Acid-catalyzed conjugate additions to 3-fluorobutenone

Article abstract of DOI:10.1016/j.jfluchem.2009.02.007

3-Fluorobutenone (2) reacts under Zn(II) catalysis in ethanol solution with active methylene compounds such as anthrone and aromatic phenols to give products of the addition of one unit of 3-fluorobutenone.

Full text of DOI:10.1016/j.jfluchem.2009.02.007

Journal of Fluorine Chemistry 130 (2009) 470–473
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Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Acid-catalyzed conjugate additions to 3-fluorobutenone
*
Timothy B. Patrick , Upendra P. Dahal
Department of Chemistry, Southern Illinois University, Edwardsville, IL 62026, USA
A R T I C L E I N F O
A B S T R A C T
Article history:
3-Fluorobutenone (2) reacts under Zn(II) catalysis in ethanol solution with active methylene compounds
such as anthrone and aromatic phenols to give products of the addition of one unit of 3-fluorobutenone.
ß 2009 Elsevier B.V. All rights reserved.
Received 26 January 2009
Received in revised form 6 February 2009
Accepted 9 February 2009
Available online 21 February 2009
Keywords:
3-Fluorobutenone
ZnCl2 catalysis
Conjugate addition
Michael reaction
1. Introduction
reaction it gives a bis-Michael product [1,2]. When we used 3-
fluorobutenone (2) in the reaction with anthrone under zinc(II)
Methyl vinyl ketone (MVK, 1) is widely known for its versatility
in organic reactions serving as a Michael acceptor [1,2], a Diels-
Alder dienophile [2–4] and as a polymerization monomer [5]. 3-
Fluorobutenone (2), a fluorinated analog of MVK, is known but has
received only limited attention in the synthesis of fluorinated
catalysis we observed only the mono-Michael adduct. Under base
catalysis the reaction between 2 and anthrone gave a very complex
mixture. Because of the mono addition selectivity observed with
the zinc(II)-catalyzed reaction we studied several other substrates
to enhance the reaction scope.
materials. Wakselman and co-worker [6] used 2 in the Robinson
annulation procedure with cyclohexanone, and Schlosser et al.
used 2 in addition reactions at both the carbonyl function and the
The substrates shown in Table 1 gave moderate to good yields of
mono-Michael adduct. Only diethyl malonate and acetophenone
showed conjugate addition products alpha to the carbonyl group.
Several other 1,3-diketones failed to react at all with 2. These
substrates consisted of pentane-2, 4-dione, 3-methylpentan-2, 4-
dione, 2-acetylcyclohenanone and 4,4-dimethylcyclohexan-1, 3-
dione.
alkene function [7,8]. Haufe has used
a-fluorenones in the Diels-
Alder reaction [9]. We have demonstrated the utility of 2 in the
Heck reaction [10]. In this paper we describe the acid-catalyzed
addition of 2 with several substrates that can display enolic forms.
The 1,4 adduct from 2-naphthol underwent internal cyclization
and reaction with the solvent ethanol to give the benzochromene
structure 17 shown in Scheme 1 below. Phenol is already known to
react with 2 with sulfuric acid catalyst to give 11, the compound
responsible for raspberry odor [6]. Compound 15 also gave an odor
of raspberry but none of the other products displayed and
distinctive smells. In competitive reactions of 3-fluorobutenone
(2) with butanone (1) in excess with 3,5-dimethylphenol (12) as
2. Results and discussion
Anthrone (3) undergoes acid-catalyzed conjugate addition with
1 to give a mono addition adduct whereas under base-catalyzed
* Corresponding author. Tel.: +1 618 650 3582; fax: +1 618 650 4665.
E-mail address: tpatric@siue.edu (T.B. Patrick).
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.02.007

T.B. Patrick, U.P. Dahal / Journal of Fluorine Chemistry 130 (2009) 470–473
471
Table 1
Zinc chloride induced conjugate addition reactions.
Substrate
Product
Yield (%)
84
F NMR (CFCl3)
À189.9 (m)
53
À194.9 (m)
52
À194.6 (m)
54
À189.2 (m)
84
À188.9 (m)
74
À186.7 (m)
43
À193.0 (m)

