Towards greener fluorine organic chemistry: Direct electrophilic fluorination of carbonyl compounds in water and under solvent-free reaction conditions

Article abstract of DOI:10.1002/adsc.201000477

Selective and efficient fluorination of organic 1,3-dicarbonyl compounds was achieved using the electrophilic fluorinating reagents Selectfluor ^TM F-TEDA-BF₄ (1-chloromethyl-4-fluoro-1,4- diazoniabicyclo[2.2.2]octane bis-tetrafluoroborate) in aqueous medium or Accufluor^TM NFSi (N-fluorobenzenesulfonimide) under solvent-free reaction conditions (SFRC). Under both reaction conditions cyclic 1,3-dicarbonyl compounds were transformed into 2-fluoro-substituted derivatives and acyclic analogues into 2,2-difluoro-substituted compounds, while the reactions of 1-trifluoromethyl-substituted 1,3-dicarbonyls in water resulted in the formation of 2,2-difluoro-3,3-dihydroxy-1-one derivatives. The reactivity of the starting material in water was found to be dependent on its enolizability, hydrophobic interactions and aggregate state at the reaction temperature. Reactions under SFRC proceeded in the molten eutectic phase of the reactants. The technique of competitive reactivity was used in order to evaluate and better understand the effects of reaction conditions on the course of these reactions.

Full text of DOI:10.1002/adsc.201000477

FULL PAPERS
DOI: 10.1002/adsc.201000477
Towards Greener Fluorine Organic Chemistry: Direct
Electrophilic Fluorination of Carbonyl Compounds in Water
and Under Solvent-Free Reaction Conditions
Gaj Stavbera and Stojan Stavbera,*
a
ˇ
Jozef Stefan Insitutute, Jamova 39, 1000 Ljubljana, Slovenia
Fax : (+386)-1-423-5400; e-mail: stojan.stavber@ijs.si
Received: June 21, 2010; Revised: September 8, 2010; Published online: October 26, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000477.
Abstract: Selective and efficient fluorination of or- fluoro-3,3-dihydroxy-1-one derivatives. The reactivity
ganic 1,3-dicarbonyl compounds was achieved using of the starting material in water was found to be de-
the electrophilic fluorinating reagents SelectfluorTM pendent on its enolizability, hydrophobic interactions
F-TEDA-BF4 (1-chloromethyl-4-fluoro-1,4-diazonia- and aggregate state at the reaction temperature. Re-
ACHTUNGTRENNUNGbicycloACHTUNGTRENNUNG[2.2.2]octane bis-tetrafluoroborate) in aque- actions under SFRC proceeded in the molten eutec-
ous medium or AccufluorTM NFSi (N-fluorobenzene- tic phase of the reactants. The technique of competi-
sulfonimide) under solvent-free reaction conditions tive reactivity was used in order to evaluate and
(SFRC). Under both reaction conditions cyclic 1,3- better understand the effects of reaction conditions
dicarbonyl compounds were transformed into 2- on the course of these reactions.
fluoro-substituted derivatives and acyclic analogues
into 2,2-difluoro-substituted compounds, while the
reactions of 1-trifluoromethyl-substituted 1,3-dicar- Keywords: fluorine; green chemistry; Selectfluor;
bonyls in water resulted in the formation of 2,2-di- solvent-free reactions; water
Introduction
lecular mass of desired product/relative molecular
masses of all reactants)[2c,d] and Sheldonꢀs E factor
In the development of new synthetic approaches, eco- (mass of total waste/mass of final product),[2e,f] which
logical points of view must be seriously taken into quantify the “greenness” of a reaction and mathemat-
consideration since the emergence of green and sus- ically predict or estimate how green each chemical
tainable chemistry represent a continuous pressing process is. The largest contributors to high values of
challenge for chemists to develop advanced processes the E factor are organic solvents; many of them are
that are not only highly efficient and selective but hazardous, volatile and ecologically harmful, especial-
also environmentally friendly. In the development of ly when used in the large volumes typical of industry.
environmentally benign synthetic pathways there is a Their use for performing organic reactions should
requirement to reduce the number of steps and conse- therefore be minimized or even avoided if this can be
quently minimize toxic waste and by-products, pro- accomplished with high efficiency, and this approach
duce simpler and safer experimental procedures and represents one of the major strategies to reduce E
design energy efficient syntheses.[1] However, these factors of reactions and their impact on the environ-
greener approaches should still exhibit high atom effi- ment. It is worth mentioning that steps toward sus-
ciency, selectivity and enable efficient transformations tainability can also be accomplished by recycling the
in larger-scale experiments which are of crucial impor- solvents used in chemical processes and thus contribu-
tance for industrial applications. Green chemistry has ting to reducing undesirable waste.
