One-pot fluorination followed by Michael addition or Robinson annulation for preparation of α-fluorinated carbonyl compounds

Article abstract of DOI:10.1039/c2gc36166c

Fluorination followed by the Michael addition or Robinson annulation of 1,3-dicarbonyl compounds is introduced for the synthesis of acyclic and cyclic α-fluoro-β-ketoesters and α-fluoro-1,3-diketones. The decarboxylation step can also be added to the reac

Full text of DOI:10.1039/c2gc36166c

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PAPER
One-pot fluorination followed by Michael addition or Robinson annulation
for preparation of α-fluorinated carbonyl compounds†
Wen-Bin Yi,*a Xin Huang,b Chun Caia and Wei Zhang*b
Received 26th July 2012, Accepted 8th September 2012
DOI: 10.1039/c2gc36166c
Fluorination followed by the Michael addition or Robinson annulation of 1,3-dicarbonyl compounds is
introduced for the synthesis of acyclic and cyclic α-fluoro-β-ketoesters and α-fluoro-1,3-diketones. The
decarboxylation step can also be added to the reaction sequence. High efficiency is achieved by the
microwave heating and atom economic one-pot synthesis.
of estrogen-dependent breast cancer,5 intermediate 1e for
1. Introduction
cytotoxic agent COTC,6 retinal-protein bacteriorhodopsin 1f,7
and antibacterial erythromycin compound 1g.8 User friendly
Fluorination of organic compounds is a topic of current interest
in medicinal chemistry.1 Shown in Scheme 1 are α-fluorinated
1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis-
carbonyl molecules including intermediate 1a for schizophrenia
(tetrafluoroborate) (Selectfluor™) and N-fluorobenzenesulfoni-
and anxiety agents,2 intermediate 1b for the human Kv1.1/Kvβ1
potassium channel inhibitor,3 antimalarial candidate compound 1c,4
aromatase inhibitor 1d as a promising candidate for the treatment
mide (NSFI) are popular fluorination reagents.9,10 Presented in
this paper is a new reaction sequence including Selectfluor™-
based fluorination followed by Michael addition or Robinson
annulation reactions for the synthesis of α-fluoro-β-ketoesters or
α-fluoro-1,3-diketones. It is a one-pot synthesis which combines
the construction of molecular frameworks and the introduction
of fluorine in a single operation. To the best of our knowledge,
there is no such transformation reported in the literature. One-pot
synthesis is an atom economic way to prepare molecules with
substitution and skeleton diversities.11 It eliminates waste gener-
ated from intermediates purification and is a favorable approach
for green organic synthesis.12
2. Results and discussion
Our first attempt of one-pot synthesis was to explore the fluorina-
tion and Michael addition reactions. This reaction sequence
could generate fluorinated quaternary carbon existing in com-
pounds 1a–c and 1g (Scheme 1). β-Ketoesters 2a, 2b and 2c
were selected for fluorination and then for Michael addition with
chalcones 3a–g. β-Ketoesters reacted with Selectfluor™
smoothly under microwave heating.13 Addition of CsCO3 and
chalcones to the reaction mixture followed by additional micro-
wave heating afforded 4a–i in quantitative yields (Table 1).14
Other than CsCO3, bases such as KOH and Et3N also worked
well for the Michael addition reactions.
The success of one-pot fluorination and Michael addition
encouraged us to extend the scope for Robinson annulation
which could lead to cyclic compounds similar to 1b–f shown in
Scheme 1. Methyl acetoacetate 2d and chalcone 3a were used
for the method development (Table 2). Different bases including
hydroxides, carbonates, and amines were attempted for the
Robinson annulation.15 Reactions with NaOH or KOH gave 5a
in less than 20% yield. Reactions with amines such as Et3N,
Scheme 1
aSchool of Chemical Engineering, Nanjing University of Science and
Technology, Xiao Ling Wei Street, Nanjing 210094, People’s Republic of
China. E-mail: yiwenbin@mail.njust.edu.cn; Fax: +86-25-84315030;
Tel: +86-25-84315514
bDepartment of Chemistry, University of Massachusetts Boston,
100 Morrissey Boulevard, Boston, MA 02125, USA.
E-mail: wei2.zhang@umb.edu; Fax: +1-617-287-6030;
Tel: +1-617-286-6147
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2gc36166c
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Table 1 One-pot fluorination and Michael additiona
improvement was observed by increasing the reaction time or
amount of base (Table 2, entries 11 and 12).
