5a; see ref 13.
ACKNOWLEDGMENTS
■
This work was supported by the Ministry of Science (Project
MD-3256.2015.3), Russian Foundation for Basic Research
(Project 15-33-20133), and the Russian Academy of Sciences.
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D
DOI: 10.1021/acs.orglett.5b00097
Org. Lett. XXXX, XXX, XXX−XXX