Two-step conversion of carboxylic esters into distally fluorinated ketones: Via ring cleavage of cyclopropanol intermediates: Application of sulfinate salts as fluoroalkylating reagents

Article abstract of DOI:10.1039/c7ob00680b

Tertiary cyclopropanols easily available from carboxylic esters have been used in the synthesis of distally fluorinated ketones. Cyclopropane ring cleavage reactions in methanol with aqueous tert-butyl hydroperoxide in the presence of a copper(ii) acetate catalyst and sodium triflinate (Langlois reagent) afford β-trifluoromethyl ketones in 16-74% isolated yields. Sodium triflinate serves as a precursor of reactive trifluoromethyl copper species, enabling ring-opening trifluoromethylation, as evidenced by mechanistic studies. We also demonstrate here that other sulfinate salts, such as sodium 1,1-difluoroethanesulfinate, sodium 2-(4-bromophenyl)-1,1-difluoroethanesulfinate and sodium 1-(trifluoromethyl)cyclopropanesulfinate, can be used as fluoroalkylation reagents, resulting in the corresponding fluorinated ketones.

Full text of DOI:10.1039/c7ob00680b

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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Two-step Conversion of Carboxylic Esters into Distally Fluorinated
Ketones via Ring Cleavage of Cyclopropanol Intermediates:
Application of Sulfinate Salts as Fluoroalkylating Reagents†
Received 00th January 20xx,
Accepted 00th January 20xx
Yulia A. Konik,a Marina Kudrjashova,b Nele Konrad,b Sandra Kaabel,b Ivar Järving,b Margus Loppb
and Dzmitry G. Kananovichb*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Tertiary cyclopropanols easily available from carboxylic esters have been used in the synthesis of distally fluorinated ketones.
Cyclopropane ring cleavage reactions in methanol with aqueous tert-butyl hydroperoxide in the presence of a copper(II)
acetate catalyst and sodium triflinate (Langlois reagent) affords β-trifluoromethyl ketones in 16-74% isolated yields. Sodium
triflinate serves as a precursor of reactive trifluoromethyl copper species, enabling ring-opening trifluoromethylation, as
evidenced by mechanistic studies. We also demonstrate here that other sulfinate salts, such as sodium
1,1-difluoroethanesulfinate,
sodium
2-(4-bromophenyl)-1,1-difluoroethanesulfinate
and
sodium
1-(trifluoromethyl)cyclopropanesulfinate, can be used as fluoroalkylation reagents, resulting in the corresponding
fluorinated ketones.
Introduction
The development of new methodologies to obtain fluorine-
containing molecules is currently in focus because of the high
need for these transformations for the synthesis of new
materials, agrochemicals and especially drugs.1 Distally
fluorinated ketones (such as β-, γ- and δ-) are suitable for the
synthesis of fluorinated heterocycles and fragments of bioactive
molecules and, consequently, methods to obtain these
compounds in an operationally simple single-step process are
required.2 Recent approaches to access these carbonyl
compounds are mostly based on transformations of alkene
substrates,3 e.g. electron-deficient olefins4 and allylic alcohols.5
The cleavage of strained cyclopropane and cyclobutane rings is
a developing alternative strategy for the preparation of distally
functionalized organofluorine compounds.6 Cyclopropanes with
activating
electron-donating
substituents,
such
as
cyclopropanols, are easily accessible from carboxylic esters via
Kulinkovich reaction7 and undergo ring cleavage under mild
conditions to afford ketone products.8 That strategy was
successfully employed for the preparation of β-fluoroketones.9
Our group,10 independently of the Dai11 and Xu12 groups, about
two years ago reported a convenient one-step procedure to
synthesize β-trifluoromethyl ketones via the copper-catalyzed
cleavage of cyclopropanols with Togni reagents (Scheme 1,
reaction 1). Soon after that, Dai et al. found that fluoroalkyl
halides as coupling partners perform a similar copper-catalyzed
ring cleavage reaction, considerably expanding the scope of the
method (Scheme 1, reaction 2).13
We previously assumed10 that cyclopropanol ring cleavage
occurs due to a reaction with high-valent СF3Cu species
generated in situ from
a copper(I) catalyst and Togni
reagent.1f,14 A similar mechanism could also exist in the case of
fluoroalkyl halides.13 Based on these considerations, we
envisioned the generation of the same reactive intermediates
from other organofluorine precursors, thus providing
alternatives to Togni reagents. Trifluoromethyl copper(I)
a.Department of Organic Chemistry, Belarusian State University, Leningradskaya
14, 220050, Minsk, Belarus.
b.Department of Chemistry, Tallinn University of Technology, Akadeemia tee 15,
12618, Tallinn, Estonia. E-mail: dzmitry.kananovich@ttu.ee
† Electronic Supplementary Information (ESI) available: Experimental details and
spectral data. See DOI: 10.1039/x0xx00000x
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Table 1 Screening of the reaction conditions a
species1d are available from trifluoromethyltrimethylsilane
(TMSCF3, Ruppert reagent)15,16 or even by direct cupration of
fluoroform,17,18 and can be converted to the corresponding
copper(II) and copper(III) compounds by oxydation.15,19,20 Solid,
stable and relatively inexpensive sodium triflinate (Langlois
reagent)21 could be used for the same purpose, providing a basis
for creating sustainable industrial processes. In the present
paper, we report the results of our studies on the application of
Langlois reagent and related sulfinate salts in a ring-opening
fluoroalkylation reaction of tertiary cyclopropanols (Scheme 1,
reaction 3) for the preparation of distally fluorinated ketones.