also developed “green” parameters to describe the
In line with this approach, organic reactions can be
sustainability of chemical reactions in order to quanti- performed in alternative reaction media including
fy their impact on the environment.[2a,b] Of these alter- ionic liquids,[3a,b] supercritical fluids, in particular
native sustainable chemical parameters, the most in- scCO2,[3c] polyethers,[3d] perfluorinated hydrocar-
fluential are Trostꢀs atom economy (AE=relative mo- bons,[3e] “bio-solvents” like ethyl lactate or polyhy-
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Adv. Synth. Catal. 2010, 352, 2838 – 2846

Towards Greener Fluorine Organic Chemistry: Direct Electrophilic Fluorination
droxyalkanoates[3f,g] and water.[4h,i] The use of water as gerous interactions of fluorinating agents with water,
the reaction medium represents the most promising or simply the incompatibility of reagents in such reac-
option in the search for cheaper, cleaner and yet effi- tion conditions. We have recently demonstrated that
cient technologies. However, in many cases the in- efficient electrophilic fluorofunctionalizations of vari-
compatibility of organic substrates and intermediates ous organic compounds can be performed efficiently
with water represents a potential obstacle to efficient under mild conditions in aqueous medium[9a] and in
transformations in such a medium. In order to over- solvent-less reaction systems[9b] using N F reagents as
À
come this problem, which is a result of the hydropho- mild and alternative F sources to hazardous molecular
bic interactions between apolar parts of organic sub- fluorine. To date only a few other attempts at fluori-
strates and water,[4a,b] usually organic co-solvents for nation of some selected test substrates in pure aque-
increasing the homogeneity of the reaction systems ous medium have been reported utilizing highly dilut-
are used,[4c] but these consequently contribute to ed molecular fluorine techniques,[10a,b] using potassium
forming additional waste. On the other hand, some bifluoride as a fluorinating agent,[10c] and some scarce
organic reactions can be performed by vigorous stir- examples of electrophilic fluorination of uracil, timin,
ring of neat reactants in an aqueous emulsion or sus- 1,3,5-trimethoxybenzene and 2,4,6-trimethoxytoluene
pension without using any organic additives under so- with Selectfluor F-TEDA-BF4.[10d,e] In the case of sol-
called “on water” conditions, but no attention has yet vent-free reactions, research has been mainly focused
been focused on work-up processes, where organic on nucleophilic fluorination including fluorofunction-
solvents are used almost exclusively.[5]
alization of epoxides and acetylenes using an excess
Another approach to reduce the impact on the en- of Bu4N+H2F3
or
a
combination of KHF2/
À
vironment is to perform organic reactions under sol- Bu4N+H2F3 at 100–1308C,[11a,b] nucleophilic aromatic
vent-free reaction conditions (SFRC). The advantages substitution of chlorodiazenes with the KF/18-crown-6
of using SRFC are cost savings, lower energy con- reagent system under microwave irradiation,[11c] elec-
sumption in view of the mild reaction conditions, sat- trochemical anodic fluorination of lactones and cyclic
isfactory purity of the products, while usually derivati- ethers in neat fluoro-substituted electrolytes,[11d] and
zation of the starting compounds can be avoided. Ex- some less efficient and selective examples of fluro-
amples show that these reactions can even proceed transformation of 1,3-dioxalane-2-one, g-butyrolac-
with higher efficiency, higher regio- and stereoselec- tone and toluene with highly diluted molecular fluo-
tivity and, in many cases, because of the higher con- rine (10–30% F2/N2) or gas-liquid micro-reactor tech-
centration and better interaction between the reac- nology.[11e–g]
À
tants, with greater rapidity.[6] When performing organ-
As a response to these challenges and in view of
ic reactions under SFRC, all of these parameters our continuing efforts in developing new greener syn-
strongly depend on the aggregate state of the sub- thetic methods for efficient and selective halogenation
strates and reagents and on their efficient homogeni- of organic molecules,[12] we now report further investi-
zation, resulting in a significant impact on the change gations on water-based and solvent-free fluorination
in the aggregate state of the reactants and conse- systems for direct electrophilic fluorination of 1,3-di-
quently on the molecular mobility. Improved interac- carbonyl compounds and solvent-free fluorination of
tions between the reactants on the macroscopic level ketones in the molten phase using the SDS catalytic
can be well established in the case of liquid-liquid or system. These studies allowed a closer insight into the
À
liquid-solid systems, while solid-phase systems usually formation of the C F bond in water and under SFRC
need additional activation energy.[7a,b] Activation can on the basis of relative kinetic studies. Special atten-
be accomplished using catalysts, immobilization of re- tion was also devoted to development of comprehen-
agents on supports,[7c] or by photochemical,[7d] micro- sive “green” work-ups where at every stage of the
wave,[7e] mechanochemical[7f] or simple thermal activa- process no organic solvents were used.
