Mild and selective α-fluorination of carbonyl compounds (ketones, 1,3-diketones, β-ketoesters, α-nitroketones, and β-ketonitriles) with Selectfluor (F-TEDA-BF4) in imidazolium ILs [BMIM/PF6 or BMIM/NTf2] with Br?nsted-acidic IL [PMIM(SO3H)/OTf] as promoter

Article abstract of DOI:10.1016/j.tetlet.2015.07.084

Structurally diverse ketones, 1,3-diketones, and β-ketoesters, were selectively monofluorinated with Selectfluor (F-TEDA-BF₄) (1 equiv) in [BMIM][PF₆] as solvent and [PMIM(SO₃H)][OTf] as promoter under mild conditions. In selected cases, the monofluorinated products were transformed to the gem-difluoro derivatives by employing an additional equivalent of Selectfluor, and gem-difluoro-derivatives were synthesized directly from the substrates by employing 2 equiv of Selectfluor. The method was extended to monofluorination of representative α-nitroketones and β-ketonitriles using [BMIM][NTf₂] without the need for promoters. The described method offers the added advantage of recycling and reuse of the IL solvent. (Chemical Equation Presented).

Full text of DOI:10.1016/j.tetlet.2015.07.084

Accepted Manuscript
Mild and Selective α-Fluorination of Carbonyl Compounds (ketones, 1,3-dike-
tones, β-ketoesters, α-nitroketones, and β-ketonitriles) with Selectfluor (F-
TEDA-BF4) in Imidazolium ILs [BMIM/PF6 or BMIM/NTf2] with Brønsted-
acidic IL [PMIM(SO3H)/OTf] as Promoter
A. Srinivas Reddy, Kenneth K. Laali
PII:
S0040-4039(15)01259-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.07.084
TETL 46573
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
23 June 2015
20 July 2015
27 July 2015
Please cite this article as: Srinivas Reddy, A., Laali, K.K., Mild and Selective α-Fluorination of Carbonyl
Compounds (ketones, 1,3-diketones, β-ketoesters, α-nitroketones, and β-ketonitriles) with Selectfluor (F-TEDA-
BF4) in Imidazolium ILs [BMIM/PF6 or BMIM/NTf2] with Brønsted-acidic IL [PMIM(SO3H)/OTf] as Promoter,
Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.07.084
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1
Revised
Mild and Selective α-Fluorination of Carbonyl Compounds (ketones, 1,3-
diketones, β-ketoesters, α-nitroketones, and β-ketonitriles) with Selectfluor (F-
TEDA-BF4) in Imidazolium ILs [BMIM/PF6 or BMIM/NTf2] with Brønsted-acidic
IL [PMIM(SO3H)/OTf] as Promoter
A. Srinivas Reddy, Kenneth K. Laali*
Department of Chemistry, University of North Florida, 1 UNF Drive, Jacksonville, Florida 32224,
USA
Abstract: Structurally diverse ketones, 1,3-diketones, and β-ketoesters, were selectively
monofluorinated with Selectfluor (F-TEDA-BF4) (1 equiv) in [BMIM][PF6] as solvent and
[PMIM(SO3H)][OTf] as promoter under mild conditions. In selected cases, the monofluorinated
products were transformed to the gem-difluoro derivatives by employing an additional equivalent of
Selectfluor, and gem-difluoro-derivatives were synthesized directly from the substrates by employing
2 equivalents of Selectfluor. The method was extended to monofluorination of representative α-
nitroketones and β-ketonitriles using [BMIM][NTf2] without the need for promoter. The described
method offers the added advantage of recycling and reuse of the IL solvent.
Keywords: α-fluorination of carbonyls; 1,3-diketones; β-ketoesters; α-nitroketones; Selectfluor;
imidazolium-IL; Brønsted-acidic IL
*Corresponding Author: Tel: 904-620-1503, Fax: 904-620-3535. E-mail: kenneth.laali@UNF.edu
(Kenneth K. Laali)