View Article Online
DOI: 10.1039/C7OB00680B
Entry
Catalyst (mol%)
Solvent
Yield of 3a
(%)b
32
70
54
0c
1
2
[Cu(CH3CN)4]BF4 (10%)
CuCl (10%)
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
t-BuOH
(CF3)2CHOH
DMF
DMF
MeOH
MeOH
3
CuI (10%)
Results and discussion
4
CuCN (10%)
5
6
CuSO4·5H2O (10%)
Cu(OTf)2 (10%)
35
55
72
77
64
23
0
Our first attempt, to our delight, gave a positive result: when 1-
benzylcyclopropanol (1a) was mixed with sodium triflinate (3
equiv.) and a catalytic amount of [Cu(CH3CN)4]BF4 (10 mol%) in
methanol and tert-butylhydroperoxide (TBHP, 70% in water)
was added drop-wise at room temperature, the desired
trifluoromethylketone 3a was formed in 32% yield, according to
1H NMR analysis (Table 1, entry 1). The other main component
of the reaction mixture was mostly unreacted cyclopropanol 1a
(about 60%). The addition of a triflinate salt and TBHP to the
same reaction mixture, however, did not reduce the amount of
the starting material, probably due to inactivation of the copper
catalyst. Using other copper(I) salts, nearly full conversion of
cyclopropanol 1a was achieved with 10 mol% of CuCl, affording
ketone 3a in 70% yield (entry 2). CuI was less active (entry 3),
and CuCN was completely inactive (entry 4). However, in the
case of CuCl-catalyzed reactions, some amount of β-chloro
ketone by-product was formed. Therefore, copper(II) salts with
non-nucleophilic anions were screened as catalysts. Although
both copper(II) sulfate (entry 5) and triflate (entry 6) led to the
formation of ketone 3a, the yields were low, the starting
material was incompletely consumed and enhanced amounts of
by-products formed. The most efficient catalyst used was
copper(II) acetate (entry 7), affording the target ketone 3a in
72% yield, with high conversion (> 85%) of the starting material.
Looking for suitable reaction conditions, we found that full
conversion of the starting cyclopropanol could be achieved in
the presence of at least 20 mol% of Cu(OAc)2, affording product
3a in a 77% yield (entry 8). Thus, the amount of copper catalyst
was shown to be crucial for higher conversion of the
cyclopropanol substrate.
7
8
9
10
11
12
13
14
15
Cu(OAc)2·H2O (10%)
Cu(OAc)2·H2O (20%)
Cu(OAc)2·H2O (20%)
Cu(OAc)2·H2O (20%)
Cu(OAc)2·H2O (20%)
Cu(OAc)2·H2O (20%)
Cu(OAc)2·H2O (100%)
−
74
75d
0e
Cu(OAc)2·H2O (100%)
0f
a
Reaction conditions: 1a (0.5 mmol), 2 (1.5 mmol), catalyst (mol%), solvent (2.5
b
mL), oxidant TBHP (1.5 mmol, 70% aqueous solution), open flask at r.t. Yields
were determined by 1H NMR spectroscopy using internal standard. c No reaction.
d
e
25% of vinyl benzyl ketone (4a) formed. No reaction f In the absence of TBHP,
ketone 4a is produced.
In the presence of other metal catalysts, such as iron,
manganese or cobalt acetates, or in the absence of any
transition metal catalyst, no trifluoromethylation reaction
occurs (entry 14). Without TBHP, slow oxidation of
cyclopropanol 1a with Cu(OAc)2 affords vinyl ketone 4a (entry
15). In contrast to trifluromethylation of cyclopropanols with
Togni reagents,10-12 no inert atmosphere was required and the
reaction was performed in an open flask. Although the
experiments were performed at room temperature, an increase
in the reaction temperature was observed when TBHP was
added. The reaction is noticeably exothermic in methanol with
20 mol% of the copper catalyst, probably due to simultaneous
solvent oxidation. On the other hand, after the cooling of the
reaction mixture to 0 °C, no reaction occurred. When the
reaction was performed at 1 mmol substrate scale (in 5 mL of
methanol) the temperature of the reaction mixture was
maintained within 30-35⁰C by slow dropwise addition of TBHP
(within 30 min). If the addition of the oxidant is too fast,
temperature can rapidly increase above 45⁰C what inevitably
leads to boiling the solvent up. The use of stoichiometric
amounts of copper salt in methanol or in DMF as the reaction
medium reduces heat evolution and makes the reaction more
easily controllable. Under the optimal reaction conditions (100
Methanol was found to be the most suitable reaction medium,
compared with other alcohols (entries 9-11). As an alternative,
dimethylformamide can also be used (entries 12-13), affording
the target ketone 3a in nearly the same yields due to the
formation of vinyl ketone by-product 4a. Peroxide oxidants
other than TBHP (e.g. K2S2O8, urea hydrogen peroxide complex
and sodium percarbonate) were inefficient in producing
trifluoromethylation product 3a. It should be noted that the
presence of copper salt and TBHP as oxidant are essential to
mol%
Cu(OAc)2,
and
methanol
as
a
solvent),
produce trifluoromethyl ketone 3a
.
1-benzylcyclopropanol 1a was converted to the corresponding
trifluoromethyl ketone 3a in 68% isolated yield (Table 2).
2 | J. Name., 2012, 00, 1-3
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To elucidate the scope of the method, the trifluoromethylative
cleavage of other cyclopropanol substrates 1b-j was The impurities were separated by column chromatography to
investigated (Table 2). These are easily accessible from afford ketones 3c and 3b in 74% and 45% isolated yields,
carboxylic esters, using Kulinkovich reactions7 (see Supporting respectively. In the latter case, the isolated yield was diminished
Information). Alkyl-substituted substrates 1b (R = n-pentyl) and due to the volatility of the product.23 Further examples of
ARTICLE
View Article Online
DOI: 10.1039/C7OB00680B
1c (R = 3-chloropropyl) reacted remarkably well. Extraction with functionalized
trifluoromethyl
ketones,
such
as
pentane and solvent evaporation afforded almost pure tetrahydropyran derivative 3d and diethylacetal 3e, also were
β-trifluoromethyl ketones 3b and 3c, with only a small amount obtained smoothly from the corresponding cyclopropanols.