tion of the reaction systems leading to the formation
of a liquid phase from the occurrence of an eutectic
molten phase system.[7g]
Results and Discussion
In recent years, halogenation of various organic
compounds with emphasis on green and sustainable The keto-enol tautomerism is one of the main factors
development has attracted considerable attention, es- regulating the reactivity of carbonyl compounds. Due
pecially when introduction of halogen atoms is per- to the high acidity of protons on the carbon atom be-
formed under mild reaction conditions in water, ionic tween two carbonyls and the possibility of additional
liquids or even under SFRC.[8] Efficient and selective stabilization of the enol form by an intramolecular hy-
fluorinations of organic compounds in aqueous drogen bond, values for keto-enol equilibrium con-
medium and under SFRC, however, have not been a stants (KE) are ordinarily much higher for 1,3-dicar-
topic of much research interest, obviously due to the bonyls than those for ketones.[13] The reactivity of 1,3-
high reactivity of molecular fluorine, potentially dan- dicarbonyl compounds towards electrophilic function-
Adv. Synth. Catal. 2010, 352, 2838 – 2846
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2839

Gaj Stavber and Stojan Stavber
FULL PAPERS
alization is therefore usually high enough for their F-TEDA-BF4 is soluble and relatively stable in
direct transformation to 2-halo- or 2,2-dihalo-substi- water,[15] making it a very convenient reagent for reac-
tuted derivatives. When these transformations are tions in such an environment. We started our further
performed in aqueous media very important factors investigations with cyclic 1,3-dicarbonyls, known to be
regulating the efficiency of the reactions are the hy- more reactive for electrophilic functionalizations than
drophobicity of reactants and their aggregate state at their acyclic analogues, since their degree of enoliza-
the reaction temperature.
We have already shown that SelectfluorTM F- sion of 1,3-diketone (1 mmol of 3, 5, 7, Table 1) or b-
TEDA-BF4 (1-chloromethyl-4-fluoro-1,4-diazonia- keto ester (1) in 5 mL of water was magnetically
bicyclo[2.2.2]octane bis-tetrafluoroborate), one of the stirred (700 rpm) at 60–808C, and after consumption
tion is very high.[13] In a typical experiment a disper-
A
ACHTUNGTRENNUNG
most commonly used electrophilic fluorinating re- of the reagent (KI starch paper test), the reaction
agents,[14] could also be efficiently used for direct fluo- mixture was cooled to room temperature. In order to
rination of organic compounds in aqueous medium.[9a] reduce the environmental impact of the overall pro-
À
Table 1. Fluorination of 1,3-dicarbonyl compounds with N F reagents in water or under solvent-free reaction conditions.
Reaction conditions
Entry
1
Fluorofunctionalization
Water[a]
SFRC[b]
Work-up
A
Yield [%]
82
Work-up
A
Yield [%]
82
2
3
A
84
74
A
78
83
B[c]
D[c]
4
5
C
91
80
C[c,d]
93
/
A
/
6
7
8
9
A
B
C
C
/
89
82
78
87
/
/
/
D
D
D
D
90
75
80
85
10
11
40
40
[a]
Reaction conditions: 1,3-dicarbonyl compound (1 mmol), F-TEDA-BF4 (1.1 mmol or 2.2 mmol in the case of 9), H2O
(5 mL), magnetic stirring (700 rpm), T=708C, reaction time 4–10 h; procedures for isolation of products (work-up): A:
extraction with tert-butyl methyl ether; B: gently separated from water and removing its traces from liquid products in a
dry atmosphere; C: filtering-off crude solid product and drying.
Reaction conditions: 1,3-dicarbonyl compound (1 mmol), NFSi (1.1 mmol), homogenization of reactants and heating at
908C for 1–4 h; procedures for isolation of crude products (work-up): A: extraction with tert-butyl methyl ether; D: distil-
lation under reduce pressure.
Synthesis also performed on the 5–20 mmol scale.
F-TEDA-BF4 used as the fluorinating reagent; after completion of the reaction, water was added to the crude reaction
mixture and the solid product filtered-off.
[b]
[c]
[d]
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Towards Greener Fluorine Organic Chemistry: Direct Electrophilic Fluorination
Table 2. Fluorination of trifluoromethyl substituted 1,3-di-
carbonyl compounds with F-TEDA-BF4 in water.[a]
cess as much as possible, special attention was paid to
procedures for isolation of the products. If possible
the use of organic solvents was avoided and the isola-
tion protocol was chosen depending on the aggregate
state of the products and their compatibility with
water. In the case of products partly soluble in water,
an extraction with tert-butyl methyl ether, often ap-
plied as a substitute for environmentally unacceptable
halogenated solvents, was used as a work-up proce-
dure (A), hydrophobic liquid products were gently
separated from water and dried under reduced pres-
sure (B), while solid products were simply filtered-off
and dried (C). Following these protocols a variety of
cyclic 1,3-dicarbonyl compounds (entries 1–5, Table 1)
were selectively and efficiently transformed to their 2-
fluoro derivatives 2, 4, 6, and 8 with high isolated
yields. Selective mono-fluorofunctionalization of acy-
clic 1,3-dicarbonyls bearing a methylene carbon atom
between two carbonyl functional groups is not an
easy task and often strict control of the reaction con-
ditions is necessary in order to diminish over-fluorina-
tion to 2,2-difluoro-substituted products, while for
Entry
Substrate 13
Work-up
Yield [%]
1
2
A
C
83
61
3
C
82
4
C
92
[a]
Reaction conditions: 1,3-dicarbonyl compound (1 mmol),
F-TEDA-BF4 (2.2 mmol), H2O (5 mL), magnetic stirring
(700 rpm), T=708C, reaction time 4–6 h; procedures for
isolation of crude products (work-up): A: extraction with
tert-butyl methyl ether; C: filtering off crude solid prod-
uct and drying.