2
The ever increasing recognition of the importance of fluorinated organics as building blocks
of pharmaceuticals, agrochemicals and functional materials has spurred rapidly growing interest
in the development of mild and efficient synthetic methods for fluorine introduction. Strategic
introduction of fluorine into organic compounds brings about dramatic changes in physical,
chemicals and biological properties including increased metabolic stability, lipophilicity, bio-
availability, and increased binding affinity to biological targets.1-4
The α-fluorinated carbonyl compounds are valuable building blocks of bioactive molecules,
and development of fluorination methods for carbonyl compounds has been continuously
5
evolving since the early 1980’s starting with the use of XeF2 , CsSO4F,6 elemental fluorine7-8, and
HF/PhIO.9 A number of two-step approaches have been reported involving deprotonation (with
NaHMDS or LDA) followed by electrophilic fluorination with NFSi and NFOBS,10 or by
TBAH/NF3O.11
With the ready availability of Selectfluor (F-TEDA-BF4) as an inexpensive, stable, non-
hydroscopic, and mild electrophilic fluorinating agent with broad-based application,12,13 a new
chapter in α-carbonyl fluorination opened up. Microwave assisted fluorination of 1-arylethanone
in MeOH gave α-fluoroketones along with dimethyl acetals, which on hydrolysis could be
converted to the α-fluoroketones in 65-85% yields.14 However, competing ring fluorination
occurred in this method with electron rich aryl groups.14 Representative α-fluoroketones were
prepared by employing Selectfluor with sulfuric acid as catalyst in MeOH or MeCN as solvent.15
Microwave-assisted monofluorination of representative 1,3-dicarbonyl derivatives were reported
with Selectfluor in MeCN, and difluorination could be effected by adding 2 equivalents of
tetrabutylammonium hydroxide (TBDH) in MeOH /MeCN.16 The natural progression of research

3
in this area has been to move toward “greener” methods that avoid the use of volatile organics and
would preferably employ no base or additives. Along these lines representative 1,3-dicarbonyl
compounds were fluorinated with Selectfluor in water by using surfactant17 or under solvent-free
conditions employing AccufluorTM or NFSi.17b
In 2002 we reported the first application of room temperature ionic liquids (RTILs) in
electrophilic fluorination of arenes employing Selectfluor.18 Our continuing interest in the
application of imidazolium ILs as solvent and catalysts for electrophilic/onium ion chemistry,19
and in electrophilic fluorination with the N-F reagents, provided the ímpetus for the present study
to develop mild/selective fluorination protocols for a wide range of carbonyl compounds by using
ILs as solvent/promoter without employing other additives, and with recycling and reuse of the
IL. Given the importance of α-nitroketones and β-ketonitriles as highly versatile moieties in
organic synthesis and limited previous work aimed at developing direct mild fluorination
protocols for these compounds,20 they were also included in our study.
A series of structurally diverse cyclic, acyclic and aromatic ketones were selectively
monofluorinated by using 1.0 equivalent of Selectfluor in [BMIM][PF6] as solvent and the
Brønsted-acidic IL [PMIM(SO3H)][OTf] as promoter (Fig.1),21 in yields ranging from 89% to
56%.22 Table 1 summarizes the outcomes along with the reaction conditions and the isolated
yields.
Figure 1. α-Fluorination of Ketones

4

5
With this data at hand, the method was then extended to representative 1,3-diketones and
β-ketoesters, and the monofluorinated derivatives were obtained in isolated yields ranging from
87% to 72% (see Table 2). In the reaction of 1-phenyl-butane-dione (entry 2) the fluoro-enol-
tautomer coexisted with the fluoro-diketone (see NMR data in supplementary information).
Direct difluorination employing 2 equivalents of Selectfluor and stepwise mono- to di
fluorination were subsequently demonstrated via the examples shown in Table 3. In entry 4, a 2 :
1 mixture of difluoro- to monofluoro derivative was obtained.

6
The possibility to replace the IL-promoter for microwave (MW) was explored using the
o
example in Table 1, entry 1. A comparable conversion could be achieved at 120 C after 30 min
o
irradiation but side-products/tar began to form. Increasing the temperature 150 C led to more
decomposition and lower conversion of the desired product. Based on this assay it was decided to
continue to employ the promoter in place of MW.

7
Chart 1. Application of microwave in place of IL promoter
The ability to synthesize the α-fluoro-nitro-carbonyl compounds by direct mild
fluorination is highly desirable.
Fig 2. Direct fluorination of α-nitroketones
A
previously reported attempt to synthesize the monofluoro-analog of
benzoylnitromethane by using base/solvent/Selectfluor led instead to oxidation to benzoic acid.20
The present study was extended to fluorination of α-nitroketones with reasonable success via the

8
examples shown in Table 4. Reactions were carried out in [BMIM][NTf2] as solvent to improve
solubility and lower the viscosity.23 Control experiments indicated that addition of Brønsted acid
IL was unnecessary and that reactions were cleaner without the promoter.

