Catalyst-free and highly selective electrophilic mono-fluorination of acetoacetamides: Facile and efficient preparation of 2-fluoroacetoacetamides in PEG-400

Article abstract of DOI:10.1039/c2gc16661e

Series of α-mono-fluorinated acetoacetamides were synthesized under mild condition with industrialized Selectfluor as the F⁺ source in PEG-400. The approach avoided the use of base or metal catalyst, and most of cases proceeded in nearly quanti

Full text of DOI:10.1039/c2gc16661e

View Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Green Chemistry
Cite this: Green Chem., 2012, 14, 1159
www.rsc.org/greenchem
PAPER
Catalyst-free and highly selective electrophilic mono-fluorination of
acetoacetamides: facile and efficient preparation of 2-fluoroacetoacetamides in
PEG-400†
Jingjing Bi, Zhiguo Zhang,* Qingfeng Liu and Guisheng Zhang*
Received 24th December 2011, Accepted 13th February 2012
DOI: 10.1039/c2gc16661e
Series of α-mono-fluorinated acetoacetamides were synthesized under mild condition with industrialized
Selectfluor as the F+ source in PEG-400. The approach avoided the use of base or metal catalyst, and
most of cases proceeded in nearly quantitative conversions regardless of the electronic nature of the
diversity substituent.
commercial chemical22 with established applications in the
Introduction
pharmaceutical industry and asymmetric synthesis,23,24 and has
“Green and sustainable chemistry” aims to develop environmen-
tally benign syntheses and processing, to reduce steps and conse-
quently minimize toxic waste and byproducts, to produce
simpler and safer experimental procedures and to design energy
efficient syntheses.1 At the same time, these greener approaches
should still take into account high atom economy, selectivity
(chemoselectivity, regioselectivity, stereoselectivity) and
efficiently convert to larger-scale preparations which are of
crucial importance for industrial applications. According to
Trost’s enigmatic atom economy2 and Sheldon’s E-factor,3 the
two most famous “green chemistry parameters”, organic solvents
should be minimized or even avoided. So naturally, water,4 poly-
alcohols, polyethers,5 ionic liquids,6,7 and supercritical fluids are
therefore employed in organic reactions, and solvent-free reac-
tion (SFR) seems to be another good choice.
To date, fluorine-containing compounds play an increasingly
important role, introduction of fluoride atom(s) into a molecule
brings out valuable properties, which are applicable to pharma-
ceuticals,8 agrochemicals,9 and materials10 bearing an outstand-
ing properties.11 Nucleophilic fluorination12 and electrophilic
fluorination13,14 are the two most direct and useful methods to
introduce fluorine selectively into organic compounds.15 Many
of them, such as electrophilic fluorinating agents FClO3,16
NF3O,17 XeF2,18 AcOF,19 PhIO/HF20 and NFSI,21 are dangerous
or expensive. So, over the past decade, easily-handled cost-effec-
tive bis(tetrafluoroborate) [F-TEDA-BF4 (TEDA = triethylene-
diamine)],14 commonly called Selectfluor, rapidly become a
attracted much attention as a stable electrophilic fluorination
reagent.