complete difluorination the presence at least equiva- ry to our previous observations in the case of halo-
À
lent amounts of a strong base was reported to be nec- genation of these kind of compounds with N X suc-
essary.[16] In our case, the fluorination of a group of
G
acyclic 1,3- dicarbonyl compounds (9a–d, Table 1) not be stopped at the monofluorination stage and
with F-TEDA-BF4 in water could also not be selec- completing reactions leading to the formation of 2,2-
tively stopped at the monofluorination stage, but by difluoro derivatives seemed to be the best choice. The
using a two-fold excess of the reagent efficient forma- introduction of fluorine atoms obviously enhanced
tion of the 2,2-difluoro-substituted products 10a–d water addition to the carbonyl group next to the elec-
was established without any additional activation of tron-withdrawing trifluoromethyl group, so that 2,2-
the starting material. We also tested two examples of difluoro-3,3-dihydroxy-1-one derivatives 14 were the
less active 1,3-dicarbonyl compounds 3-oxobutyric final products isolated following organic solvent-less
acid ethyl ester (9e, entry 10, Table 1) and diethyl isolation protocols.
malonate, and found that fluorination of 9e with
Direct transformation of a carbon-hydrogen bond
F-TEDA-BF4 in water gave a complex reaction mix- to a carbon-fluorine bond under solvent-free reaction
ture of mono- and difluoro products, hydrolyzed conditions (SFRC) remains a challenging task. The
À
products and hydrates, while the reaction under formation of a C F bond, the strongest single bond in
SFRC with NFSi selectively and efficiently yielded organic molecules, is an energy releasing process
2,2-difluoro-3-oxobutyric acid ethyl ester 10e. Diethyl often causing stability problems in such reaction sys-
malonate was found to be resistant under both reac- tems. The migration of reactants and the consequent
tion conditions. On the other hand, 2-benzyl-3-oxobu- possibilities of their efficient contact for successful ex-
tyric acid ethyl ester 11 could not be transformed to change of electrons are considerably different from
its 2-fluoro-substituted product 12 with more than those taking place in solution. The aggregate state of
60% yield under these reaction conditions.
the reactants at the reaction temperature is a very im-
The trifluoromethyl functional group, due to its portant factor regulating the course of reactions.
strong negative inductive effect, regulates to a consid- Liquid-liquid reaction systems represent the simplest
erable extent the reactivity of trifluoromethyl-substi- situation, while solid-liquid systems and especially
tuted organic molecules. Enolization of CF3-substitut- solid-solid systems are more complex, which could
ed 1,3-dicarbonyl compounds is very high and stabili- cause problems, but also opens up new exciting possi-
zation of the enol form is additionally supported by bilities.[6] Following our preliminary investigations,[9b]
involvement of the trifluoromethyl group in the intra- fluorotransformation of various types of organic com-
molecular hydrogen bond,[13] and therefore its reactiv- pounds under SFRC could be efficiently performed
ity towards electrophilic transformation is expected to using SelectfluorTM F-TEDA-BF4 or AccufluorTM
be enhanced. Fluorination of trifluoromethyl-substi- NFSi (N-fluorobenzenesulfonimide). Going further as
tuted 1,3-diketones (13, Table 2) with F-TEDA-BF4 in shown in Table 1, a variety of 1,3-dicarbonyl com-
pure water was found to be very efficient, but contra- pounds could be selectively and effectively fluorinat-
Adv. Synth. Catal. 2010, 352, 2838 – 2846
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FULL PAPERS
Table 3. Effect of reaction medium on the relative reactivity of 1,3-dicarbonyl compounds towards fluorination with F-
TEDA-BF4.
Relative rate factors (krel)[a]
Substrate
H2O
0.05% aqueous SDS
dry MeCN
SFRC
1
2
3
4
5
6
9a liquid
1.0
10.2
0.4
0.2
20.0
23.0
1.0
15.0
1.7
0.4
>100
>100
1.0
3.5
9.5
<0.001
>100
>100
1.0
7.1
<0.01
<0.01
>100
>100
9b mp 548C
9c mp 778C
11 liquid
3a liquid
5 mp 668C
[a]
Relative rate factors were calculated from the equation[18]
krel =kA/kB =log
N
G
Ingold–Show relation,[19] where A and B are the amounts (in mmols) of starting materials and X and Y the amounts of
products derived from them and determined from 19F NMR spectra of crude reaction mixtures using octafluoronaphtha-
lene as the internal standard.
ed under SFRC and the results obtained were compa- tors (krel).[18,19] As evident from Table 3, 1-phenylbu-
rable to those observed after analogous reactions in tane-1,3-dione 9b was found to be from 3.5 (in dry
water medium. The efficiency of a particular transfor- MeCN) to 15.0 (in aqueous solution of the amphi-
mation was found to be crucially dependent on the phile) fold more reactive than the reference substrate
aggregate state of the starting material. In the case of 3-oxo-3-phenylpropionic acid ethyl ester 9a (entry 2).
