α-Fluorotricarbonyl Derivatives as Versatile Fluorinated Building Blocks: Synthesis of Fluoroacetophenone, Fluoroketo Ester and Fluoropyran-4-one Derivatives

Article abstract of DOI:10.1002/ejoc.202000503

Fluorinated acyl-Meldrum's acid derivatives were synthesized by electrophilic fluorination of appropriate phenacyl Meldrum's acid substrates using Selectfluor. Reactions with water, ethanol, Grignard, and alkynyllithium reagents gave rise to the correspon

Full text of DOI:10.1002/ejoc.202000503

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: a-Fluorotricarbonyl derivatives as versatile fluorinated building
blocks: synthesis of fluoro-acetophenone, fluoro-ketoester and
fluoro-pyran-4-one derivatives
Authors: Antal Harsanyi, Anne Lueckener, Hedvig Pasztor, Zahide
Yilmaz, Lawrence Tam, Dmitry Yufit, and Graham Sandford
This manuscript has been accepted after peer review and appears as an
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using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000503
Link to VoR: https://doi.org/10.1002/ejoc.202000503
01/2020

10.1002/ejoc.202000503
European Journal of Organic Chemistry
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-Fluorotricarbonyl derivatives as versatile fluorinated building
blocks: synthesis of fluoro-acetophenone, fluoro-ketoester and
fluoro-pyran-4-one derivatives
Antal Harsanyi, Anne Lückener, Hedvig Pasztor, Zahide Yilmaz, Lawrence Tam, Dmitry S.
Yufit and Graham Sandford*
Abstract: Fluorinated acyl-Meldrum’s acid derivatives were
synthesised by electrophilic fluorination of appropriate phenacyl
Meldrum’s acid substrates using Selectfluor. Reactions with water,
ethanol, Grignard and alkynyl lithium reagents gave rise to the
corresponding fluoro-acetophenone, -1,3-ketoester, -1,3-diketone
and -pyran-4-one products respectively from the same selectively
fluorinated scaffold in one-step procedures.
systems. Thus, there remains a requirement for the development
of synthetic routes to multi-functional fluorinated aliphatic building
blocks for applications in diversity oriented synthesis as part of
drug discovery programmes.
While the chemistry of synthetically versatile 2-fluoro-1,3-
dicarbonyl derivatives continues to develop,[5] reports on the
preparation and synthetic utility of related -fluorotricarbonyl
compounds are very rare in the literature despite their potential
utility as versatile fluorinated building blocks. Tricarbonyl systems
can be accessed readily, for example, acylation of Meldrum’s acid
gives corresponding -tricarbonyl derivatives by either
condensation with carboxylic acids using appropriate coupling
reagents or from the corresponding mixed anhydride or acid
chloride.[6] However, despite the use of readily available acyl
Meldrum’s acid derivatives in organic synthesis, there are very
few reports in the literature concerning the synthesis and use of
corresponding -fluoro-derivatives. Formation of fluoro-
tricarbonyl systems by double acylation of ethyl fluoroacetate[7]
and fluorination of tricarbonyl compounds using perchloryl
fluoride[8] have been reported previously. In addition, Kim and co-
workers showed that triethyl 2-fluorophosphonoacetate can be
acylated twice using an MgCl2-Et3N reagent system to afford 2-
fluoro-diketo-ester derivatives.[9]
Introduction
The development of robust and scalable methods for the
synthesis of polyfunctional aliphatic fluorinated building blocks
continues to be of interest due, in part, to the increasing number
of new chemical entities bearing fluorine atoms at sp3 carbon sites
that are entering pharmaceutical, agrochemical and materials
company product pipelines[1] Consequently, methodology for
fluorination at sp3 sites utilising a variety of nucleophilic and
electrophilic fluorinating agents continues to be developed to
meet the needs for exploring new fluorinated chemical space.[2]
Alternatively, the construction of polyfunctional fluorinated
aliphatic systems by early stage fluorination and subsequent
elaboration into more structurally complex systems offers a
complementary approach. Consequently, many fluorine
containing building blocks have been assessed in a variety of
reaction processes and, in particular, the chemistry of a range of
fluorinated diesters,[3] amides, ketones and aldehydes, for
example, has been established.[4] However, the availability of a
sufficiently wide range of fluorinated building blocks with
established robust reactivity profiles can be
a significant
bottleneck in the synthesis of polyfunctional fluoroaliphatic
Dr A. Harsanyi, A. Lückener, H. Pasztor, Z. Yilmaz, L. Tam, Dr. D.S. Yufit
Prof. G. Sandford*
Department of Chemistry
Scheme 1. Strategy for the synthesis and use of -fluorotricarbonyl compounds
Durham University
derived from Meldrum’s acid.