ð1Þ
ð2Þ
α-Fluoro-1,3-dicarbonyl compounds, especially α-mono-
fluorinated 1,3-dicarbonyl compounds, are widely used in asym-
metric synthesis25–29 and construction of biologically active mol-
ecules.30,31 They have been synthesized by treating the parent
dicarbonyls (eqn (1)) or their enolates with fluorine (eqn
(2)),32–35 base (commonly used strong base, such as NaH,
LiHMDS etc.) and/or metal as catalysts, acetonitrile and dichloro-
methane being the two most commonly used solvents.24 But
most of the reaction inevitably produced a mixture of mono and
di-fluorinated products that must be troublesome to separate (eqn
(1)).36–38 Therefore, high yielding of mono-fluorinated products
remains a much more challenging task. Currently, a few cases
have so far focused on the preparation of α-mono-fluorinated
acetoacetamides, in which acetoacetamides were a special case
of β-dicarbonyl compounds (Scheme 1). Lawrence et al.39
demonstrated that 1,3-dicarbonyl compounds including β-keto-
amides 2a and 2b are converted efficiently to 2-monofluoro
derivatives, and thence to 2,2-difluoro derivatives. Xiao and
Shreeve37 also showed that the mono-fluorination of less reactive
ketoamide 2b could be accelerated dramatically under micro-
wave assistance, but at the end of the reaction process traces of
2,2-difluorinated products often formed in these reactions
judging from the NMR spectral analyses. ω-Bromoacetoacetani-
lide 1c can be regiospecifically fluorinated at the α-position in
organic solvent.30 In Davis et al.’s38 study of the electrophilic
College of Chemistry and Environmental Science, Key Laboratory of
Green Chemical Media and Reactions, Ministry of Education; Henan
Key Laboratory for Environmental Pollution Control, Henan Normal
University, Xinxiang, Henan 453007, PR China. E-mail:
zhangzhiguo3030@yahoo.com.cn, zgs6668@yahoo.com;
Fax: (+86) 373-3325250
†Electronic supplementary information (ESI) available: Detailed exper-
1
imental procedure, including H NMR, 13C NMR and IR spectra for all
fluorinations
by
using
N-fluoro-o-benzenedisulfonimide
compounds. See DOI: 10.1039/c2gc16661e
(NFOBS), mono- (2d) and difluorination (3d) are both observed
This journal is © The Royal Society of Chemistry 2012
Green Chem., 2012, 14, 1159–1162 | 1159

View Online
Table 1 Survey of reaction conditionsa
Selectfluor
(eq.)
Entry Condition
T/°C Time Product Yieldb/%
1
2
3
4
5
6
7
8
9
H2O
H2O
1.1
1.1
1.1
1.1
1.1
1.1
25
60
25
60
60
60
60
60
60
30 h 2j
8 h 2j
30 h 2j
51c
52d
87e
95
PEG-400
PEG-400
PEG-400
PEG-400
[BMIM]BF4 1.1
[BMIM]PF6 1.1
8 h
8 h
8 h
8 h
8 h
2j
2j
2j
2j
2j
97f
94g
86h
69i
97
Scheme 1 Related works of other researchers.
PEG-400
2.2
19 h 3j
a All reactions were carried out with acetoacetarylamide 1j (1.0 mmol),
Selectfluor as the fluorine source, unless otherwise indicated. b Isolated
yield and trace 3j (≤3%) was detected by HPLC in all reactions. c 48%
3j was found. d 40% 1j was recovered. e 9% 1j was recovered.
f Microwave irradiation with power range was up to 800 W. g Ultrasound
was used. h 12% 1j was recovered. i 28% 1j was recovered.
in the best ratio of 16 : 1 when using water as a cosolvent, mono-
fluorination increases at the expense of difluorination. N-Aceto-
acetylated oxazolidinones 1e and 1f also give 2e and 2f in good
yield in CH3CN.40 Togni et al.36 isolated a 1 : 1 mixture of
mono (2g) and difluorination (3g) of β-ketoamide with Selec-
tfluor using CpTiCl3 as a catalyst. Very recently, Kitamura’s
group20 reported that 3-ketoamides underwent fluorination to
give the corresponding 2-fluorinated products 2h and 2i in yields
of 25% and 52%, respectively, by direct use of 55% aqueous
hydrofluoric acid and iodosylbenzene (PhIO). To the best of our
knowledge, there is no detailed investigation of the controlled
synthesis of α-mono-fluorination of acetoacetamides, especially
consideration of greener methods such as avoiding the use of
alkali, organic solvent, and minimizing fluoride reagents and
with enhanced selectivity, etc. Herein, we wish to report an
efficient catalyst-free α-electrophilic mono-fluorination of aceto-
acetamides under green conditions.