liquid compounds, reactions using either reagent gave These results could be explained by the fact that the
comparable results, but with F-TEDA-BF4 the con- degree of enolization is ordinarily higher in 1,3-dike-
sumption of starting material needed considerably tones than b-keto esters, while enolization was estab-
longer reaction times (4–24 h), while reactions with lished as considerably higher in aqueous solutions of
solid substrates gave much better results using NFSi amphiphiles, and generally lower in MeCN than in
as the reagent. In the first case we were dealing with pure water.[13] In the case of 1,3-diphenylpropane-1,3-
reactions in a liquid-solid system, where potentially dione 9c other factors regulate its reactivity. Although
better solubility of the reagent in a particular sub- 9c is even more enolizable than 9b, its reactivity in
strate at the reaction temperature (80–908C) could pure water was found to be twice as low as that of 9a.
enhance the reaction rate. On the other hand, we ob- Due its higher hydrophobic character and higher
À
served that formation of a C F bond using NFSi melting point, its incompatibility with water became
under SFRC proceeded in a molten phase system the main factor decreasing its reactivity. In the pres-
which works as a new reaction medium, enabling ence of catalytic amounts of SDS as an anionic am-
rapid migration of reactants and efficient interactions phiphile the improved homogeneity of the reaction
between them. Further potential inconveniences de- mixture accelerated fluorination, while in the totally
rived from reactions performed under SFRC are con- homogeneous MeCN system the expected high rela-
nected with uneven energy transport, often resulting tive reactivity was established (entry 3). Despite the
in the formation of hot-spots with high localized mi- fact that 2-benzyl-3-oxobutyric acid ethyl ester 11 ex-
croscopic temperatures.[17] Since these problems hibited a high degree of enolization in water,[12h] hy-
become more evident in scaled-up processes, we tack- drophobic interactions and steric hindrance in the
led this challenge and performed larger-scale fluorina- enolic tautomeric form played an important role in its
tions under SFRC, and in both model cases (entry 3: low reactivity under all the reaction conditions stud-
3b to 4b; molten phase system and entry 4: 5 to 6; ied (entry 4). Both the cyclic 1,3-dicarbonyls liquid 2-
liquid-solid system) no uncontrollable exothermicity acetylcyclohexanone (3a, entry 5) and solid 2-acetyl-
was observed. Compound 11 was again found to be 1-tetralone (5, entry 6), due to their high degree of
unsuitable for fluorination, also under SFRC enolization, showed the expected relative reactivity;
(entry 10).
in pure water they were found to be more than
In order to evaluate the structural effects of 1,3-di- twenty fold more reactive than the reference material
carbonyls on fluorination with F-TEDA-BF4 in differ- 9a, while in the other three reaction media a reactivi-
ent reaction media, we measured the relative reactivi- ty more than two decades higher was established.
ty of some cyclic and acyclic 1,3-dicarbonyls in pure
Direct electrophilic fluorination of ketones has for
water, in a 0.05% aqueous solution of the amphiphile a long represented a problem, one which was partly
sodium dodecyl sulfate (SDS), in dry acetonitrile, and resolved a decade ago following direct fluorofunction-
under SFRC using the technique of competitive reac- alization of various structural types of carbonyl com-
À
tivity and calculated their values as relative rate fac- pounds using N F reagents in MeCN or MeOH
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Towards Greener Fluorine Organic Chemistry: Direct Electrophilic Fluorination
Table 4. Transformation of ketones to corresponding a-fluoro ketones using F-TEDA-BF4 in the SDS aqueous micelle-based
system[21] or NFSi in the molten phase solvent-free reaction system.[a]
Ketone
Transformation to a-fluoro ketone [%] in
aqueous SDS
SFRC
1
2
3
4
5
6
1-Indanone
1-Tetralone
Benzosuberone
Propiophenone
5-Nonanone
2-Octanone
100
100
100
90
95
95
58
62
61
65
0
0
[a]
Reaction conditions: ketone (1 mmol), NFSi (1 mmol), SDS (0.1 mmol), heating at 908C for 24 h.
medium,[20] and very recently, after an unsuccessful at- the reactivity. Fluorination under SFRC was found to
tempt in pure water,[9a] the application of the SDS be faster than in water; reactions proceeded in the
aqueous micelle-based system was shown to be a molten eutectic phase enabling better homogenization
promising alternative.[21] However, direct transforma- of the reaction system and consequently more rapid
tions of ketones to their a-fluoro derivatives under migration of reactants, their more efficient contact,
SFRC still remains a challenging task.[9b] We tried to and more regular heat transfer. To our satisfaction,
À
solve this problem by the addition of Lewis or Brønst- we succeeded in the transformation of a C H into a
ed acid catalysts, usually used as enolization promot- C F bond with high selectivity and efficiency and ex-
À
ers. Unfortunately none of acid activators such as p- tended the methodology to scaled-up procedures.