of the corresponding β-chloro ketone by-products (up to 10- Cyclopropanol 1f with a Boc-protected piperidine moiety in the
15%; presumably formed due to the presence of NaCl impurity presence of a 20 mol% copper(II) acetate catalyst afforded
in the commercial samples of Langlois reagent22).
ketone 3f in 63% yield (79% b.r.s.m, since 22% of the starting
material 1f was recovered). In addition to benzyl cyclopropanol
1a, the reactions of cyclopropanol substrates 1g-i with aryl
moieties affording ketones 3g-i were investigated. In
comparison with aliphatic substrates, diminished yields of the
Table 2 Substrate scope for the reactions of cyclopropanols with sodium triflinatea
target fluoroketones 3 were observed in these cases due to the
formation of ketone by-products accompanying ring-cleavage
reaction, which was especially noticeable for cyclopropanol 1i
with an electron-donating methoxy substituent in the phenyl
ring.24
The results obtained with aromatic substrates prompted us to
test the behavior of cyclopropanol 1j with a terminal double
bond, which could undergo radical trifluoromethylation.21
Although the yield of the corresponding trifluoromethyl ketone
3j was low in this case, the major product identified in the
reaction mixture was the corresponding vinyl ketone 4j (about
50% yield) with unaffected terminal double bond, while the
content of products originating from trifluoromethylation of the
latter did not exceed 15%. It should be noted that an attempt to
cleave the cyclobutane ring in 1-phenylcyclobutanol failed
under the reaction conditions used, and the formation of the
expected γ-trifluoromethyl ketone was not observed.
The performing of brief substrate screening allowed us to
conclude that Langlois reagent can serve as a suitable
replacement for the Togni reagents performing ring-opening
trifluoromethylation of cyclopropanols. Compared with Togni
reagents, the limitation of the method arises from the necessity
of using an external oxidant (TBHP) which could enable an
oxidation side reaction for sensitive functional groups and the
cyclopropanol unit itself.25 However, considering the higher
stability of sodium triflinate26 and its lower cost, such a
replacement should still be considered, especially when the
desired product does not contain aromatic or other labile
towards oxidation or radical trifluoromethylation functional
groups.
In order to clarify the mechanism of the cleavage reaction, some
special experiments were performed. First, in order to get
evidence for the participation of radical species in the
trifluoromethylation of cyclopropanol 1b, the reaction was
performed in the presence of a radical scavenger TEMPO (3
equiv.). We found that TEMPO efficiently blocks the
trifluoromethylation of cyclopropanol 1b (Scheme 2, a) to
afford only a small amount (ca. 8%) of trifluoromethyl
ketone 3b. Instead, the formation of TEMPO-CF3 adduct in 52%
yield was observed (see Supporting information). This result
indicates the presence of CF3 radicals under the reaction
conditions, which was known before for the oxidation of a
a
Reaction conditions (unless otherwise noted): 1 (1 mmol), CF3SO2Na (3
mmol), Cu(OAc)2·H2O (1 mmol), TBHP (3 mmol, 70% in water, dropwise
addition 15-30 min), and MeOH (5 mL), open flask, r.t. Isolated yields after
b
column chromatography on silica gel, NMR yields are given in parentheses.
c Isolated yield is low due to high volatility of the compound 3b. d The reaction
was performed in the presence of 20 mol% Cu(OAc)2. e Starting compound 1f
was recovered after the reaction in 22% yield. f TBDPS = tert-butyldiphenylsilyl.
g Corresponding vinyl ketone 4j is formed as major product
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trifluoromethyl copper species. The process poVsiseiwbAlyrticbleeOgnilnines
with oxidation of sodium triflinaDtOeI: 10w.10it3h9/C7tOeBr0t-0b6u8t0yBl
hydroperoxide in the presence of Cu(I) catalyst,27 generating a
trifluoromethyl radical. The latter could react with copper(II)
and/or with copper(I) species to afford the corresponding
trifluoromethyl copper(III) and copper(II) complexes, which are
the actual trifluoromethylating agents. Both species may lead to
the ring cleavage of the cyclopropanol via the preliminary ligand
exchange step, and the subsequent single electron transfer step
to afford β-oxocarbonyl radical or, alternatively, via an
electrophilic attack resulting in β-metaloketone intermediate.
The reductive elimination of copper(I) from the latter gives β-
trifluoromethyl ketone, and the same product could also form
via the β-oxocarbonyl radical pathway. These two alternative
pathways result in opposite regioselectivity of the ring cleavage
in the case of 1,2-disubstututed cyclopropanols: the reactions
mediated by β-oxocarbonyl radicals proceed via a selective
cleavage of the most substituted C1-C2 bond, affording more
stable secondary radical (SET pathway), while the electrophilic
species usually attack the less substituted C1-C3 bond of
cyclopropane. In our case of 1-methyl-2-butyl cyclopropanol
Scheme 2 TEMPO inhibition experiment (a) and ring cleavage of disubstituted
cyclopropanol 1k (b). Standard conditions: CF3SO2Na (3 equiv.), Cu(OAc)2 (1 equiv.),
TBHP (3 equiv.). Yields were determined by 19F NMR spectroscopy using internal
standard.
Langlois reagent with TBHP.21 On the other hand, when the
same experiment was performed in the presence of Fe(OAc)2
(which is inefficient in catalyzing trifluoromethyl ketone
formation), the formation of TEMPO-CF3 adduct was also
observed. These results lead to the assumption that although
CF3 radicals are necessary to initiate the reaction, they cannot
accomplish the ring cleavage of a cyclopropanol substrate.
Instead, they serve as precursors of other reactive species.
Based on that assumption, and taking into account that the
copper catalyst is essential for the reaction, we may propose
that trifluoromethyl copper species are the actual reactive
intermediates that perform the ring-cleavage of cyclopropanols
(Scheme 3).