in 8 h, and also 40% 1j was recovered (entry 2 vs. 4). Under
other green conditions, microwave irradiation was as good as
heating method during the process (entry 5 vs. 4) and ultrasound
was inefficient (entry 6 vs. 4). In hydrophilic ionic liquids,
[BMIM]BF4 (1-butyl-3-methylimidazolium tetrafluoroborate),
and hydrophobic ionic liquids, [BMIM]PF6 (1-butyl-3-methyl-
imidazolium hexafluorophosphate), the reactions gave 2j 86%
and 69% yield after 8 h at 60 °C and 12% and 28% 1j was
recovered, respectively. It is noteworthy that the reaction was fast
in hydrophilic ionic liquid than in hydrophobic ionic liquid
1
(entries 7 and 8). From the H NMR and 13C NMR we did not
find 2,2-difluoro acetoacetamide 3j.37 In order to confirm
whether or not the reaction generates di-fluorinated products in
the end, we analyzed the HPLC spectrum of all attempts in
Table 1. The HPLC data showed that not more than 3% di-fluori-
nated product 3j was produced in all surveys. When using 2.2
equiv. of Selectfluor for α-fluorination of acetoacetamides 1j, in
PEG-400, the di-fluorinated product 3j could be obtained with a
yield of 97% at 60 °C (Table 1, entry 9). So we determined entry
4 as the final optimal conditions for the preparation of mono-
fluorinated products, considering the factors of price, ease to get
and industrialization.
Having concluded from the above results that the optimal reac-
tion solvent system was PEG-400 for mono-fluorination, the
effect of various β-keto amides were then further evaluated using
similar reaction conditions (Table 2). It was apparent that all
reactions could finish in 27 h at 60 °C or slightly higher tempera-
ture with a yield of 90–100% (Table 2, compounds 2j–2y). The
diverse substituents on the aryl, whether electron-donating
groups (EDG) or electron-withdrawing groups (EWG), had no
significant effect on the yield of α-mono-fluorinated acetoaceta-
mides (Table 2, compounds 2j–2t). In the case of β-keto amide
1g, 2-fluoro-β-keto amide 2g could be isolated in yield of 84%
which HPLC yield was 93%.36 The yield of mono-fluorinated
products of aliphatic β-keto amide 2h, 2i and 2u were also satis-
factory.20 Acyl changes are permitted too, isobutyryl and
benzoyl substituted amides can smoothly slide into the products
Results and discussion
On the basis of our studies on acetoacetamides in recent
years,41–45 we found α-fluorination of β-keto amides is a very
important class of reaction. But the intolerable reaction mixture
often is annoying to isolate. In some cases, the ratio of mono to
di-fluorinated products was significantly lower as well as the
yield.20,36–38 DesMarteau et al.’s findings46 showed that the enol
content of 1,3-dicarbonyl compounds was the key factor, which
could affect the number of fluorine atoms at the α-position. And
solvent is one of the factors affecting enol content of the sub-
strates. So we hypothesize that selecting the appropriate solvent
(s) should be able to control the final fluorinated products.47
Under the guidance of this assumption, we examined the direct
fluorination of acetoacetamides under a variety of green reaction
conditions, using a commercially available Selectfluor as the
fluorine source. The attempts are summarized in Table 1.
α-Monofluorinated β-keto amide 2j could be obtained with 95%
yield when we treated 1j with Selectfluor (1.1 equiv.) in
PEG-400 (3 mL) for 8 h at 60 °C, while it will take a longer
time at room temperature (entry 3 vs. 4). If water was chosen as
solvent, at room temperature, the yield of 2j was significantly
lower and the reaction time was very long (entry 1). Even
heating at 60 °C, the yield of 2j was not higher than in PEG-400
1160 | Green Chem., 2012, 14, 1159–1162
This journal is © The Royal Society of Chemistry 2012

View Online
Table 2 The preparation of α-mono-fluorinated acetoacetamidesa,b
mono- and di-fluorinated products was more than 30 : 1 and the
approach avoided the use of base or metal catalyst, and most
cases proceeded in nearly quantitative conversions regardless of
the electronic nature of the diversity substituent. At the same
time, this efficient procedure avoided complicated separation,
just recrystallization or evaporating the extraction solvent. The
electrophilic fluorination of other 1,3-dicarbonyl derivatives to
form 2-monofluoro-l,3-dicarbonyl analogues under green con-
ditions are in progress.