Under the optimized condition of using Selectfluor™ as a
fluorination agent and CsCO3 as a base, reactions of β-ketoester
2d and 1,3-diketone 2e with α,β-unsaturated ketones gave the
corresponding product 5a–f in 80–89% isolated yield (Table 3).
The Robinson annulation was further extended for the reaction
of β-ketoester 2a and α,β-unsaturated ketones 3h and 3i
(Scheme 2). In this case, the acidic proton for the cyclization
comes from the α,β-unsaturated ketones instead of the β-keto-
esters shown in Table 3. The reaction condition was slightly
modified by using CsCO3 and sodium ethoxide as bases to
promote the cyclization to give products 5g and 5h in 83% and
86% yields, respectively.
We thought it could be possible to perform decarboxylation at
the end of fluorination and Robinson annulation reactions. It was
found that decarboxylation could be easily achieved by heating
the reaction mixture of Robinson annulation at 120 °C for 1 h.
Thus, reactions of 2d with 3a, 3c, and 3g using Cs2CO3 and
NaOEt as bases under microwave heating at 120 °C gave decar-
boxylation products 5i–k in 81%, 87% and 84% yields, respecti-
vely (Scheme 3).
Entry R1
R2
Ph
R3
Ph
Product Yieldb (%) dr
1
Ph
4a
96
84c
79d
94
92
96
90
95
97
97
93
3/1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
4-Me–Ph
4b
4c
4d
3/1
4/1
3/1
3/1
3/1
3/1
3/1
4/1
4-MeO–Ph Ph
4-Me–Ph
Ph
Ph
4-NO2–Ph 4e
Ph
Ph
4-Me–Ph Ph
4-NO2–Ph Ph
Ph
Ph
4f
4g
4-MeO–Ph 4-MeO–Ph 4h
PhCHvCH Ph 4i
a β-Ketoester (1 mmol), chalcone (1 mmol), Selectfluor™ (1 mmol),
Cs2CO3 (0.5 equiv.), microwave heating at 90 °C for 15 min. b Isolated
yield. c KOH (0.5 equiv.). d Et3N (0.5 equiv.).
Table 3 One-pot fluorination and Robinson annulationa
Table 2 Optimization of fluorination and Robinson annulationa
Entry
R1
R2
Product
Time (min)
Yieldb (%)
1
2
3
4
5
6
OMe
OMe
OMe
Me
Me
Me
Ph
5a
5b
5c
5d
5e
5f
30
30
30
15
15
15
89
87
82
86
82
80
4-MeO–Ph
PhCHvCH
Ph
4-MeO–Ph
PhCHvCH
Entry
Base
Time (min)
Yieldb (%)
a 2d or 2e (1 mmol), α,β-unsaturated ketone (1 mmol), Selectfluor™
(1 mmol), Cs2CO3 (1 mmol), microwave heating at 90 °C. b Isolated
yield, dr > 20/1.
1
2
3
4
5
6
7
8
NaOH
KOH
20
20
30
30
30
60
60
60
60
30
60
30
11
17
38
61
89
24
21
37
19
39c
87
90d
Na2CO3
K2CO3
Cs2CO3
Et3N
DABCO
DMAP
DIPEA
Cs2CO3
Cs2CO3
Cs2CO3
9
10
11
12
a 2d (1 mmol), 3a (1 mmol), Selectfluor™ (1 mmol), base 1 mmol,
microwave heating at 90 °C. b Isolated yield, dr > 20/1. c NSFI was used.
d 1.5 equiv. of base.