toluensulfonic acid (PTSA), 4-dodecylbenzensulfonic Direct fluorination of ketones under SFRC was found
acid (DBSA), sulfuric acid, acetic acid, or niobic acid ineffective, but following the application of the SDS
gave an at least moderate degree of fluorotransforma- catalytic system moderate yields of a-fluoro ketones
tion. Furthermore, we checked the effects of the addi- were obtained. The use of pure aqueous or solvent-
tion of amphiphiles, and catalytic amounts of SDS (up free reaction conditions for direct electrophilic fluori-
to 10 mol%), which gave to some extent acceptable nation of carbonyl compounds, including the develop-
results, but the transformation of aryl alkyl ketones to ment of environmentally friendlier work-up proce-
their a-fluoro derivatives (entries 1–4, Table 4) did dures, represents a significant step towards greener
not reach more than 65%, while dialkyl ketones fluorine organic chemistry.
seemed to be resistant under these reaction condi-
tions.
Experimental Section
Conclusions
Direct Fluorination of 1,3-Dicarbonyl Compounds in
Water: General Procedure
To promote efforts for a green chemical approach to
selective and efficient fluorination of organic com-
pounds, protocols for fluorination of organic 1,3-dicar-
bonyl compounds in water using SelectfluorTM F-
TEDA-BF4, or under solvent-free reaction conditions
(SFRC) using AccufluorTM NFSi, were developed
with additional attention to avoidance of organic sol-
vents also in the phase of isolation of reaction prod-
A solid or liquid 1,3-dicarbonyl compound (1 mmol) was
placed in a glass flask (25 mL) equipped with a magnetic
stirrer, 5 mL of deionized water were then added and the re-
action system was intensively stirred (700–800 rpm) at 60–
808C to obtain a well dispersed aqueous system. F-TEDA-
BF4 (1.10–2.10 mmol; 390–744 mg) was added in two por-
tions to the aqueous dispersion and stirred at 60–808C until
the KI (0.1M) test showed consumption of the fluorinating
ucts. A series of cyclic and acyclic 1,3-dicarbonyl com- reagent. The reaction mixture was cooled to room tempera-
ture and the resulting 2-fluoro- or 2,2-difluoro 1,3-dicarbon-
yls were isolated under the following “green” isolation pro-
cedures:
Method A: In the case of less hydrophobic 2-fluoro or
2,2-difluoro products (2, 3a, 8, 10a), the reaction system was
diluted with water (10 mL) and extracted with tert-butyl
methyl ether (2ꢂ5 mL). The combined ether phases were
dried over anhydrous Na2SO4 and solvent was then removed
under reduced pressure.
pounds were efficiently transformed to their 2-fluoro-
or 2,2-difluoro-substituted derivatives without the
need for prior activation of the starting compounds or
the use of acid activators, while their reactivity in
pure water was found to be regulated by their enoliz-
abilities, aggregate state at the reaction temperature
and hydrophobic interactions. The effects of aggre-
gate state and hydrophobicity could be diminished by
addition of the anionic amphiphile sodium dodecyl
Method B: In the case of liquid hydrophobic 2-fluoro or
sulfate (SDS) to the reaction system, which improved 2,2-difluoro products (4b, 10b), the aqueous phase was
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Gaj Stavber and Stojan Stavber
FULL PAPERS
gently separated from the heavier dense products collected
on the bottom of the reaction vessel. The isolated crude
liquid products were then dried under vacuum and distilled
to obtain the final pure 2-fluoro- or 2,2-difluoro-1,3-dicar-
bonyl compounds.
Method C: The reaction mixture was cooled in an ice-
bath and solid crystalline 2-fluoro or 2,2-difluoro products
(6, 10c, 10d) which crystallized efficiently from aqueous so-
lution were filtered off under reduced pressure, washed with
water (3ꢂ10 mL) and dried.
3.7 Hz, CArH), 132.2 (t, J=3.7 Hz, CAr), 135.6 (CArH), 191.9
(t, J=29.4 Hz, CO); IR: n=3435, 1682, 1599, 1206, 1076,
960, 844, 723, 672; MS: m/z=270 (M+, 3), 269 (M+À1, 100),
253 (18), 233 (20), 155 (15), 147 (45), 121 (83); HR-MS:
m/z=269.0237, calcd. for C10H7F5O3: 269.0239; anal. calcd.
for C10H7F5O3: C 44.46, H 2.61; found: C 44.59, H 2.56.