2j, 8 h, 95%
2k, 12 h, 94%
2l, 10 h, 92%
Experimental
2m, 14 h, 97%
2p, 20 h, 91%c
2n, 5 h, 99%
2q, 8 h, 98%c
2o, 6 h, 92%
2r, 5 h, 96%
General procedure for synthesis of 2-fluoro-acetoacetamides 2
(see ESI† for more details)
The mixture of 3-oxo-N-p-tolylbutanamide 1j (191 mg,
1.0 mmol) and Selectfluor (390 mg, 1.1 mmol) in PEG-400
(3.0 mL) was well stirred for 8 h at 60 °C oil bath, then to the
mixture was added water (10 mL), then extracted with
diethyl ether (15 mL × 4). The solvent was removed under
reduced pressure, and the residue was purified by a short flash
silica gel column chromatography to give compound 2j
(199 mg, 95%) as a yellow solid (eluent: petroleum ether–ethyl
acetate = 5 : 1).
2s, 8 h, 94%
2t, 24 h, 90%d
2g, 10 h, 84%, (93%)e
2h, 11 h, 98%
2v, 17 h, 96%
2y, 14 h, 100%
2i, 8 h, 94%
2w, 2 h, 97%
2u, 27 h, 76%,c (96%)e
2x, 6 h, 81%, (98%)e
Acknowledgements
Financial supports of this research by NSFC (21002051,
21172056), PCSIRT (IRT1061), IRTSTHN (2012IRTSTHN006)
and the program of Foundation and Frontier Technology
Research of Henan Province (112300410312).
a Unless otherwise indicated, all reactions were carried out with
acetoacetamide
1 (1.0 mmol), Selectfluor (1.1 mmol), PEG-400
References
(3.0 mL) at 60 °C. b Isolated yield and trace 3 (≤3%) was detected by
HPLC in all reactions. c 80 °C was used. d 9% 1t was recovered and
prolonged reaction time did not improve the yield of 2t. e HPLC yield.
1 (a) P. T. Anastas and J. C. Warner, Green Chemistry: Theory and Prac-
tice, Oxford University Press, Oxford, 1998; (b) P. T. Anastas and T.
C. Williamson, Green Chemistry: Frontiers in Benign Chemical Synth-
eses and Processes, Oxford Science Publications, New York, 1998;
(c) M. Poliakoff, J. M. Fitzpatrick, T. R. Farren and P. T. Anastas,
Science, 2002, 297, 807; (d) P. Anastas and N. Eghbali, Chem. Soc. Rev.,
2010, 39, 301–312.
2 (a) B. M. Trost, Science, 1991, 254, 1471; (b) B. M. Trost, Angew.
Chem., Int. Ed. Engl., 1995, 34, 259.
3 R. A. Sheldon, Chem. Technol., 1994, 24, 38.
4 D. Dallinger and C. O. Kappe, ChemInform, 2007, 38, 2563.
5 D. Wilms, S.-E. Stiriba and H. Frey, Acc. Chem. Res., 2010, 43, 129.
6 J. P. Hallett and T. Welton, ChemInform, 2011, 42, 3508.
7 M. A. P. Martins, C. P. Frizzo, D. N. Moreira, N. Zanatta and H.
G. Bonacorso, Chem. Rev., 2008, 108, 2015.
8 (a) O. Iwao, Fluorine in Medicinal Chemistry and Chemical Biology,
Blackwell Publishing Ltd., 2009; (b) J. P. Bégué and D. Bonnet-Delpon,
Bioorganic and Medicinal Chemistry of Fluorine, John Wiley & Sons,
Inc., Hoboken, New Jersey, 2008.