DABCO, DMAP and DIPEA also gave low yield. Cesium car-
bonate performed better than potassium and sodium carbonates
and produced 5a in 89% yield. A similar reaction using NSFI
instead of Selectfluor™ gave the product in 39% yield (Table 2,
entry 10). For the reaction with Selectfluor™, no significant
Scheme 2
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(m, 1H), 4.29 (q, J = 7.2 Hz, 2H), 4.79 (m, 1H), 6.88 (m, 2H),
7.10–7.50 (m, 8H), 7.61–7.90 (m, 4H); 13C NMR (CDCl3,
75 MHz) δ 13.9, 39.1, 45.1, 55.5, 63.2, 113.6, 113.7, 127.3,
128.2, 128.6, 129.1, 129.2, 129.9, 130.4, 133.2, 195.0, 200.3,
215.9; 19F NMR (CFCl3, 300 MHz) δ 167.9, 168.0; MS (ACPI)
m/z: 449.1 (M+ + 1).
Ethyl 1-phenyl-2-fluoro-3-phenyl-5-(4′-methylphenyl)-1,5-pen-
tanedione-2-carboxylate (4d). White solid. 1H NMR (CDCl3,
300 MHz) δ 1.23 (t, J = 7.2 Hz, 3H), 2.38 (s, 3H), 3.39 (m, 1H),
3.73 (m, 1H), 4.33 (q, J = 7.2 Hz, 2H), 4.82 (m, 1H), 7.09–7.49
(m, 10H), 7.50–7.81 (m, 4H); 13C NMR (CDCl3, 75 MHz)
δ 13.6, 13.9, 21.6, 39.3, 39.4, 39.7, 44.7, 45.0, 45.3, 62.6, 63.1,
127.2, 127.7, 128.1, 128.2, 128.6, 129.0, 129.1, 129.2, 129.6,
129.8, 129.9, 129.9, 130.0, 133.1, 134.1, 137.2, 137.7, 143.8,
144.0, 196.0, 199.4, 200.2, 215.8; 19F NMR (CFCl3, 300 MHz)
δ 167.5, 167.9; MS (ACPI) m/z: 433.2 (M+ + 1).
Scheme 3
3. Experimental
Chemicals and solvents were purchased from commercial
1
sources and used as received. H and 13C NMR spectra were
recorded on a 300 MHz Varian NMR spectrometer. The ratio of
the diastereomers was determined by H NMR. Only the peaks
1
from the major diastereomer are given below. LC-MS was per-
formed on the Agilent 2100 system with a C18 column for separ-
ation. Mass spectra were recorded in APCI (atmospheric
pressure chemical ionization). Flash chromatography separations
were performed on the Yamazen system with Agela silica gel
columns.
Ethyl
1,5-diphenyl-2-fluoro-3-(4′-nitrophenyl)-1,5-pentane-
dione-2-carboxylate (4e). Yellowish solid. 1H NMR (CDCl3,
300 MHz) δ 1.26 (t, J = 7.2 Hz, 3H), 3.22 (m, 1H), 3.68 (m,
1H), 4.33 (q, J = 7.2 Hz, 2H), 4.89 (m, 1H), 7.35–7.68 (m, 9H),
7.76–7.90 (m, 2H), 8.04–8.18 (m, 3H); 13C NMR (CDCl3,
75 MHz) δ 13.8, 14.1, 39.3, 39.7, 63.0, 63.6, 117.3, 123.3,
123.4, 128.0, 128.5, 128.7, 128.8, 128.8, 129.3, 130.0, 130.1,
130.7, 130.9, 133.5, 134.0, 134.6, 163.8, 164.1, 195.8, 200.2,
212.5; 19F NMR (CFCl3, 300 MHz) δ 166.8, 167.7; MS (ACPI)
m/z: 464.1 (M+ + 1).