(1k) reaction at standard reaction conditions in the presence of
100 mol% of the copper catalyst (Scheme 2, b), the preferred
formation of ketone 3ka was observed. This result indicates the
domination of the electrophilic pathway, although minor
amounts of isomeric ketone 3kb could be formed via the SET
pathway initiated by copper(II) species. Similar regioselectivity
was observed in the case of Togni reagents,11-12 indicating the
similarity of both reaction mechanisms with the action of similar
reactive intermediates in both transformations.
In order to obtain further evidence for the generation of
trifluoromethyl copper intermediates, the trifluoromethylation
reaction was performed in DMF-d7 and monitored by 19F NMR
spectroscopy. Although paramagnetic copper(II) species are
unobservable by NMR, trifluoromethyl complexes of
diamagnetic copper(I) and copper(III) are well documented15-19
The mechanism of cyclopropanol ring cleavage with Langlois
reagent leading to β-trifluoromethyl ketone product presented
in Scheme 3 is close to that proposed for the Togni reagent.10
The only difference may be the origin of the active
Scheme 3 Plausible mechanism of the cyclopropanol trifluoromethylation reaction.
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29
and can be observed by the characteristic “CuCF3” region in the attributed to known CuCF3 and Cu(CF3)2– species. The further
View Article Online
19F NMR spectrum (–20 to –40 ppm).28 After the addition of addition of TBHP (up to 3 equiv.) led to the appearance of
DOI: 10.1039/C7OB00680B
nearly 1 equiv. of TBHP to the NMR tube containing premixed several additional resonance lines in the same region of the
cyclopropanol 1b, the copper(II) acetate catalyst (1 equiv.) and spectrum (see Supporting Information), with chemical shifts
the Langlois reagent (3 equiv.), we observed, besides the close to the known trifluoromethyl copper(III) complexes (about
formation of the expected trifluoromethyl ketone 3b (t, –66.6 −35 ppm).15,19
ppm), two singlet signals at –28.7 and –32.6 ppm, which can be
Table 3. Substrate scope for the reactions with different sulfinate salts a
Entry Starting compound 1
Sulfinate salt
CH3CF2SO2Na
Product
Yield
(%)b
1
59 (76)
50 (69)
CH3CF2SO2Na
CH3CF2SO2Na
2
3
66 (75)c
67 (77)
4
5
23 (47)
13 (17)
CFH2SO2Na
CFH2SO2Na
6d
7d
13 (20)
a Reaction conditions (unless otherwise noted): 1 (0.5 mmol), RFSO2Na (1.5 mmol), Cu(OAc)2·H2O (0.1 mmol, 20 mol%), TBHP (1.5 mmol, 70% in water, dropwise addition
b
15min), and MeOH (2 mL), open flask, r.t. Isolated yields after column chromatography on silica gel, NMR yields are given in parentheses. c Starting compound 1f
recovered after reaction in 12% yield. d The reaction was performed using 100 mol% of Cu(OAc)2·H2O catalyst.
We expected that, besides the Langlois reagent, the related affording the corresponding γ-difluoroketones
5 in 50-66%
sulfinate salts30-32 would react via a similar mechanism and, isolated yields (entries 1-3), including ketone 5c with a Boc-
therefore, could be used for the preparation of more diverse protected piperidine moiety. Sodium 2-(4-bromophenyl)-1,1-
functionalized fluorinated ketones (Table 3). Indeed, sodium difluoroethanesulfinate also reacted smoothly with benzyl
1,1-difluoroethanesulfinate (CH3CF2SO2Na) behaved similarly, cyclopropanol 1a under standard reaction conditions, giving the
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6 in good yield (67%) and with only a were given in δ value with CHCl3 (δ = 7.26) and CDCl3V(iδew=Ar7ti7cl.e1O6n)lianes
corresponding ketone
1
13
DOI: 10.1039/C7OB00680B
minor amount of benzyl vinyl ketone 4a as the by-product internal standards for H NMR and C NMR spectra, respectively.
(entry 4). The solid compound could be recrystallized to afford HRMS data was obtained on an Agilent HPLC/Q-TOF G6540A Mass
a single crystal suitable for X-ray analysis, thus providing proof Spectrometer. Single crystal X-ray diffraction data was collected at
of its structure (see Supporting Information).‡
123.0K on a Rigaku Compact HomeLab diffractometer, equipped
6
In contrast to α,α-difluoromethanesulfinate salts, the same with a Saturn 944 HG CCD detector and Oxford Cryostream cooling
reaction with sodium 1-(trifluoromethyl)cyclopropanesulfinate system using monochromatic Cu-Kα radiation (1.54178Å) from a
was not as successful, affording cyclopropyl ketone
7
in only MicroMaxTM-003 sealed tube microfocus X-ray source. Melting
23% isolated yield (47% by NMR, entry 5). Moreover, we found points were determined with Stuart SMP40 apparatus.
that sodium fluoromethylsulfinate (CFH2SO2Na) is unsuitable in
affording high yields of the corresponding fluorinated ketones
General procedure for the preparation of β-trifluoromethyl
ketones 3a-j.
under the standard reaction conditions. Thus, only minor
A 25 mL round-bottomed flask was charged with Cu(OAc)2·H2O
amounts (13% yield) of γ-fluoroketones 8a and 8b were isolated
(200 mg, 1 mmol, 100 mol%) and CF3SO2Na (468 mg, 3 mmol).
when CFH2SO2Na was employed as the fluoroalkylating agent
Methanol (1 mL) was added and mixture was stirred for 5 min
(entries 6 and 7).
allowing partial dissolution of the salts. Then a solution of
cyclopropanol
1 (1 mmol) in methanol (4 mL) was added. After
that, tert-butyl hydroperoxide solution (70% in water, 0.41 mL,
3 mmol) was added dropwise via syringe (without a metal
needle) for 30 min. During the addition of oxidant, the reaction
mixture usually warms up. The solution was stirred for an hour
and then diluted with saturated ammonium chloride (5 mL)
upon cooling with cold water bath. Water phase was extracted
with appropriate solvent (pentane or methylene chloride, 4 × 5
mL) and dried (MgSO4). The solvent was carefully evaporated
Conclusions
We have demonstrated that ring-opening fluoroalkylation of
cyclopropanols can be easily achieved with a Langlois reagent
and related sulfinate salts as an alternative to Togni reagents,
affording distally fluorinated ketones in satisfactory yield. We
can confirm that the copper-catalyzed trifluoromethylation of
cyclopropanols with both Langlois and Togni reagents proceeds
via similar reactive trifluoromethyl copper species, which are
responsible for the cyclopropanol substrate ring opening. Some
experimental evidence for the formation of trifluoromethyl
copper species under the reaction conditions were obtained.