9
Extension of the method to β-ketonitriles was less satisfactory and the limited substrates
that were tested gave lower isolated yields of the monofluoro-derivative. In a previous study20
employing a two-step deprotonation/fluorination approach α-benzoylacetonitrile reacted with
NaH/THF/Selectfluor to give a mixture of mono- and difluoro compounds, and the difluoro-
derivative was obtained in 60% yield by using 2.2 equivalents of Selectfluor. Clearly further
studies are needed to improve on these methods.
Finally, an attempt to introduce a fluorine alpha to carbonyl in a Mannich base resulted in
elimination (Figure 3).
O
NH
O
Selectfluor
IL-1; IL-2
70 oC, 3 h
Cl
72%
Cl
Fig 3. Attempted fluorination of a Mannich base

10
Focusing on the efficacy of the recycling and reuse of the IL solvent in this method,
fluorination of ethyl benzoylacetate (entry 4; Table 2) was selected, and following an initial fresh
run, the reaction was repeated for four more cycles.24 The results sketched in chart 1 shows a
gradual decrease in the isolated yields from 87% with the fresh IL down to 69% after a total of 5
consecutive reactions.
Recycling and Reuse of the IL Solvent
100
80
60
40
20
0
1
2
3
4
5
Run #
Chart 1.Recycling and reuse of [BMIM][PF6] for entry 4 in Table 2
In summary a mild and selective fluorination method that is applicable to structurally
diverse ketones, 1,3-diketones, and β-ketoesters has been presented that employs [BMIM][PF6]
as recyclable solvent, utilizes the readily available Selectfluor, and uses the Brønsted-acidic IL
[PMIM(SO3H)][OTf] as promoter. Selective monofluorination of α-nitroketones was also
achieved in acceptable isolated yields by using [BMIM][NTf2] as solvent without any promoter.
Fluorination of β-ketonitriles proved more challenging with lower isolated yields and further
studies are called for.

11
Supplementary Information (see footnote on the first page of this article): experimental
procedures, spectral/characterization data, and selected NMR spectra.
Acknowledgements: KL thanks UNF for the award of Presidential Professorship.
References and Notes
1)
2)
3)
Advances in Organic Synthesis, Vol. 2, Modern Organofluorine Chemistry. Synthetic
Aspects; Rahman, A.-U., Laali, K. K., Eds.; Bentham, Hilversum, The Netherlands, 2006
Modern Fluoroorganic Chemistry. Synthesis, Reactivity, Application; Kirsch, P., Ed.;
Wiley: Weinheim, Germany, 2004
Methods in Organic Chemistry (Houben-Weyl), 4th Ed.; Vols. E 10a-c: Organo-Fluorine
Compounds; Baasner, B.; Hagemann, H.; Tatlow, J. C. Eds.; Thieme: Strutgart, Germany,
1999
4)
5)
Böhm, H.-J.; Banner, D.; Bendels, S.; Kany, M.; Kuhn, B.; Müller, K.; Obst-Sander, U.;
Stahl, M. ChemBioChem, 2004, 5, 637-643
(a) Zajc, B.; Zupan, M. J. Chem. Soc. Chem. Commun. 1980, 759-760; (b) Zajc, B.;
Zupan, M. J. Org. Chem. 1982, 47, 573-575
6)
7)
Stabver, S.; Sket, B.; Zajc, B.; Zupan, M. Tetrahedron, 1989, 45, 6003-6010
Purrington, S. T.; Bumgardner, C. L.; Lazaridis, N. V.; Singh, P. J. Org. Chem. 1987, 52,
4307-4310