South Road, Durham, DH1 3LE, U.K.
E-mail: Graham.Sandford@durham.ac.uk
Homepage: https://www.dur.ac.uk/chemistry/staff/profile/?id=199
In this paper, we report the synthesis of -fluoro-acyl Meldrum’s
acid derivatives using Selectfluor™ to gain access to potentially
useful polyfunctional fluorinated tricarbonyl systems and, in proof-
of-concept studies, show how these scaffolds may be used to
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.202000503
European Journal of Organic Chemistry
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yield as fine powders. Crystalline products for diffraction studies
were obtained by further recrystallisation from acetone.
provide access to fluoro-acetophenone, -ketoester and -pyran-4-
one derivatives by reaction with appropriate nucleophiles
following a synthetic strategy outlined in Scheme 1. Neither the
synthesis nor reactivity of fluorinated acyl Meldrum’s acid
derivatives have been described previously.
Results and Discussion
Syntheses of appropriate acyl Meldrum’s acid derivatives 3 were
carried out by acylation of Meldrum’s acid 1 using a variety of
aromatic acid chloride substrates 2 in acetonitrile in the presence
of DMAP at ambient temperature by adapting a literature
procedure.[10] After the reaction had reached completion, aqueous
hydrochloric acid was added to dissolve the precipitated DMAP
hydrochloride salt and acetonitrile was evaporated from the
mixture under reduced pressure to precipitate the desired
tricarbonyl product which was dried and recrystallized from
acetone if required (Table 1). X-ray crystallography confirmed the
structures of 3a and 3g showing that the systems exist as the enol
forms in the solid state (Figure 1) with typical enol intra-molecular
OH…O(carbonyl) hydrogen bonds.
Figure 1. Molecular structures of 3a and 3g
Table 1. Synthesis of acyl Meldrum's acid derivatives 3.
Table 2. Fluorination of acyl Meldrum's acid derivatives.
Fluorinations of acyl Meldrum’s acid derivatives 3 were carried out
using electrophilic fluorinating reagent Selectfluor™ in acetonitrile
at ambient temperature over 16 h (Table 2) after which 19F NMR
spectroscopic analysis of the reaction mixture confirmed full
conversion to the desired product. Isolation of the desired -
fluoro-tricarbonyl products were achieved by selective dissolution
of the crude residue into ethyl acetate and evaporation of the
solvent after filtration from Selectfluor™ salt residues. When
required, the crude product was further purified by dissolving in a
small volume of dichloromethane/hexane and, after cooling at 0-
Under these reaction conditions, competing electrophilic
fluorination of the aromatic ring was not observed, even in the
case of the electron rich thiophene and furan derivatives and the
o
5 C, the desired fluorotricarbonyl products precipitated in good
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products were found to be stable for a long time (over a month) in
a refrigerator if moisture was excluded.
electrophilic ester functionality of the -fluorotricarbonyl
substrates leads to decarboxylation to the fluoracetophenone
system. Of course, fluoroacetophenones may be synthesised by
a variety of methods including fluorination of appropriate enolate
systems by Selectfluor[11] but, here, the concept of selective
reactions of nucleophiles with -fluorotricarbonyl derivatives was
established.
X-ray crystallographic analysis of fluorinated acyl Meldrum’s acid
derivatives 4a,c,d (Figure 2) showed that the cyclohexane ring of
these compounds adopts a distorted boat conformation where the
torsion angle between the fluorine atom and the C=O oxygen
atoms of the ring is approximately 30o. This conformation is
further stabilized by short intra-molecular CH...O(carbonyl)
contacts (2.4-2.47Å) which can be regarded as weak hydrogen
bonds. The difference between the two methyl groups can also
be observed in the solution phase by 1H and 13C NMR
spectroscopy where separate chemical shifts corresponding to
the axial and equatorial environments are observed (for example,
3a: 1.92 ppm and 1.86 ppm).