Typical procedure for one-pot fluorination and Michael addition
The β-ketoester 2a (192 mg, 1 mmol) was added to a solution of
Selectfluor™ (354 mg, 1 mmol) in CH3CN (2 mL). After
irradiation in a Biotage Initiator microwave reactor at 90 °C for
40 min, the chalcone 3a (208 mg, 1 mmol) and Cs2CO3 (50 mol
%, 163 mg) were added and the mixture was then stirred at
90 °C for 15 min. EtOAc (10 mL) and H2O (20 mL) were
added. The organic layer was washed with aqueous HCl (2 M,
10 mL) and H2O (10 mL), and dried over Na2SO4. After evapor-
ation of the solvent, the residue was purified by flash column
chromatography (6 : 1 hexane–EtOAc) to give fluorinated adduct
4a (401 mg, 96%).
Ethyl 1-(4′-methylphenyl)-2-fluoro-3,5-diphenyl-1,5-pentane-
dione-2-carboxylate (4f). White solid. 1H NMR (CDCl3,
300 MHz) δ 1.26 (t, J = 7.2 Hz, 3H), 2.34 (s, 3H), 3.38 (m, 1H),
3.75 (m, 1H), 4.30 (q, J = 7.2 Hz, 2H), 4.81 (m, 1H), 7.12–7.65
(m, 12H), 7.89 (d, 2H); 13C NMR (CDCl3, 75 MHz) δ 13.9,
21.7, 39.6, 45.0, 63.1, 127.3, 128.0, 128.2, 128.3, 128.6, 129.0,
129.4, 129.9, 133.2, 196.1, 199.4, 200.2; 19F NMR (CFCl3,
300 MHz) δ 167.0, 167.2; MS (ACPI) m/z: 433.2 (M+ + 1).
Ethyl 1,5-diphenyl-2-fluoro-3-phenyl-1,5-pentanedione-2-car-
boxylate (4a). White solid. H NMR (CDCl3, 300 MHz) δ 1.27
Ethyl
1-(4′-nitrophenyl)-2-fluoro-3,5-diphenyl-1,5-pentane-
1
dione-2-carboxylate (4g). Yellowish solid. 1H NMR (CDCl3,
300 MHz) δ 1.32 (t, J = 7.2 Hz, 3H), 3.39 (m, 1H), 3.74 (m,
1H), 4.34 (q, J = 7.2 Hz, 2H), 4.81 (m, 1H), 7.14–7.69 (m, 9H),
7.90 (m, 2H), 8.15 (m, 1H), 8.38 (m, 2H); 13C NMR (CDCl3,
75 MHz) δ 13.6, 13.9, 39.2, 39.3, 39.8, 45.2, 45.5, 63.1, 63.6,
123.2, 123.7, 127.7, 128.0, 128.4, 128.6, 128.6, 129.5, 129.8,
129.9, 129.9, 131.0, 131.1, 133.2, 133.3, 136.4, 137.0, 149.6,
171.6, 172.5, 196.1; 19F NMR (CFCl3, 300 MHz) δ 169.0,
169.1; MS (ACPI) m/z: 464.2 (M+ + 1).
(t, J = 7.2 Hz, 3H), 3.43 (m, 1H), 3.76 (m, 1H), 4.31 (q, J =
7.2 Hz, 2H), 4.80 (m, 1H), 7.11–7.69 (m, 13H), 7.90–8.12 (m,
2H); 13C NMR (CDCl3, 75 MHz) δ 13.7, 13.9, 39.6, 45.0, 45.2,
62.7, 63.2, 127.3, 127.8, 128.2, 128.3, 128.5, 128.6, 128.7,
129.1, 129.2, 129.6, 129.9, 130.0, 130.1, 133.1, 133.2, 133.3,
134.2, 172.4, 196.5, 200.3; 19F NMR (CFCl3, 300 MHz)
δ 167.5, 167.6; MS (ACPI) m/z: 419.1 (M+ + 1).