2,2-Difluoro-4,4,4-trifluoro-3,3-dihydroxy-1-naphthalen-2-
ylbutan-1-one (14c): Crystallization from CHCl3/n-hexane,
1
4:1; yield: 294 mg (92%); solid, mp 75.5–77.08C; H NMR:
d=4.91 (bs, 2H, OH), 7.61 (ddd, J=9.0 Hz, J=6.1 Hz, J=
0.9 Hz, 1H), 7.69 (ddd, J=9.0 Hz, J=6.2 Hz, J=0.8 Hz,
1H), 7.88–8.07 (m, 4H), 8.73 (bm, 1H); 19F NMR: d=
À81.5 (t, J=11.1 Hz, 3F, CF3), À111.8 (qt, J=11.1 Hz, J=
1.1 Hz, 2F); 13C NMR: d=92.9 (m, J=27.5 Hz, C-3), 112.4
(t, J=267.4 Hz, CF2), 121.3 (q, J=288.7 Hz, CF3), 124.7 (t,
J=2.3 Hz, CArH), 127.3 (CArH), 127.8 (CArH), 129.4 (t, J=
1.5 Hz, CAr), 130.0 (CArH), 130.2 (CArH), 130.4 (CArH), 132.1
(CAr), 133.9 (t, J=4.6 Hz, CArH), 136.3 (CAr), 190.8 (t, J=
30.5 Hz, CO); IR: n=3420, 1673, 1626, 1202, 1172, 1109,
1075, 972, 799; MS: m/z=320 (M+, 20%), 155 (100), 127
(70), 77 (10); HR-MS: m/z=320.0465, calcd for C14H9F5O3:
320.0472; anal. calcd. C14H9F5O3: C 52.52, H 2.83; found: C
52.30, H 2.73,
The 2-fluoro- or 2,2-difluoro-1,3-dicarbonyl compounds
1
obtained were characterized by H, 19F, 13C NMR and MS
analysis and spectroscopic data for known compounds are
presented in Supporting Information.
2-Benzoyl-2-fluorocyclohexanone (4b): Distillation under
residue pressure; yield: 183 mg (83%); yellow viscous
1
liquid; H NMR: d=1.85–2.16 (m, 5H), 2.52–2.62 (m, 1H),
2.67–2.77 (m, 2H), 7.44 (m, 2H), 7.56 (m, 1H), 8.01 (m,
2H); 19F NMR: d=- 151.5 (tm, J=17.1 Hz); 13C NMR: d=
21.9 (d, J=7.6 Hz, C-4), 27.2 (C-5), 37.3 (d, J=21.5 Hz, C-
3), 40.4 (C-6), 102.1 (d, J=198.5 Hz, C-2), 128.5, 129.9 in
133.7 (CArH), 134.4 (CAr), 194.7 (d, J=27.2 Hz, COPh), 204.0
(d, J=18.1 Hz, CO); IR: n=2950, 2870, 1731, 1686, 1595,
1447, 1273, 1223, 1107, 843, 692, 616 cmÀ1; MS: m/z=220
(M+, 1%), 200 (14), 172 (18), 105 (100), 77 (65); HR-MS:
m/z=220.0899, calcd. for C13H13FO2: 220.0906; anal. calcd.
for C13H13FO2: C 70.90, H 5.95; found: C 70.79, H 6.07.
Fluorination of 1,3-Dicarbonyl Compounds using
À
N F Reagents under SFRC; General Procedure
In the case of liquid substrates, 1 mmol of starting material
and 1.10–2.10 mmol of finely powdered NFSi were mixed in
a 15 mL glass vessel and the reaction mixture formed was
then heated at 858C for 30–120 min. In the case of solid
starting materials, the substrate and NFSi were triturated in
a glass mortar to obtain a well homogenized mixture, quan-
titatively transferred to a glass vessel and heated at 85–958C
to obtain a reactive molten phase system and the tempera-
ture was maintained for 2 h. The course of reaction was
monitored by TLC and the resulting 2-fluoro- or 2,2-di-
fluoro-1,3-dicarbonyls were isolated under the following
“green” isolation procedures:
Method A: In the case of temperature-sensitive 2-fluoro-
1,3-dicarbonyl products (2, 4a) the reaction mixture was di-
luted with water (10 mL) and extracted with tert-butyl
methyl ether (2ꢂ5 mL). The combined organic phases were
then treated with a 40% aqueous solution of Na2SO3 (2ꢂ
10 mL) and afterward dried over anhydrous Na2SO4. After
removal of solvent under reduced pressure, the crude prod-
ucts obtained were purified by flash column chromatogra-
phy on silica to yield the final pure fluoro-substituted 1,3-di-
carbonyl products.
2,2-Difluoro-3-oxo-3,N-diphenylpropionamide
(10d):
Crystallization from water and distillation under residue
pressure; yield: 239 mg (87%); white solid, mp 97.0–99.0;
1H NMR: d=7.15–7.20 (m, 1H), 7.31–7.36 (m, 2H), 7.47–
7.57 (m, 4H), 7.62–7.67 (m, 1H), 8.13–8.18 (m, ArH+NH,
3H); 19F NMR: d=- 108.3 (bs); 13C NMR: d=110.8 (t, J=
267.0 Hz, CF2), 120.4, 126.0 128.9 and 129.3 (CArH), 130.5 (t,
J=3.0 Hz, CAr), 135.1 (CArH), 136.4 (CAr), 159.3 (t, J=
27.4 Hz, CONH), 187.3 (t, J=27.4 Hz, COPh); IR: n=3334,
1721, 1683, 1599, 1537, 1448, 1159, 1123, 745, 685 cmÀ1; MS:
m/z=275 (M+,15%), 120 (2), 105 (100), 77 (41); HR-MS:
m/z=275.0758, calcd.for C15H11F2NO2: 275.0766; anal.
calcd.for C15H11F2NO2: C 65.45, H 4.04, N 5.09; found: C
65.35, H 4.00, N 5.05.