Subsequently, the most effective hydrolysis reaction conditions
were applied to a range of aromatic and heteroaromatic
fluorinated
Meldrum’s
acid
derivatives
4
to
give
fluoroacetophenone derivatives 5 in good yield after flash column
chromatography (Table 3). The higher yield obtained in the
synthesis of 5d suggests that an ortho substituent capable of
further activating the system towards nucleophilic attack can
improve the selectivity of the decarboxylation. The molecular
structures of 5a and 5d were confirmed by X-ray crystallography
(Figure 3). The presence of an ortho-nitro-substituent results in
almost perpendicular orientation of the carbonyl group relative to
the aromatic ring in 5d.
Table 3. Synthesis of -fluoroacetophenone derivatives 5
Figure 2. Distorted boat conformation of fluorinated Meldrum's acid derivatives
4a,c,d
With a range of -fluorotricarbonyl derivatives 4 in hand we began
to explore reactions between these systems and some
representative nucleophiles. Initially, a range of acid catalysed
hydrolysis conditions were screened on 1 mmol scale to develop
the hydrolysis reaction of 4a to form the corresponding fluoro-
acetophenone derivative 5a (see Supporting Information, Table
SI1). The screening experiments (Table SI1) revealed that p-
toluenesulfonic acid monohydrate was the most suitable reagent
combination. Additional water improved the selectivity and
conversion of the reaction, but more than 0.1 mL of water per
mmol of starting material did not have any further benefit. After
purification by column chromatography, 2-fluoroacetophenone 5a
was isolated in 56% yield. Attack by water at the more
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NMR of the product mixture but purification via column
chromatography and recrystallization gave the desired 2-fluoro-
1,3-diphenylpropane-1,3-dione 8 albeit in low yield (Scheme 2).
Scheme 2. Reaction of 4a with Grignard reagent 7
Figure 3. Molecular structure of fluoroacetophenones 5a and 5d
With model reactions between fluorotricarbonyl substrates 4 and
water as the nucleophile established, reactions of fluoro-
tricarbonyl derivatives with ethoxide were carried out to access
the corresponding -fluoro-ketoesters. Treating compound 4
a,g,h in ethanol in basic conditions (Et2NH) at 0 oC for 6 h afforded
the desired products 6a,g,h in excellent yield without any further
purification required (Table 4).
Analogous reactions of carbanions derived from terminal alkynes
were next studied. Deprotonation of 1-hexyne 9a using n-BuLi at
-78°C in THF under an argon atmosphere followed by addition of
4a and stirring of the reaction mixture overnight at room
temperature gave a crude product which was purified by column
chromatography and recrystallisation to give the unexpected 3-
fluoro-4H-pyran-4-one derivative 10a in moderate yield (22%)
from a mixture of unidentified products (Table 5). Analogous
syntheses of pyran-4-one derivatives 10b-d were performed
using ethynylbenzene 9b, ethynylcyclopropane 9c and
ethynylcyclohexane 9d substrates to give the fluoropyran-4-one
products 10b-d respectively The structures of pyranone products
10 a-d were confirmed by X-ray crystallography (Figure 4).
Table 4: Synthesis of -fluoro--ketoester derivatives 6
Table 5. Synthesis of fluoro-pyran-4-one derivatives 10
Thus, reactions of -fluoro-tricarbonyl derivatives can lead to
highly useful fluoroketoester building blocks upon reaction with
ethanol in basic conditions, providing alternative synthetic routes
to fluorination of ketoesters by fluorine gas[12] and Selectfluor[13]
Fluorination of -ketoesters by fluorine gas is effective[12] but can
lead to difluorination at the enolic site and unselective fluorination,
particularly on electron rich aromatic substituents such as the
furan and thiophene moieties, in 6g,h.We next studied reactions
of appropriate carbon centred nucleophiles. Phenylmagnesium
bromide 7 was formed in dry THF at r.t. from bromobenzene and
magnesium turnings and added to 4a and the reaction mixture
that was heated at reflux for 1 h. Numerous unidentified side
products were formed during this reaction as observed by 19F
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Scheme 3. Formation of 10
While well-known 4H-pyran-2-one sub-units are found in various
natural products[14] and generally synthesised by -acylation of
1,3-diketones with carboxylic ester substrates,[15] corresponding
2-fluoro-4H-pyran-2-ones have not been reported in the literature,
despite their relatively simple structures.