Ethyl 1,5-diphenyl-2-fluoro-3-(4′-methylphenyl)-1,5-pentane-
dione-2-carboxylate (4b). White solid. 1H NMR (CDCl3,
300 MHz) δ 1.02 (t, J = 7.2 Hz, 3H), 2.27 (s, 3H), 3.25 (m, 1H),
3.62 (m, 1H), 3.97 (q, J = 7.2 Hz, 2H), 4.82 (m, 1H), 7.06–7.25
(m, 1H), 7.26–7.70 (m, 11H), 7.92 (d, 1H), 8.10 (d, 2H); 13C
NMR (CDCl3, 75 MHz) δ 13.7, 21.1, 39.9, 44.3, 44.6, 62.6,
128.1, 128.5, 128.7, 129.0, 129.4, 129.7, 130.0, 130.1, 133.0,
134.0, 134.2, 137.3, 172.1, 196.6, 200.2; 19F NMR (CFCl3,
300 MHz) δ 168.1, 168.3; MS (ACPI) m/z: 433.2 (M+ + 1).
Ethyl 1-phenyl-2-fluoro-3,5-di(4′-methoxyphenyl)-1,5-penta-
nedione-2-carboxylate (4h). White solid. 1H NMR (CDCl3,
300 MHz) δ 1.26 (t, J = 7.2 Hz, 3H), 3.31 (m, 1H), 3.63 (m,
1H), 3.68 (s, 3H), 3.86 (s, 3H), 4.28 (q, J = 7.2 Hz, 2H), 4.68
(m, 1H), 6.67–6.91 (m, 4H), 7.27 (m, 4H), 7.47 (m, 2H), 7.71
(m, 1H), 7.90 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 13.8,
13.9, 39.2, 39.7, 44.5, 44.8, 55.0, 55.4, 62.6, 63.1, 113.5, 113.6,
113.7, 128.2, 128.6, 129.1, 129.2, 129.6, 130.0, 130.0, 130.4,
130.6, 130.9, 131.0, 134.1, 158.6, 163.5, 195.1, 195.2, 199.5,
200.3; 19F NMR (CFCl3, 300 MHz) δ 167.6, 167.7; MS (ACPI)
m/z: 479.2 (M+ + 1).
Ethyl 1-phenyl-2-fluoro-3-phenyl-5-(4′-methoxyphenyl)-1,5-
pentanedione-2-carboxylate (4c). White solid. 1H NMR (CDCl3,
300 MHz) δ 1.26 (t, J = 7.2 Hz, 3H), 3.32 (m, 1H), 3.63
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Ethyl 1-phenyl-2-fluoro-3-phenyl-5-styryl-1,5-pentanedione-2-
carboxylate (4i). White solid. 1H NMR (CDCl3, 300 MHz)
δ 1.29 (t, J = 7.2 Hz, 3H), 3.06 (m, 1H), 3.35 (m, 1H), 4.32 (q,
J = 7.2 Hz, 2H), 4.70 (m, 1H), 6.65 (d, J = 16.2 Hz, 1H),
7.10–7.53 (m, 14H); 13C NMR (CDCl3, 75 MHz) δ 13.7, 13.9,
41.6, 45.0, 45.3, 63.2, 125.8, 127.4, 127.8, 128.2, 128.3, 128.3,
128.6, 128.9, 129.1, 129.2, 129.5, 129.8, 129.9, 130.0, 130.0,
130.5, 130.6, 133.3, 134.2, 137.5, 142.9, 143.1, 196.4, 199.5,
200.2; 19F NMR (CFCl3, 300 MHz) δ 168.0, 168.1; MS (ACPI)
m/z: 445.2 (M+ + 1).
128.9, 129.0, 129.1, 129.2, 129.2, 131.1, 131.2, 136.9, 137.6,
161.4, 190.4, 190.7; 19F NMR (CFCl3, 300 MHz) δ 164.2,
172.2, 172.4; MS (ACPI) m/z: 309.1 (M+ + 1).