The obtained results provide expectations for further
development of the method for the preparation of distally
fluorinated ketones from cyclopropanols.
(at about 400-200 mmHg) and β-trifluoromethyl ketones 3 were
purified by silica gel column chromatography.
5,5,5-Trifluoro-1-phenylpentan-2-one (3a). Isolated yield: 68%
(147 mg). Column chromatography eluent – pentane/diethyl
1
ether, 20:1. Н NMR (400 MHz, CDCl3): δ = 7.38–7.26 (m, 3H),
7.22–7.18 (m, 2H), 3.73 (s, 2H), 2.71 (m, 2H), 2.43–2.31 (m, 2H).
13C NMR (100.6 MHz, CDCl3): δ = 204.72, 133.61, 129.47, 129.07,
127.50, 127.00 (q, J = 275.7 Hz), 50.19, 34.33 (q, J = 2.6 Hz),
28.09 (q, J = 29.8 Hz). 19F NMR (376 MHz, CDCl3): δ = −66.6 (t, JHF
= 10.9 Hz). Spectral data correspond to those previously
Acknowledgements
Funding from the European Union’s Seventh Framework
Program for research, technological development and
demonstration grant No. 621364 (TUTIC-Green), from the
Centre of Excellence in Molecular Cell Engineering grant No.
2014-2020.4.01.15-0013, from the Estonian Ministry of
Education and Research grant IUT 19-32 and from Tallinn
University of Technology grant No B58 is gratefully
acknowledged. Y.K. is grateful to the Dora Plus program for
financial support of a short research stay at the Tallinn
reported 10
.
1,1,1-Trifluorononan-4-one (3b). Isolated yield: 45% (88 mg).
Column chromatography eluent – pentane/diethyl ether, 20:1.
1Н NMR (400 MHz, CDCl3): δ = 2.67 (m, 2H), 2.47–2.37 (m, 4H),
1.59 (quint, J = 7.2 Hz, 2H), 1.22–1.37 (m, 4H), 0.89 (t, J = 7.1 Hz,
3H). 13C NMR (100.6 MHz, CDCl3): δ = 207.41, 127.13 (q, J =
275.7 Hz), 42.94, 34.99 (q, J = 2.5 Hz), 31.45, 28.05 (q, J = 29.8
University of Technology. S.K. and I.J. are grateful to research Hz), 23.60, 22.55, 14.02. 19F NMR (376 MHz, CDCl3): δ = −66.7 (t,
JHF = 10.9 Hz). HRMS (AJESI) calcd. for C9H15F3ONa+ [M+Na]+
219.0973, found m/z 219.0985.
grants IUT19-9 and PUT692 for support.
7-Chloro-1,1,1-trifluoroheptan-4-one (3c). Isolated yield: 74%
(150 mg). Column chromatography eluent – pentane/diethyl
ether, 20:1. Н NMR (400 MHz, CDCl3): δ = 3.58 (t, J = 6.2 Hz,
Experimental
1
Sodium triflinate (Langlois reagent) and other sulfinate salts were
purchased from Sigma-Aldrich. The only exception was sodium
fluoromethylsulfinate, which was purchased from Aspira Scientific.
All solvents and chemicals were used as obtained from commercial
suppliers. Silica gel 40–100 μm was used for column
chromatography; silica gel 60 F254 plates were used for TLC. 1H NMR
(400 MHz), 19F NMR (376 MHz) and 13C NMR (100.6 MHz) spectra
were taken on a Bruker Avance III spectrometer. Chemical shifts
2H), 2.71 (m, 2H), 2.66 (t, J = 7.0 Hz, 2H), 2.48–2.36 (m, 2H), 2.07
(quint, J = 6.8 Hz, 2H). 13C NMR (100.6 MHz, CDCl3): δ = 205.93,
127.00 (q, J = 275.7 Hz), 44.35, 39.45, 35.22 (q, J = 2.6 Hz), 28.00
(q, J = 29.9 Hz), 26.24. 19F NMR (376 MHz, CDCl3): δ = −66.7 (t,
JHF = 10.9 Hz). Spectral data correspond to those previously
reported 10
.
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Organic & Biomolecular Chemistry
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Journal Name
4,4,4-trifluoro-1-(tetrahydro-2H-pyran-4-yl)butan-1-one
ARTICLE
(3d). (s, 3H), 3.25 (m, 2H), 2.65–2.53 (m, 2H). 13C NMR (100.6 MHz,
View Article Online
DOI: 10.1039/C7OB00680B
Isolated yield: 64% (135 mg). Column chromatography eluent – CDCl3): δ = 196.31, 160.08, 137.58, 129.92, 127.28 (q, J = 275.7
pentane/diethyl ether, 5:1. 1Н NMR (400 MHz, CDCl3): δ = 4.02 Hz), 120.74, 120.18, 112.42, 55.63, 31.49 (q, J = 2.6 Hz), 28.54
(ddd, J = 11.5, 4.2, 2.6 Hz, 2H), 3.43 (td, J = 11.5, 2.8 Hz, 2H), 2.72 (q, J = 29.7 Hz). 19F NMR (376 MHz, CDCl3): δ = −66.4 (t, JHF = 10.9
(m, 2H), 2.59 (tt, J = 11.1, 4.3 Hz, 1H), 2.48–2.36 (m, 2H), 1.82– Hz). HRMS (AJESI) calcd. for C11H10F3O3− [M−H]− 247.0582, found
1.66 (m, 4H). 13C NMR (100.6 MHz, CDCl3): δ = 208.24, 127.07 m/z 247.0565.