Conclusions
In this paper, the synthesis and reactivity of fluorinated acyl
Meldrum’s acid derivatives with representative oxygen and
carbon centred nucleophiles was described. Meldrum’s acid was
acylated and subsequent fluorination carried out using
Selectfluor™ to provide access to the desired fluoro-tricarbonyl
compounds in good yield. Reactions of the fluoro-tricarbonyl
scaffolds with oxygen and carbon centred nucleophiles led to
appropriate fluoro-acetophenone, -ketoester, -diketone and -
pyran-4-one derivatives by simple processes. These proof-of-
concept studies demonstrate that -fluorotricarbonyl derivatives
can be common substrates that allow access to a wide range of
fluorinated aliphatic and heterocyclic building blocks.
.
Figure 4. Molecular structures of fluoropyran-4-one derivatives 10a-d
Experimental Section
Carbanions formed by deprotonation of the alkynes attack an
ester group of the Meldrum’s acid moiety and, after elimination of
acetone and decarboxylation, an enolate intermediate is formed.
Intramolecular Michael-type addition forms the observed six-
membered ring products (Scheme 3).
5-Benzoyl-2,2-dimethyl-1,3-dioxane-4,6-dione 3a
Meldrum’s acid 1 (14.4 g, 100 mmol) and DMAP (24.4 g, 200 mmol) were
dissolved in acetonitrile (250 mL) and cooled in ice-water. Benzoyl chloride
2a (14.1 g, 100 mmol) was dissolved in acetonitrile (50 mL) and added
dropwise over 40 min. The mixture was stirred for 16 h, then 1M HCl (200
mL) was added, the mixture stirred for 5 min (clear solution) and was
concentrated to approximately 150 mL under vacuum. The precipitated
product was filtered, washed with water (15 mL) and dried (MgSO4) to give
5-benzoyl-2,2-dimethyl-1,3-dioxane-4,6-dione 3a (22.5 g, 90 %) as a
yellow solid. Mp. 95-97 °C (with decomposition) (lit.16 103-104 oC, from
acetone). IR (cm-1): 2998, 1736, 1652. 1H NMR (400 MHz, CDCl3)  1.84
3
3
(s, 6H, CH3), 7.47 (t, JHH 7.9, 2H, C3-H), 7.60 (tm, JHH 7.5, 1H, C4-H),
7.66 - 7.69 (m, 2H, C2-H), 15.47 (bs, 1H, OH). 13C NMR (100 MHz, CDCl3)
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2
2
 26.91 (CH3), 91.06 (C(CH3)2), 106.11 (C=COH), 128.17 (C3-H), 129.58
(C2-H), 132.82 (C1-C), 133.44 (C4-H), 159.90 (C=COH), 171.09 (C=O),
189.37 (C=O). m/z (ESI): 247 [M-H]- , 207 (100 %, [M-C3H5]-). HRMS (ESI)
m/z calculated for [M]+, C13H11O5 requires: [M]+, 247.0606; found 247.0605.
CDCl3)  189.6 (d, JCF 20.0 Hz, C11-C), 164.9 (d, JCF 24.1 Hz, C3-C),
134.5 (C6-C), 133.4 (d, 3JCF 1.9 Hz, C9-C), 129.5 (d, 4JCF 3.3 Hz, C8,10-C),
1
128.8 (C5,7-C), 89.9 (d, JCF 197.1 Hz, C1-C), 62.65 (C14-C), 13.90
(C15-C); HRMS (ESI) m/z calculated for [M−H]− C11H10O3F− 209.0614,
found 209.0602.