3-(4′-Methoxyphenyl)-5-phenyl-6-fluoro-6-acetyl-2-ene-cyclo-
hexanone (5e). White liquid. 1H NMR (CDCl3, 300 MHz)
δ 2.02 (d, J = 5.7 Hz, 3H), 3.04 (dd, J = 4.8 Hz, J = 18 Hz, 1H),
3.34 (dd, J = 4.8 Hz, J = 18 Hz, 1H), 3.85 (m, 1H), 3.89 (s, 3H),
6.53 (s, 1H), 6.55–7.00 (m, 2H), 7.28–7.41 (m, 5H), 7.53–7.58
(m, 2H); 13C NMR (CDCl3, 75 MHz) δ 28.3, 28.6, 31.1, 32.0,
46.7, 47.0, 55.4, 113.7, 114.3, 114.3, 120.3, 120.5, 121.7, 128.0,
128.1, 128.3, 128.7, 128.9, 129.0, 129.0, 129.3, 130.3, 130.8,
136.8, 143.9, 160.4, 161.9, 162.0, 190.2, 190.4, 207.2;
19F NMR (CFCl3, 300 MHz) δ 164.0, 172.0, 172.1; MS (ACPI)
m/z: 339.1 (M+ + 1).
Typical procedure for one-pot fluorination and Robinson
annulation
The β-ketoester 2d (116 mg, 1 mmol) was added to a solution of
Selectfluor™ (354 mg, 1 mmol) in CH3CN (2 mL). After stir-
ring at 90 °C for 40 min on a Biotage Initiator microwave instru-
ment, the chalcone 3a (208 mg, 1 mmol) and Cs2CO3 (100 mol%,
326 mg) were added and the mixture was then stirred at 90 °C
for 30 min. EtOAc (10 mL) and H2O (20 mL) were added. The
organic layer was washed with aqueous HCl (2 M, 10 mL) and
H2O (10 mL), and dried over Na2SO4. After evaporation of the
solvent, the residue was purified by flash column chromato-
graphy (6 : 1 hexane–EtOAc) to give fluorinated cyclohexenone
compound 5a (288 mg, 89%).
3-Styryl-5-phenyl-6-fluoro-6-acetyl-2-ene-cyclohexanone (5f).
White solid. H NMR (CDCl3, 300 MHz) δ 2.01 (d, J = 5.4 Hz,
1
3H), 3.10 (m, 1H), 3.93 (m, 1H), 3.89 (s, 3H), 6.22 (s, 1H),
6.93–7.12 (m, 2H), 7.33–7.53 (m, 10H); 13C NMR (CDCl3,
75 MHz) δ 28.3, 28.6, 28.6, 46.4, 46.6, 48.4, 48.6, 125.1, 125.2,
127.5, 128.0, 128.3, 128.4, 128.8, 129.0, 129.0, 129.0, 129.0,
129.7, 129.7, 135.4, 135.5, 136.9, 137.3, 137.4, 158.2, 199.5;
19F NMR (CFCl3, 300 MHz) δ 163.6, 171.4, 171.6; MS (ACPI)
m/z: 335.1 (M+ + 1).
Ethyl 2-ene-cyclohexanone-3,5-diphenyl-4-fluoro-4-carboxy-
1
Methyl 2-ene-cyclohexanone-3,5-diphenyl-6-fluoro-6-carboxy-
late (5g). White solid. H NMR (CDCl3, 300 MHz) δ 1.08 (t,
1
late (5a). White liquid. H NMR (CDCl3, 300 MHz) δ 3.18 (m,
J = 7.2 Hz, 3H), 2.80 (m, 1H), 3.52 (m, 1H), 4.08 (m, 3H), 6.52
(s, 1H), 7.24–7.55 (m, 10H); 13C NMR (CDCl3, 75 MHz)
δ 14.0, 14.1, 39.3, 39.4, 49.0, 49.3, 62.8, 117.6, 127.7, 127.9,
127.9, 128.3, 128.6, 128.7, 128.7, 128.9, 129.0, 129.5, 129.6,
130.4, 135.7, 197.0; 19F NMR (CFCl3, 300 MHz) δ 178.7,
178.8; MS (ACPI) m/z: 309.1 (M+ + 1).