in the yield of 96% and 97%, respectively (Table 2, compounds
2v–2w). To our delight, the reaction could also be conducted
successfully when N,N′-(1,4-phenylene)bis(acetoacetamide) 1x
was employed, despite its poor solubility in PEG-400, 81% yield
of 2x was isolated which HPLC yield was 98%. We also
explored the possibility of the reaction by using α-methyl-substi-
tuted β-keto amide 1y in a single case; as a result, quantitative
yield of 2y was obtained in 14 h. A significant amount of
mono-fluorinated of acetoacetamides was found in the water
during work-up, which account for the low isolated yields of
compound 2g, 2u and 2x. It must be mentioned that traces of
difluorinated compounds 3 (≤3%) were detected by HPLC in all
reactions.
9 (a) Organofluorine Chemistry
–
Principles and Commercial
Applications, ed. R. E. Banks, B. E. Smart and J. C. Tatlow, Plenum
Press, New York, 1994; (b) Chemistry of Organic Fluorine Compounds
II, ed. M. Hudlicky and A. E. Pavlath, American Chemical Society,
Washington, DC, 1995.
10 (a) P. Eyerer, M. Weller and C. Hübner, Polymers – Opportunities and
Risks II: Sustainability, Product Design and Processing, Springer-Verlag,
Berlin, Heidelberg, 2010; (b) G. W. Stachowiak, Wear: Materials, Mech-
anisms and Practice, John Wiley & Sons, Inc., 2005.
11 (a) G. A. Olah, R. D. Chambers and G. K. S. Prakash, Synthetic Fluorine
Chemistry, John Wiley, New York, 1992; (b) R. D. Chambers, Fluorine
in Organic Chemistry, Blackwell Publishing, Oxford, 2004; (c)
Conclusions
In conclusion, a highly efficient approach to α-mono-fluoro ace-
toacetamides has been developed via selective α-electrophilic
mono-fluorination of acetoacetamides using industrialized Sele-
ctfluor as the F+ source in green solvent PEG-400. The ratio of
This journal is © The Royal Society of Chemistry 2012
Green Chem., 2012, 14, 1159–1162 | 1161

View Online
G. F. Georgii, Adv. Heterocycl. Chem., 2004, 86, 129–224; G. F. Georgii,
Adv. Heterocycl. Chem., 2004, 87, 273–383; G. F. Georgii, Adv. Hetero-
cycl. Chem., 2005, 88, 231–310; G. F. Georgii, Adv. Heterocycl. Chem.,
2006, 90, 239–310.
30 C. Bonnefous, J. E. Payne, J. Roppe, H. Zhuang, X. Chen, K. T. Symons,
P. M. Nguyen, M. Sablad, N. Rozenkrants, Y. Zhang, L. Wang,
D. Severance, J. P. Walsh, N. Yazdani, A. K. Shiau, S. A. Noble, P. Rix,
T. S. Rao, C. A. Hassig and N. D. Smith, J. Med. Chem., 2009, 52, 3047.
31 I. Hussain, M. A. Yawer, M. Lau, T. Pundt, C. Fischer, H. Reinke,
H. Görls and P. Langer, Eur. J. Org. Chem., 2008, 503.
32 T. Tsushima, K. Kawada, T. Tsuji and S. Misaki, J. Org. Chem., 1982,
47, 1107.
33 S. T. Purrington, C. L. Bumgardner, N. V. Lazaridis and P. Singh, J. Org.
Chem., 1987, 52, 4307.
34 R. D. Chambers, M. P. Greenhall and J. Hutchinson, Tetrahedron, 1996,
52, 1.
35 G. S. Lal, J. Org. Chem., 1993, 58, 2791.
36 D. P. Huber, K. Stanek and A. Togni, Tetrahedron: Asymmetry, 2006, 17,
658.