5-benzoyl-5-fluoro-2,2-dimethyl-1,3-dioxane-4,6-dione 4a
2-Fluoro-1,3-diphenyl-1,3-propanedione 8
5-Benzoyl-2,2-dimethyl-1,3-dioxane-4,6-dione 3a (2.48 g, 10.0 mmol) was
dissolved in acetonitrile (50 mL) and Selectfluor (5.50 g, 15.5 mmol) was
added to the mixture which was stirred at rt for 16 h. The reaction mixture
was evaporated to dryness under vacuum, the solids suspended in ethyl
acetate (50 mL), filtered and washed with ethyl acetate (30 mL). The ethyl
acetate solution was evaporated under reduced pressure, the residue
dissolved in dichloromethane (20 mL), hexane (60 mL) was added and the
solution was concentrated at atmospheric pressure until solids started to
appear (approximately 30 mL). After cooling at 4 oC overnight the product
was filtered and dried under vacuum to give 5-benzoyl-5-fluoro-2,2-
dimethyl-1,3-dioxane-4,6-dione 4a (1.98 g, 74 %) as a yellow solid. Mp.
109-112 oC. IR (cm-1): 3071, 3019, 1797, 1756, 1675. 1H NMR (400 MHz,
CDCl3)1.86 (s, 3H, CH3), 1.92 (s, 3H, CH3), 7.53 (m, 2H, C3-H), 7.69 (m,
1H, C4-H), 8.22 (m, 2H, C2-H). 19F NMR (376 MHz, CDCl3)- 157.97 (t,
5JHF 1.9 Hz). 13C NMR (101 MHz, CDCl3)27.67 (CH3), 30.19 (CH3), 92.13
(d, 1JCF 216 Hz, C-F), 109.43 (C(CH3)2), 128.90 (C3-H), 130.87 (d, 4JCF 6.1
Phenyl magnesium bromide was pre-formed by treating a mixture of Mg
turnings (85 mg, 3.5 mmol) and a single Iodine crystal in dry THF (3 mL)
at r.t. with bromobenzene (0.26 ml, 2.5 mmol), followed by stirring under
argon during reflux for 1 h. After having cooled to r.t. the supernatant was
removed and was then added dropwise to an ice/water bath cooled
solution of 5-benzoyl-5-fluoro-2,2-dimethyl-1,3-dioxane-4,6-dione 4a (300
mg, 1.13 mmol) in dry THF (1.5 mL) under an argon atmosphere and
stirred overnight at r.t. Afterwards the mixture was stirred under reflux for
approximately 30 min before being quenched with sat. aq. NH4Cl (3 mL).
The solution was diluted with a small amount of water and the aqueous
layer extracted with Et2O. The combined organic layers were dried
(MgSO4) and concentrated. The crude product was purified by column
chromatography on silica gel (9:1 n-Hexane:EtOAc; Rf.: 0.2) and
recrystallisation from DCM and n-hexane to give 2-fluoro-1,3-diphenyl-1,3-
propanedione 8[18] (63 mg, 0.21 mmol, 22%) as a white solid. M. p. 66-
67°C; M. p.[18] 66-67°C. IR (cm-1): 3071, 1673. 1H NMR (400 MHz, CDCl3)
8.13 - 8.06 (m, 4H, ArH), 7.62 (ddt, J = 8.0, 6.9, 1.3 Hz, 2H, ArH),
3
2
Hz, C2-H), 132.06 (d, JCF 4.1 Hz, C1-C), 135.51 (C4-H), 159.15 (d, JCF
2
23.2, C=O), 188.16 (d, JCF 26.4, C=O). m/z (ASAP): 223 (27 %, [M-
C3H7]+); 165 (100 %, [M-CH3COCH3-CO2]+).
7.52 - 7.45 (m, 4H, ArH), 6.54 (d, JHF 49.2 Hz, 1H, CHF). 19F NMR (376
2
1
MHz, CDCl3) -186.88 (d, JCF 49.2 Hz).13C NMR (101 MHz, CDCl3)
191.31 (d, 2JCF 20.2 Hz, C=O), 134.65 (s), 133.69 (d, 5JCF 1.9 Hz), 129.96
(d, 4JCF 3.5 Hz), 128.92 (s), 96.72 (d, 1JCF 198.9 Hz, CHF). HRMS (ASAP)
m/z calculated for [M+H]+ C15H12FO2 243.0816, found 243.0822.