J = 12.0 Hz, 2H), 3.67 (s, 3H), 3.84 (m, J = 12.0 Hz, 1H), 4.78
(m, 1H), 6.38 (s, 1H), 7.25–7.42 (m, 7H), 7.48–7.64 (m, 3H);
13C NMR (CDCl3, 75 MHz) δ 32.5, 32.6, 48.7, 48.9, 52.9,
122.4, 123.3, 126.2, 126.3, 127.4, 127.8, 128.3, 128.4, 128.7,
128.9, 130.7, 130.9, 136.1, 137.2, 161.3, 191.2; 19F NMR
(CFCl3, 300 MHz) δ 166.2, 166.3; MS (ACPI) m/z: 325.1
(M+ + 1).
Ethyl
2-ene-cyclohexanone-3-phenyl-5-(4′-chlorophenyl)-4-
fluoro-4-carboxylate (5h). Yellowish solid. 1H NMR (CDCl3,
300 MHz) δ 1.08 (t, J = 7.2 Hz, 3H), 3.42–3.79 (m, 1H), 3.78
(m, 2H), 4.21 (m, 1H), 4.41 (m, 1H), 5.66 (m, 1H), 7.17–7.74
(m, 7H), 7.83–7.94 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ
14.0, 14.1, 37.4, 44.8, 51.1, 59.6, 59.6, 88.1, 88.9, 91.6, 106.7,
127.6, 128.0, 128.2, 128.8, 128.9, 128.9, 129.0, 129.4, 129.4,
131.2, 133.1, 134.1, 134.3, 141.1, 170.1; 19F NMR (CFCl3,
300 MHz) δ 178.7, 178.8; MS (ACPI) m/z: 372.1 (M+).
Methyl 2-ene-cyclohexanone-3-(4′-methoxyphenyl)-5-phenyl-
6-fluoro-6-carboxylate (5b). White liquid. 1H NMR (CDCl3,
300 MHz) δ 3.15 (m, 1H), 3.68 (s, 3H), 3.79 (m, 2H), 3.87
(s, 3H), 6.62 (s, 1H), 6.97 (m, 2H), 7.37 (m, 5H), 7.64 (m, 2H);
13C NMR (CDCl3, 75 MHz) δ 32.5, 32.6, 48.9, 49.1, 53.0, 55.6,
114.5, 121.6, 127.7, 128.0, 128.1, 128,3, 128.6, 128.9, 129.2,
129.4, 136.4, 160.8, 162.2, 192.0, 199.7, 200.9; 19F NMR (CFCl3,
300 MHz) δ 166.1, 166.2; MS (ACPI) m/z: 355.2 (M+ + 1).
3,5-Diphenyl-6-fluoro-2-ene-cyclohexanone (5i). Yellowish
1
Methyl 2-ene-cyclohexanone-3-styryl-5-phenyl-6-fluoro-6-car-
liquid. H NMR (CDCl3, 300 MHz) δ 3.18 (dd, J = 12.1 Hz,
1
boxylate (5c). White solid. H NMR (CDCl3, 300 MHz) δ 3.05
1H), 3.25 (dd, J = 12.1 Hz, 1H), 3.61 (m, J = 12.1 Hz, 1H),
4.96–5.03 (dd, J = 2.7 Hz, J = 20.1 Hz, 1H), 6.51 (s, 1H),
7.18–7.47 (m, 10H); 13C NMR (CDCl3, 75 MHz) δ 31.7, 31.8,
45.5, 45.7, 90.6, 93.0, 123.1, 126.5, 127.9, 128.3, 128.4, 128.8,
129.0, 129.1, 130.9, 137.9, 138.7, 160.1, 193.5; 19F NMR (CFCl3,
300 MHz) δ 199.9, 200.2; MS (ACPI) m/z: 267.1 (M+ + 1).
(m, 2H), 3.62 (s, 3H), 3.71 (m, 1H), 6.21 (s, 1H), 6.92–7.12
(m, 2H), 7.37–7.53 (m, 10H); 13C NMR (CDCl3, 75 MHz) δ
28.6, 28.8, 47.0, 47.3, 53.0, 122.7, 126.5, 126.6, 128.3, 128.5,
128.9, 128.9, 129,1, 129.2, 129.2, 131.1, 131.2, 136.9, 137.6,
161.4, 190.4, 190.7; 19F NMR (CFCl3, 300 MHz) δ 165.6,
165.7; MS (ACPI) m/z: 351.2 (M+ + 1).