(q, J = 275.7 Hz), 67.25, 47.69, 32.75 (q, J = 2.6 Hz), 28.18, 28.03 1,1,1-Trifluorotetradec-13-en-4-one (3j). Isolated yield: 16% (41
(q, J = 29.9 Hz). 19F NMR (376 MHz, CDCl3): δ = −66.6 (t, JHF = 10.8 mg). Column chromatography eluent – pentane/diethyl ether,
Hz). HRMS (APCI) calcd. for C9H14F3O2+ [M+H]+ 211.0946, found 50:1. 1Н NMR (400 MHz, CDCl3): δ = 5.81 (ddt, J = 16.9, 10.2, 6.7
m/z 211.0928.
Hz, 1H), 4.99 (ddt, J = 16.9, 2.4, 1.6 Hz, 1H), 4.93 (ddt, J = 10.2,
1,1-Diethoxy-6,6,6-trifluorohexan-3-one (3e). Isolated yield: 56% 2.4, 1.3 Hz, 1H), 2.67 (m, 2H), 2.47–2.34 (m, 4H), 2.03 (m, 2H),
(136 mg). Column chromatography eluent – pentane/diethyl 1.59 (m, 2H), 1.37 (m, 2H), 1.28 (m, 8H). 13C NMR (100.6 MHz,
1
ether, 20:1. Н NMR (400 MHz, CDCl3): δ = 4.87 (t, J = 5.6 Hz, CDCl3): δ = 207.40, 139.30, 127.13 (d, J = 275.7 Hz), 114.30,
1H), 3.71–3.63 (m, 2H), 3.56–3.49 (m, 2H), 2.77–2.74 (m, 4H), 42.98, 35.00 (q, J = 2.5 Hz), 33.92, 29.44, 29.41, 29.27, 29.19,
2.46–2.34 (m, 2H), 1.19 (t, J = 7.0 Hz, 6H). 13C NMR (100.6 MHz, 29.03, 28.06 (q, J = 29.7 Hz), 23.90. 19F NMR (376 MHz, CDCl3):
CDCl3): δ = 204.32, 127.05 (q, J = 275.6 Hz), 99.96, 62.64, 47.69, δ = −66.6 (t, JHF = 10.9 Hz). HRMS (APCI) calcd. for C14H24F3O+
36.47 (q, J = 2.6 Hz), 27.80 (q, J = 29.9 Hz), 15.31. 19F NMR (376 [M+H]+ 265.1774, found m/z 265.1757.
MHz, CDCl3): δ = -66.7 (t, JHF = 10.9 Hz). Spectral data correspond
10
to those previously reported
.
General procedure for the preparation of distally fluorinated
ketones 5-8 using sulfinate salts.
tert-Butyl 4-(4,4,4-trifluorobutanoyl)piperidine-1-carboxylate (3f).
The reaction was performed using 20 mol% of Cu(OAc)2·H2O
catalyst (0.2 mmol, 40 mg). Isolated yield: 63% (194 mg). Column
chromatography eluent – petroleum ether/ethyl acetate (15:1
– 2:1). Starting material 1f was recovered in 22% yield (52 mg).
1Н NMR (400 MHz, CDCl3): δ = 4.13 (br s, 2H), 2.84–2.70 (m, 4H),
A 10 mL vial was charged with Cu(OAc)2·H2O (20 mg, 0.01 mmol,
20 mol%) and the corresponding sodium sulfinate salt (1.5
mmol). Then a solution of cyclopropanol
1 (0.5 mmol) in
methanol (2 mL) was added. After that, tert-butyl
hydroperoxide solution (70% in water, 0.21 mL, 1.5 mmol) was
2.50 (tt, J = 11.5, 3.8 Hz, 1H), 2.46–2.35 (m, 2H), 1.83 (br d, J = added via syringe (without a metal needle) for 15 min. The
12.7 Hz, 2H) 1.62–1.48 (m, 2H), 1.46 (s, 9H). 13C NMR (100.6
MHz, CDCl3): δ = 208.48, 154.74, 127.05 (q, J = 275.9 Hz), 79.88,
48.76, 43.20 (br s), 33.04 (q, J = 2.6 Hz), 28.55, 28.01 (q, J = 29.8
Hz), 27.56. 19F NMR (376 MHz, CDCl3): δ = −66.6 (t, JHF = 10.9 Hz).
copper catalyst slowly dissolves upon addition of oxidant. The
solution was stirred until the reaction is complete (usually
within 1h) and then diluted with saturated ammonium chloride
(5 mL) upon cooling with cold water bath. Water phase was
extracted with pentane or diethyl ether (4 × 5 mL) and dried
(MgSO4). The solvent was carefully evaporated (at about 400-
200 mmHg) and corresponding fluorinated ketones were
purified by silica gel column chromatography.
−
HRMS (AJSE) calcd. for C14H21F3NO3 [M−H]− 308.1479, found
m/z 308.1482.
6,6,6-Trifluoro-1-phenylhexan-3-one (3g). Isolated yield: 64% (147
mg). Column chromatography eluent – pentane/diethyl ether,
1
20:1. Н NMR (400 MHz, CDCl3): δ = 7.31–7.26 (m, 2H), 7.22–
5,5-Difluoro-1-phenylhexan-2-one (5a). Isolated yield: 59% (63
mg). Column chromatography eluent – pentane/diethyl ether,
7.16 (m, 3H), 2.92 (t, J = 7.5 Hz, 2H), 2.78 (t, J = 7.5 Hz, 2H), 2.64
(m, 2H), 2.45–2.33 (m, 2H). 13C NMR (100.6 MHz, CDCl3): δ =
206.23, 140.68, 128.72, 128.40, 127.03 (q, J = 275.7 Hz), 126.44,
44.39, 35.31 (q, J = 2.6 Hz), 29.82, 27.99 (q, J = 29.9 Hz). 19F NMR
1
20:1. Н NMR (400 MHz, CDCl3): δ = 7.37–7.31 (m, 2H), 7.30–
7.27 (m, 1H), 7.23–7.18 (m, 2H), 3.73 (s, 2H), 2.73–2.59 (m, 2H),
2.22–2.05 (m, 2H), 1.57 (t, JHF = 18.4 Hz, 3H). 13C NMR (100.6
MHz, CDCl3): δ = 206.53, 134.01, 129.52, 128.97, 127.33, 123.72
(t, J = 238.0 Hz), 50.32, 34.83 (t, J = 3.8 Hz), 31.85 (t, J = 25.7
Hz), 23.86 (t, J = 27.8 Hz). 19F NMR (376 MHz, CDCl3): δ = −92.5
(m). HRMS (AJESI) calcd. for C12H15F2O+ [M+H]+ 213.1085, found
m/z 213.1081.