2,2-Difluoro-4,4,4-trifluoro-3,3-dihydroxy-1-thiophen-2-yl-
butan-1-one (14a): Preparative TLC (SiO2, CH2Cl2/EtOH,
9.5:0.5); yield: 229 mg (83%); highly hygroscopic volatile
white solid, mp 47.5–49.08C; 1H NMR: d=4.80 (bs, 2H,
OH), 7.28 (t, J=4.7 Hz, 1H), 7.96 (d, J=4.7 Hz, 1H), 8.19
(bs, 1H); 19F NMR: d=- 81.6 (t, J=10.8 Hz, 3F, CF3),
À114.4 (qd, J=10.8 Hz, J=1.7 Hz, 2F); 13C NMR: d=92.9
(m, J=33.2 Hz, C-3), 111.1 (t, J=266.5 Hz, CF2), 121.3 (q,
J=288.3 Hz, CF3), 129.8 (CArH), 137.4 (t, J=3.0 Hz, CAr),
138.2 (t, J=6.0 Hz, CArH), 139.2 (CArH), 183.5 (t, J=28.6 Hz,
CO); MS: m/z=276 (M+, 1%), 258 (4), 183 (3), 162 (3), 111
(100), 83 (9), 69 (5); HR-MS: m/z=275.9890, calcd. for
C8H5F5O3S: 275.9879.
Method D: Various 2-fluoro- or 2,2-difluoro-1,3-dicarbon-
yl products (4b, 10b–d) were isolated from the crude reac-
tion mixture following distillation under reduced pressure.
Determination of Relative Rate Factors (krel) for the
Fluorination of 1,3-Dicarbonyls in Various Reaction
Media or under Solvent-Free Reaction Conditions;
Typical Experimental Procedure
2,2-Difluoro-4,4,4-trifluoro-3,3-dihydroxy-1-phenylbutan-
1-one (14b): Crystallization from CHCl3/n-hexane 4:1; yield:
221 mg (82%); solid, mp 49.5–51.08C; 1H NMR: d=4.70
(bs, 2H, OH), 7.52–7.57 (m, 2H), 7.72 (d, J=6.1 Hz, 1H),
8.12 (d, J=6.1 Hz, 2H); 19F NMR: d= À1.6 (t, J=11.1 Hz,
3F, CF3), À112.4 (qd, J=11.1 Hz, J=1.4 Hz, 2F); 13C NMR:
d=93.3 (m, J=33.0 Hz, C-3), 111.8 (t, J=271.0 Hz, CF2),
121.3 (q, J=287.5 Hz, CF3), 129.3 (CArH), 131.0 (t, J=
The relative rate factors of the studied 1,3-dicarbonyls (3a,
5, 9a–c, and 11) were determined using the technique of
competitive reactivity,[13,14] which was carried out as follows:
1 mmol of reference 3-oxo-3-phenylpropionic acid ethyl
2844
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Adv. Synth. Catal. 2010, 352, 2838 – 2846

Towards Greener Fluorine Organic Chemistry: Direct Electrophilic Fluorination
ester 9a, 1 mmol of the comparative 1,3-dicarbonyl com-
pound (9b, c, 11, 3a, or 5) and 1 mmol of fluorinating agent
F-TEDA-BF4 were dispersed or dissolved in 5 mL of the re-
action media (pure H2O, 0.05% aqueous SDS, anhydrous
MeCN), or mixed when the reactivities were compared
under SFRC. The reaction systems were stirred at 708C (sol-
vents) or held at 908C (SFRC) for 10 h. Thereafter, the re-
action mixtures were cooled to room temperature, extracted
with tert-butyl methyl ether (15 mL) and the organic phases
were then washed with 20 mL of water. After removal of
the solvent under reduced pressure, the amounts (mmol) of
a-fluoro-substituted products were determined from
19F NMR spectra using octafluoronaphthalene as the inter-
nal standard. The relative reactivity expressed by the rela-
tive rate factor (krel) was calculated from the equation,[18] de-
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rived from the Ingold–Show relation:[19]
krel =kA/kB =log
[(AÀX)/A]/log [(BÀY)/B], where A (compared) and B (ref-
erence) is the amount (mmol) of starting material and X
(compared) and Y (reference) the amounts (mmol) of corre-
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in Table 3 are the average values of three independent
measurements with 2.0% maximum error.
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Supporting Information
General remarks, experimental protocols for large-scale syn-
thesis, characterization data of products identified as the
known compounds and copies of NMR spectra of new com-
pounds are supplied in the Supporting Information.
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Acknowledgements
We are grateful to the staff of the National NMR Centre at
the National Institute of Chemistry in Ljubljana and the staff
of the Mass Spectroscopy Centre at the “Jozef Stefan” Insti-
tute. We thank the Slovenian Research Agency (Programme
ARRS P1-0134) and European Regional Development Fund
(OP 13.1.1.2.02.0005) for financial support.
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Adv. Synth. Catal. 2010, 352, 2838 – 2846