37 J. Xiao and J. M. Shreeve, J. Fluorine Chem., 2005, 126, 473.
38 F. A. Davis, W. Han and C. K. Murphy, J. Org. Chem., 1995, 60, 4730.
39 R. E. Banks, N. J. Lawrence and A. L. Popplewell, J. Chem. Soc., Chem.
Commun., 1994, 343.
40 Y. Pan, Y. Zhao, T. Ma, Y. Yang, H. Liu, Z. Jiang and C. Tan, Chem.–Eur.
J., 2010, 16, 779.
12 S. Rozen, Acc. Chem. Res., 1988, 21, 307.
13 S. D. Taylor, C. C. Kotoris and G. Hum, Tetrahedron, 1999, 55, 12431.
14 R. P. Singh and J. M. Shreeve, Acc. Chem. Res., 2004, 37, 31.
15 J.-A. Ma and D. Cahard, Chem. Rev., 2008, 108, PR1.
16 H. Machleidt and V. Hartmann, Justus Liebigs Ann. Chem., 1964, 679, 9.
17 O. D. Gupta and J. M. Shreeve, Tetrahedron Lett., 2003, 44, 2799.
18 B. Zajc and M. Zupan, J. Org. Chem., 1982, 47, 573.
19 S. Rozen and D. Hebel, J. Org. Chem., 1990, 55, 2621.
20 T. Kitamura, S. Kuriki, M. H. Morshed and Y. Hori, Org. Lett., 2011, 13,
2392.
21 P. M. Pihko, Angew. Chem., Int. Ed., 2006, 45, 544.
22 An Material Safety Data Sheet is available from Dr Helen M. Marsden,
Air Products PLC, European Technology Group, Chineham,
Basingstoke, Hampshire RG24 OFE, UK or Dr G. P. Pez, Air Products
and Chemicals Inc., 7201 Hamilton Boulevard, Allentown, PA
18195-1501, USA.
23 L. Hintermann and A. Togni, Angew. Chem., Int. Ed., 2000, 39, 4359.
24 R. Frantz, L. Hintermann, M. Perseghini, D. Broggini and A. Togni, Org.
Lett., 2003, 5, 1709.
41 Z. Zhang, Q. Zhang, S. Sun, T. Xiong and Q. Liu, Angew. Chem., Int.
Ed., 2007, 46, 1726.
25 S. Hong, J. Lee, M. Kim, Y. Park, C. Park, M. Kim, S. Jew and H. Park,
J. Am. Chem. Soc., 2011, 133, 4924.
42 Z. Zhang, Q. Zhang, Z. Ni and Q. Liu, Chem. Commun., 2010, 46, 1269.
43 Z. Zhang, Q. Zhang, Z. Yan and Q. Liu, J. Org. Chem., 2007, 72, 9808.
44 Q. Zhang, Z. Zhang, Z. Yan, Q. Liu and T. Wang, Org. Lett., 2007, 9,
3651.
45 Z. Zhang, C. Xue, X. Liu, Q. Zhang and Q. Liu, Tetrahedron, 2011, 67,
7081.
26 Z. Jiang, Y. Pan, Y. Zhao, T. Ma, R. Lee, Y. Yang, K. Huang, M.
W. Wong and C. Tan, Angew. Chem., Int. Ed., 2009, 48, 3627.
27 S. Delarue-Cochin, B. Bahlaouan, F. Hendra, M. Ourévitch, D. Joseph,
G. Morgant and C. Cavé, Tetrahedron: Asymmetry, 2007, 18, 759.
28 H. Li, S. Zhang, C. Yu, X. Song and W. Wang, Chem. Commun., 2009,
2136.
46 Z. Xu, D. D. DesMarteau and Y. Gotoh, J. Chem. Soc., Chem. Commun.,
1991, 179.
29 X. Han, J. Luo, C. Liu and Y. Lu, Chem. Commun., 2009, 2044.
47 R. H. Meyer and K. H. Meger, Ber. Dtsch. Chem. Ges., 1914, 47, 826.
1162 | Green Chem., 2012, 14, 1159–1162
This journal is © The Royal Society of Chemistry 2012