1-Chloro-7,7-difluorooctan-4-one (5b). Isolated yield: 50% (50
mg). Column chromatography eluent – pentane/diethyl ether,
20:1. 1Н NMR (400 MHz, CDCl3): δ = 3.58 (t, J = 6.3 Hz, 2H), 2.66
(t, J = 7.2 Hz, 4H), 2.16 (tt, JHF = 16.9, JHH = 7.5 Hz, 2H), 2.10 –
2.01 (m, 2H), 1.61 (t, JHF = 18.3 Hz, 3H). 13C NMR (100.6 MHz,
CDCl3): δ = 207.81, 123.69 (t, J = 238.0 Hz), 44.49, 39.56, 35.67
(t, J = 3.8 Hz), 31.83 (t, J = 25.8 Hz), 26.37, 23.91 (t, J = 27.8 Hz).
19F NMR (376 MHz, CDCl3): δ = −92.5 (m). GC-MS (EI) m/z 198,
200 (M+).
(376 MHz, CDCl3): δ = −66.6 (t, JHF = 10.9 Hz). Spectral data
10
correspond to those previously reported
.
1-((tert-Butyldiphenylsilyl)oxy)-5,5,5-trifluoropentan-2-one (3h).
Isolated yield: 56% (220 mg). Column chromatography eluent –
pentane/diethyl ether, 20:1. 1Н NMR (400 MHz, CDCl3): δ =
7.65–7.62 (m, 4H), 7.48–7.38 (m, 6H), 4.20 (s, 2H), 2.83 (m, 2H),
2.44–2.32 (m, 2H), 1.11 (m, 9H). 13C NMR (100.6 MHz, CDCl3): δ
= 207.33, 135.64, 132.44, 130.28, 128.10, 127.08 (q, J = 275.7
Hz), 69.70, 31.51 (q, J = 2.8 Hz), 27.65 (q, J = 30.0 Hz), 26.88,
19.34. 19F NMR (376 MHz, CDCl3): δ = −66.7 (t, JHF = 10.8 Hz).
10
Spectral data correspond to those previously reported
.
4,4,4-Trifluoro-1-(3-methoxyphenyl)butan-1-one (3i). Isolated
yield: 45% (112 mg). Column chromatography eluent –
pentane/diethyl ether, 20:1. 1Н NMR (400 MHz, CDCl3): δ = 7.54
(m, 1H), 7.49 (m, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.14 (m, 1H), 3.86
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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Organic & Biomolecular Chemistry
Page 8 of 10
ARTICLE
Journal Name
tert-Butyl 4-(4,4-difluoropentanoyl)piperidine-1-carboxylate (376 MHz, CDCl3): δ = −220.5 (tt, JHF = 47.3, 27.V0iewHAzr)t.iclHe ORnMlinSe
+
+
DOI: 10.1039/C7OB00680B
(5c). Isolated yield: 66% (100 mg). Column chromatography (AJSESI) calcd. for C14H24FNO3Na [M+Na] 296.1632, found m/z
eluent – petroleum ether/ethyl acetate (15:1 – 2:1). Starting 296.1635.
material 1f was recovered in 12% yield (14 mg). Н NMR (400
1
MHz, CDCl3): δ = 4.11 (br s, 2H), 2.78 (m, 2H), 2.68 (m, 2H), 2.50
(tt, J = 11.4, 3.7 Hz, 1H), 2.15 (tt, JHF = 17.1, JHH = 7.5 Hz, 2H),
Notes and references
1.88–1.76 (m, 2H), 1.61 (t, JHF = 18.3 Hz, 3H), 1.60–1.48 (m, 2H),
1.45 (s, 9H). 13C NMR (100.6 MHz, CDCl3): δ = 210.37, 154.79,
123.72 (t, J = 238.0 Hz), 79.81, 48.89, 43.36 (br s), 33.36 (t, J =
3.7 Hz), 31.77 (t, J = 25.6 Hz), 28.57, 27.65, 23.99 (t, J = 27.8 Hz).
19F NMR (376 MHz, CDCl3): δ = −92.7 (m). HRMS (AJESI) calcd.
for C15H25F2NO3Na+ [M+Na]+ 328.1695, found m/z 328.1702.
6-(4-Bromophenyl)-5,5-difluoro-1-phenylhexan-2-one (6). Isolated
yield: 67% (124 mg). Column chromatography eluent –
petroleum ether/diethyl ether, 10:1. Colorless needles,
mp 88.0 °C (from diethyl ether/hexane). 1Н NMR (400 MHz,
CDCl3): δ = 7.46–7.41 (m, 2H), 7.36–7.30 (m, 2H), 7.29–7.25 (m,
1H), 7.21–7.16 (m, 2H), 7.08 (d, J = 8.1 Hz, 2H), 3.70 (s, 2H), 3.05
(t, JHF = 15.9 Hz, 2H), 2.66 (m, 2H), 2.11–1.96 (m, 2H). 13C NMR
(100.6 MHz, CDCl3): δ = 206.39, 133.95, 132.08, 132.07, 131.77,
129.49, 128.96, 127.33, 123.28 (t, J = 242.6 Hz), 121.75, 50.33,
43.07 (t, J = 26.2 Hz), 34.22 (t, J = 3.5 Hz), 29.95 (t, J = 25.0 Hz).