2-Fluoroacetophenone 5a
5-Fluoro-5-(benzoyl)-2,2-dimethyl-1,3-dioxane-4,6-dione 4a (1.07 g, 4.0
mmol) and p-toluenesulfonic acid monohydrate (0.76 g, 4.0 mmol) were
dissolved in acetone (20 mL) in a microwave vial (25 mL). Water (0.4 mL)
was added, the vial sealed and irradiated at 100 oC for 30 min. After the
mixture was allowed to cool to ambient temperature, the pressure was
released by piercing the rubber septum with a needle. The mixture was
evaporated to dryness, the residue dissolved in ethyl acetate (50 mL),
washed with saturated NaHCO3 solution (2x20 mL) and brine (20 mL).
After drying (Na2SO4), the solvent was removed under reduced pressure
and the product was purified by silica gel column chromatography
(hexanes : ethyl acetate, 5 : 1) to afford 2-fluoroacetophenone 5a (0.31 g,
56 % yield) as a yellow oil. Rf.: 0.27 (hexanes : ethyl acetate, 5 : 1). IR (cm-
1): 3066, 2938, 1703, 1598. 1H NMR (400 MHz, CDCl3)5.53 (d, 2JHF 46.9
Hz, 2H, CH2F), 7.45 – 7.54 (m, 2H, C3-H), 7.58 – 7.66 (m, 1H, C4-H), 7.83
6-Butyl-3-fluoro-2-phenyl-4H-pyran-4-one 10a
A solution of 1-hexyne 9a (0.13 mL, 1.13 mmol) in dry THF (1.5 mL) was
cooled to -78 ºC under an argon atmosphere. n-BuLi (0.54 mL, 2.5 M in
hexanes, 1.35 mmol) was added dropwise and the resulting solution stirred
at -78 ºC for 1 h. A solution of 5-benzoyl-5-fluoro-2,2-dimethyl-1,3-dioxane-
4,6-dione 4a (300 mg, 1.13 mmol) in dry THF (2.5 mL) was added
dropwise at 0 ºC and the solution was slowly warmed to r.t. while stirring
overnight. After quenching with sat. aq. NH4Cl (3 mL) the solution was
diluted with water (5 mL) and the aqueous layer extracted with Et2O. The
combined organic layers were washed with brine before being dried over
MgSO4 and concentrated. The crude product was purified by column
chromatography on silica gel (7:3 n-Hexane:EtOAc; Rf.: 0.2) and
recrystallised from DCM and n-hexane, to give 6-butyl-3-fluoro-2-phenyl-
4H-pyran-4-one 10a (62 mg, 22%) as a white solid. M. p. 39-40°C. IR
(cm−1): 3261, 2954, 2932, 1635. 1H NMR (700 MHz, CDCl3) 7.88 - 7.82
2
- 7.92 (m, 2H, C2-H). 19F NMR (376 MHz, CDCl3)- 231.44 (t, JHF 47.0
Hz). 13C NMR (101 MHz, CDCl3)83.64 (d, 1JCF 182.6 Hz, CH2F), 127.94
4
(d, JCF 2.6 Hz, C2-H), 129.03 (C3-H), 133.80 (C1-C), 134.24 (C4-H),
2
193.52 (d, JCF 15.5 Hz, C=O). m/z (ASAP): 139 (49 %, [M+H]+). HRMS
(ESI) m/z calculated for [M+H]+, C8H8FO, 139.0559; found 139.0559.