12
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(a) Chambers, R. D.; Greenhall, M. P.; Hutchinson, J. J. Chem. Soc. Chem. Commun.
1995, 21-22; (b) Chambers, R. D.; Hutchinson, J.; Batsanov, A. S.; Lehman, C. W.;
Naumov, D. Y. J. Chem. Soc. Perkin. Trans 1, 1996, 2271-2275
9)
Kitamura, T.; Kuriki, S.; Morshed, M. H.; Hori, Y. Org. Lett. 2011, 13, 2392-2394
Davis, F. A.; Han, W.; Murphy, C. K. J. Org. Chem. 1995, 60, 4730-4737
Gupta, O. D.; Shreeve, J. M. Tetrahedron.Lett. 2003, 44, 2799-2801
10)
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Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincent, S. P.; Wong, C.-H. Angew. Chem.
Int. Ed. 2005, 44, 192-212
13)
Stavber, S.; Zupan, M. in Advances in Organic Synthesis; Modern Organofluorine
Chemistry – Synthetic Aspects; Laali, K. K. (Ed), Vol 2, 2006, pp 213-268, Bentham
Science Publishers, The Netherlands
14)
15)
Thvedt, T. H. K.; Fuglseth, E.; Sundby, E.; Hoff, B. H. Tetrahedron, 2009, 65, 9550-9556
Liu, J.; Chan, J.; Bryant, C. M.; Duspara, P. A.; Lee, E. E.; Powell, D.; Yang, H.; Liu, Z.;
Walpole, C.; Roberts, E.; Batey, R. A. Tetrahedron.Lett. 2012, 53, 2971-2975
16)
17)
Xiao, J.-C.; Shreeve, J. M. J. Fluorine. Chem. 2005, 126, 475-478
(a) Stavber, G.; Zupan, M.; Jereb, M. Stavber, S. Org. Lett. 2004, 6, 4973-4976;
(b) Stavber, G.; Stavber, S. Adv. Synth. Catal. 2010, 352, 2838-2846
Laali, K. K.; Borodkin, G. I. J. Chem. Soc. Perkin.Trans.2 2002, 953-957
18)

13
19)
For representative recent examples see: Jamalian, A.; Rathman, B.; Borosky, G. L.;
Laali, K. K. Applied Catalysis A: General 2014, 486, 1-11; Nandi, G. C.; Rathman, B.
M.; Laali, K. K. Tetrahedron. Lett. 2013, 54, 6258-6263; Kumar, G. G. K. S. N.; Laali,
K. K. Tetrahedron.Lett 2013, 54, 965-969; Kumar, G. G. K. S. N.; Laali, K. K. Org.
Biomol. Chem. 2012, 10, 7347-7355; Aridoss, G.; Laali, K. K. Tetrahedron.Lett. 2011,
52, 6859-6866.
20)
Peng, W.; Shreeve, J. M. Tetrahedron. Lett. 2005, 46, 4905-4909 and references cited
therein.
21)
22)
The Brønsted acidic IL promotes the reaction via acid-catalyzed enolization
Typical procedure for fluorination of carbonyl compounds: The carbonyl compound
(0. 25 mmol) and Selectfluor (0.25 mmol) were added to [BMIM][PF6] (25 equiv.) in a
Schlenk tube, and [PMIM(SO3H)][OTf] (~ 0.5 mmol) was introduced at r.t. with stirring
under a nitrogen atmosphere. The reaction mixture was stirred at 80 °C for the specified
period of time (see Tables). After completion of the reaction (TLC monitoring), the
reaction mixture was extracted several times with diethyl ether (4 x 10 mL), and the
combined organic extracts was washed with aqueous saturated NaHCO3 followed by
water, dried (MgSO4), and the solvent was evaporated under vacuum. The crude product
was purified by silica gel column chromatography using 3 to 6% diethyl ether in hexane
as eluent.
23)
General procedure for fluorination of α-nitro-ketones: The α-nitro-ketone (0.25
mmol) and Selectfluor (0.25 mmol) were added to [BMIM][NTf2] (25 equiv.) in a
o
Schlenk tube at r.t., and the reaction mixture was stirred at 75 C for 10 to 12 h. After

14
completion of reaction (TLC monitoring), the reaction mixture was extracted several
times with 40% ethyl acetate in hexane (4 x10 mL) and the combined organic extract was
washed with water, dried over MgSO4, and the solvent was evaporated under vacuum.
The crude mixture was purified by silica gel column chromatography using 12 % ethyl
acetate in hexane as eluent.
24)
Recycling and re-use of IL (fluorination of ethylbenzoylacetate): Following the
extraction of the product from the IL phase in an earlier run (as described above), the
o
Schlenk tube containing the IL was placed under vacuum for 10 h, at 70 C. Upon
cooling to r.t. it was re-charged with fresh substrate and Selectfluor, along with a small
quantity (~ 0.3 mmol) of the fresh Brönsted acidic IL, and the reaction was repeated
(control experiments in which additional [PMIM(SO3H)][OTf] was not introduced
resulted in noticeably lower conversions).