19F NMR (376 MHz, CDCl3): δ = −94.5 (quint, JHF = 16.7 Hz). HRMS
(AJESI) calcd. for C18H18BrF2O+ [M+H]+ 367.0504, found
m/z 367.0511.
‡ Crystal data for 6:
C18H17BrF2O, Mr = 367.22 g/mol, orthorhombic, Pnma (no. 62),
a = 34.5876(4) Å, b = 9.19962(10) Å, c = 4.92247(5) Å, V =
1566.29(3) Å3, Z = 4, T = 123.0 K, μ(Cu-Kα) = 3.762 mm−1, ρcalc
=
1.557 g/cm3, 13397 reflections measured (5.11° ≤ 2Θ ≤ 134.43°)
of which 1462 unique (Rint = 0.0195, Rsigma = 0.0074), final R1
[F2>2σ(F2)] = 0.0235, wR2 = 0.0627. The crystallographic data is
deposited with the Cambridge Crystallographic Data Centre
(CCDC 1536256) and can be obtained free of charge from The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
1
For the recent reviews, see: a) C. Ni and J. Hu, Chem. Soc. Rev.,
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1-phenyl-4-(1-(trifluoromethyl)cyclopropyl)butan-2-one
(7).
Isolated yield: 23% (30 mg). Column chromatography eluent –
petroleum ether/diethyl ether, 10:1. 1Н NMR (400 MHz, CDCl3):
δ = 7.38–7.31 (m, 2H), 7.31–7.26 (m, 1H), 7.23–7.19 (m, 2H),
3.70 (s, 2H), 2.66 (m, 2H), 1.80 (m, 2H), 0.92 (m, 2H), 0.53 (m,
2H). 13C NMR (100.6 MHz, CDCl3): δ = 207.40, 134.09, 129.51,
128.90, 127.6 (q, J = 273.8 Hz), 127.25, 50.38, 39.48, 26.10,
21.97 (q, J = 32.3 Hz), 9.36 (q, J = 2.7 Hz). 19F NMR (376 MHz,
CDCl3): δ = −69.4 (s). HRMS (APCI) calcd. for C14H16F3O+ [M+H]+
257.1148, found m/z 257.1134.
5-Fluoro-1-phenylpentan-2-one (8a). Isolated yield: 13% (12 mg).
Column chromatography eluent – pentane/diethyl ether, 20:1.
1Н NMR (400 MHz, CDCl3): δ = 7.37–7.31 (m, 2H), 7.30–7.24 (m,
1H), 7.23–7.18 (m, 2H), 4.41 (dt, JHF = 47.3, JHH = 5.8 Hz, 2H), 3.71
(s, 2H), 2.61 (t, J = 7.1 Hz, 2H), 1.94 (dtt, JHF = 26.7, JHH = 7.1, 5.8
Hz, 1H). 13C NMR (100.6 MHz, CDCl3): δ = 207.47, 134.20,
129.51, 128.93, 127.25, 83.26 (d, J = 164.6 Hz), 50.40, 37.45 (d,
J = 4.4 Hz), 24.57 (d, J = 20.1 Hz). 19F NMR (376 MHz, CDCl3): δ =
4
5
a) X.-J. Tang, Z. Zhang and W. R. Dolbier, Chem. Eur. J., 2015,
21, 18961; b) L. Zhu, L.-S. Wang, B. Li, B. Fu, C.-P. Zhang and
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Kashiwagi, S. Selvakumar, S. A. Moteki and K. Maruoka, Org.
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,
878.
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Comm., 2013, 49, 7346; b) X. Liu, F. Xiong, X. Huang, L. Xu, P.
Li and X. Wu, Angew. Chem. Int. Ed., 2013, 52, 6962; c) Z.-M.
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Zhang, Angew. Chem. Int. Ed., 2013, 52, 9781; d) S. Martinez-
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−220.2 (tt, JHF = 47.4, 26.7 Hz). Spectral data correspond to those
9a,b
previously reported
tert-Butyl
.
6
a) F.-Q. Huang, Y.-W. Wang, J.-G. Sun, J. Xie, L.-W. Qi and B.
Zhang, RSC Advances, 2016,
6
, 52710; b) N. O. Ilchenko, M.
, 1056; c) T.-P.
4-(4-fluorobutanoyl)piperidine-1-carboxylate
(8b).
Hedberg and K. J. Szabo, Chem. Sci., 2017,
8
Isolated yield: 13% (18 mg). Column chromatography eluent –
petroleum ether/ethyl acetate, 5:1. 1Н NMR (400 MHz, CDCl3):
δ = 4.45 (dt, JHF = 47.3, JHH = 5.7 Hz, 2H), 4.11 (br s, 2H), 2.77 (br
t, J = 12.4 Hz, 2H), 2.62 (t, J = 7.1 Hz, 2H), 2.47 (tt, J = 18.2, 5.1
Hz, 1H), 1.97 (dtt, JHF = 27.0, JHH = 7.1, 5.7 Hz, 2H), 1.81 (m, 2H),
1.58–1.50 (m, 2H), 1.45 (s, 9H). 13C NMR (100.6 MHz, CDCl3): δ
= 211.33, 154.80, 83.29 (d, J = 164.5 Hz), 79.79, 48.87, 43.23,
36.00 (d, J = 4.1 Hz), 28.57, 27.63, 24.48 (d, J = 20.0 Hz). 19F NMR
Yang, Q. Li, J.-H. Lin and J.-C. Xiao, Chem. Comm., 2014, 50
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8 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
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Organic & Biomolecular Chemistry
Page 10 of 10
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DOI: 10.1039/C7OB00680B
Graphical Abstract
Synthesis of distally fluorinated ketones from easily available cyclopropanols using sulfinate salts
as fluoroalkylating reagents.