(m, 2H, C11,15-H), 7.55 - 7.49 (m, 3H, C12,13,14-H), 6.31 (dd, JHF 6.6,
4
1.3 Hz, 1H, C4-H), 2.63 (t, J 7.7 Hz, 2H, C6-H), 1.71 (p, J 7.6 Hz, 2H, C7-
H), 1.56 - 1.29 (m, 2H, C8-H), 0.97 (tt, J 7.4, 1.1 Hz, 3H, C9-H). 19F NMR
Ethyl 2-fluoro-3-oxo-3-phenylpropanoate 6a
4
(376 MHz, CDCl3)  -158.88 (d, JHF 6.6 Hz).13C NMR (176 MHz, CDCl3)
2
2
172.40 (d, JCF 16.4 Hz,C3-C), 168.73 (C5-C), 150.79 (d, JCF 24.2 Hz,
C1-C), 149.28 (d, 1JCF 253.5 Hz,C2-F), 131.29 (d, 5JCF 1.4 Hz, C12,14-C),
5-Benzoyl-5-fluoro-2,2-dimethyl-1,3-dioxane-4,6-dione
4a
(1.00 g,
3.76 mmol) was dissolved in EtOH (10 mL) and the solution was cooled to
0 °C. Diethylamine (0.4 ml, 3.76 mmol) was added and the reaction was
stirred at 0 °C for 16 h. The solvent was removed and the residue
dissolved in DCM (30 mL). The organic layer was washed with sodium
bicarbonate (10 mL) and brine (10 mL), dried and concentrated to give
ethyl 2-fluoro-3-oxo-3-phenylpropanoate 6a[17](745 mg, 94%) as a yellow
oil without any further purification; IR (cm−1): 1693, 1759, 1597, 1580. 1H
NMR (700 MHz, CDCl3) 8.00 (d, J 8.6 Hz, 2H, C8,10-H), 7.60 (t, J 7.5
Hz, 1H, C6-H), 7.46 (dd, J 8.4, 7.4 Hz, 2H, C5,7-H), 5.88 (d, J 48.7 Hz, 1H,
C1-H), 4.25 (qd, J 7.1, 2.8 Hz, 2H, C14-H), 1.20 (t, J 7.2 Hz, 3H, C15-H).
19F NMR (376 MHz, CDCl3)  -190.4 (d, J 48.8 Hz). 13C NMR (176 MHz,
3
4
129.03 (C13-C), 128.65 (d, JCF 5.2 Hz, C10-C), 127.60 (d, JCF 7.6 Hz,
C11,15-C), 114.21 (d, JCF 6.9 Hz, C4-C), 33.42(C6-C), 29.15(C7-C),
3
22.17(C8-C), 13.81(C9-C). HRMS (ASAP) m/z calculated for [M+H]+
C15H16FO2+ 247.1129, found 247.1123.
Acknowledgments
The research included in this publication received funding from
the European Community´s Seventh Framework Programme
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[18] K. Sato, G. Sandford, K. Shimizu, S. Akiyama, M.J. Lancashire, D.S.
Yufit, A. Tarui, M. Omote, I. Kumadaki, S. Harusawa, A. Ando,
Tetrahedron 2016, 72, 1690-1698.
(FP7/2007-2013) and EFPIA companies’ in kind contribution for
the Innovative Medicine Initiative under Grant Agreement No.
115360 (Chemical manufacturing methods for the 21st century
pharmaceutical industries, CHEM21). We thank the European
Union Erasmus+ programme (research internships for AL and ZY)
and Durham University M.Chem. programme (LT) for funding.
Keywords: organofluorine • fluorocarbonyl • fluoroketoester •
fluoroheterocycle • pyran-4-one
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10.1002/ejoc.202000503
European Journal of Organic Chemistry
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Fluorine Chemistry
Fluorinated acyl-Meldrum’s acid
derivatives, synthesised by
electrophilic fluorination react with
nucleophiles to give fluoro-
acetophenones, 2-fluoro-1,3-
ketoester, 2-fluoro-1,3-diketone and
fluoro-pyran-4-one products from the
same fluorinated scaffold.
Antal Harsanyi, Anne Luckener, Hedvig
Pasztor, Zahide Yilmaz, Lawrence Tam,
Dmitry S. Yufit and Graham Sandford*
Page No. – Page No.
-Fluorotricarbonyl derivatives as
versatile fluorinated building blocks:
synthesis of fluoro-acetophenone,
fluoro-ketoester and fluoro-pyran-4-
one derivatives
This article is protected by copyright. All rights reserved.