3-Styryl-5-phenyl-6-fluoro-2-ene-cyclohexanone (5j). Yellow-
ish liquid. 1H NMR (CDCl3, 300 MHz) δ 2.90 (dd, J = 12.1 Hz,
1H), 3.13 (m, 1H), 3.55 (m, 1H), 5.12–5.33 (dd, J = 12.6 Hz,
J = 48.3 Hz, 1H), 6.21 (s, 1H), 6.96 (m, 2H), 7.26–7.55 (m,
10H); 13C NMR (CDCl3, 75 MHz) δ 32.9, 33.0, 46.7, 46.9,
91.3, 93.9, 126.0, 127.0, 127.4, 127.5, 127.6, 127.8, 128.1,
128.5, 128.8, 128.9, 130.0, 129.6, 130.9, 135.4, 137.0, 139.0,
3,5-Diphenyl-6-fluoro-6-acetyl-2-ene-cyclohexanone (5d). White
liquid. H NMR (CDCl3, 300 MHz) δ 2.03 (d, J = 2.7 Hz, 3H),
3.08 (dd, J = 4.8 Hz, J = 18 Hz, 1H), 3.37 (dd, J = 4.8 Hz, J =
18 Hz, 1H), 3.98 (m, 1H), 6.58 (s, 1H), 7.26–7.48 (m, 8H),
7.56–7.61 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 28.6, 28.8,
31.7, 31.8, 47.0, 47.3, 122.5, 122.7, 126.5, 126.6, 128.3, 128.5,
1
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155.6, 193.8, 200.4; 19F NMR (CFCl3, 300 MHz) δ 196.6,
196.7; MS (ACPI) m/z: 293.2 (M+ + 1).
acknowledges the financial support of NUST Research Funding
(2011ZDJH07), Jiangsu Provincial Natural Science Foundation
of China for Key Projects (BK2010070) and the National
Natural Science Foundation of China (20902047).
3-(4′-Methoxyphenyl)-5-phenyl-6-fluoro-2-ene-cyclohexanone
1
(5k). Yellowish liquid. H NMR (CDCl3, 300 MHz) δ 3.12 (dd,
J = 4.8 Hz, J = 18 Hz, 1H), 3.31 (dd, J = 1.8 Hz, J = 6.9 Hz,
1H), 3.84 (s, 1H), 3.87 (s, 3H), 4.91–5.09 (dd, J = 2.7 Hz, J =
20.1 Hz, 1H), 6.88 (d, J = 8.7 Hz, 2H), 7.30 (m, 5H), 7.50 (m,
2H); 13C NMR (CDCl3, 75 MHz) δ 31.2, 32.3, 45.2, 45.5, 55.4,
90.4, 92.8, 114.3, 121.0, 127.6, 128.0, 128.2, 128.2, 128.8,
129.7, 130.9, 138.7, 159.3, 161.8, 171.9, 193.1, 199.5;
19F NMR (CFCl3, 300 MHz) δ 199.7, 200.0; MS (ACPI) m/z:
297.1 (M+ + 1).
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4. Conclusions
We have developed a green and efficient one-pot synthesis pro-
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by Michael addition or Robinson annulation with α,β-unsatu-
rated ketones for the synthesis of acyclic and cyclic α-fluoro-
β-ketoesters and α-fluoro-1,3-diketones. The decarboxylation
can also be included in the one-pot reaction process by using a
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Acknowledgements
We acknowledge the support from the Center for Green Chem-
istry at the University of Massachusetts Boston. W.Y.
This journal is © The Royal Society of Chemistry 2012
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