472
T.B. Patrick, U.P. Dahal / Journal of Fluorine Chemistry 130 (2009) 470–473
substrate we found equal reactivity between 1 and 2. The results
show that 3-fluorobutenone (2) is effective in the acid-catalyzed
Michael reaction and that its reactivity is little influenced by the
fluorine atom in comparison with 1.
An alternate preparation of 2 comes from the aqueous ring
opening of 1-chloro-2-methoxy-2-methylcyclopropane (18) in
quinoline solution [10], a modified method described by Schlosser
and co-workers [8]. The preparation of the cyclopropane from 2-
methoxypropene and fluorodichloromethane described by Schlos-
ser works well but the required fluorodichloromethane is now very
expensive. We found that we could prepare 18 by addition of
trichlorofluoromethane to 2-methoxypropane by using Mg/LiCl as
described by Hu and Tu [11]. Trichlorofluoromethane is still readily
available and has not suffered a substantial rise in cost.
3. Experimental procedure
3.1. General
1H NMR data were recorded at 300.0 MHz with tetramethylsi-
lane (
recorded at 75.5 MHz with deuterated chloroform (CDCl3
= 77.0 ppm) as internal reference. 19F NMR (Table 1) was
recorded at 282.3 MHz with trifluoroacetic acid (TFA
= 0.00 ppm) as external reference, and is corrected to CFCl3.
d
= 0.00 ppm) as internal reference. 13C NMR spectra were
d
Scheme 1.
d
Deuterated chloroform was the solvent in all cases.
3.2. Preparation of 1-chloro-1-fluoro-2-methoxy-2-
The reaction mixture was filtered to remove unreacted anthrone.
Eight fractions were collected in column chromatography with
hexane/ethyl acetate gradient solvent system to purify the crude
product. NMR showed 10-(2-fluoro-3-oxo-butyl)-4a, 10-dihydro-
9aH-anthracen-9-one (5) in the fifth fraction (84 % yield). mp 164–
methylcyclopropane (18)
A 200 mL three-necked round bottom flask was flame dried. The
necks were stoppered and argon gas was introduced into the flask.
1.34 g (55 mmol) magnesium and 2.12 g (50 mmol) LiCl were
placed in the flask. Dry THF (40 mL) and 9.9 mL (7.23 g, 100 mmol))
2-methoxypropene were charged by syringe. After cooling the
flask to À23 8C (carbon tetrachloride/dry ice), 0.9 mL (1.37 g,
10 mmol) of trichlorofluoromethane was added drop wise by
syringe. The reaction mixture was left 5 min and a second fraction
of 4.6 mL (6.86 g, 50 mmol) of trichlorofluoromethane was added
drop wise. The reaction mixture was stirred for 1 h and 5 mL water
was added to quench the reaction. The product was extracted three
times with 15 mL of diethyl ether. The organic phase was dried
over MgSO4 and the solvent was removed by fractional distillation
to give
167 8C, 1H NMR (CDCL3, TMS)
CH2 2H), 4.5 (m, JHF = 50 Hz, CHF, 1H), 4.45 (m, CH, 1H),
(m, aromatic, 8H); 13C NMR (CDCl3, TMS)
26.1 (d, J = 5 Hz, CH3),
39.0 (d, J = 21 Hz, CH2), 43.9 (CH), 93.2 (d, J = 187 Hz, CHF), 127.0,
d
2.13 (d, J = 5 Hz, CH3, 3H), 2.3 (m,
7.4–8.4
d
d
d
128.2, 133.1, 134.0, 142.8 144.0 (aromatic), 184.5 (s, CO), 207.0 (d,
J = 26 Hz, CO).
3.4. Analytical data for the Michael addition products in Table 1
(All compounds gave satisfactory C, H, and F elemental analysis
data).
2-(2-Fluoro-3-oxo-butyl)-malonic acid diethyl ester (7): 1H
1-Chloro-1-fluoro-2-methoxy-2-methylcyclopropane
(5.54 g, 40 mmol, 67% yield). 1H NMR
1.01–1.40 (m, CH2, 2H)
1.50 (d, J = 2 Hz, CH3,3H),
3.38 (s, OCH3, 3H); 13C NMR
16.7 (d,CH3), 27.9 (d, CH2), 55.2 (d, OCH3), 63.2 (d, C),
98.0 (d, CClF); 19F NMR (TFA = 0, 76.6 relative to CDCl3)
(M, CF),
À151.7 (m, CF) [8].
(18).
NMR (CDCL3, TMS)
(d, J = 5 Hz, CH3, H),
(dt, J = 48 Hz CHF, 1H).
4-Fluoro-1-phenylhexane-1,5-dione (9) 1H NMR
J = 5 Hz, CH3 3H), 2.0 (m, CH2, 2H), 2.4 (m, CH2, 2H), 4.80 (dm, J = 5
d
1.15 (t, J = 7 Hz, CH3, 6H), 2.1 (s, CH3, 3H), 2.23
d
d
3.45 (m, CH, 1H), 4.17 (m, CH2, 6H), 4.78
d
d
d
d
d
d
d
14.1–
93.6–
À141.6
d
d
d 2.29 (d,
d
d
d
8 Hz, CHF, 1H), 7.25–7.9 (m, 5H aromatic).
3-Fluoro-4-(4-hydroxyphenyl)butan-2-one (11) raspberry
3.3. The preparation of 3-fluorobuteone (2) has been described
previously. [10]
odor, 1H NMR
d
2.15 (d, J = 5 Hz, CH3, 3H), 2.95–3.14 (m, CH2,
2H), 4.2 (OH), 4.94 (dm, JHF = 50 Hz, CHF), 6.79, 7.15 (dd, J = 9 Hz,
CH, 4H aromatic); 13C NMR
26.8 (d, J = 9 Hz, CH3), 37.54 (d,
d
3.3.1. General reaction procedure described for the preparation of 10-
(2-fluoro-3-oxo-butyl)-4a,10-dihydro-9aH-anthracen-9-one (5)
A Fisher pressure hydrolysis tube was charged with 1.5 mL of
ethanol, 350 mg (3.98 mmol) of 3-fluorobutenone (2), 390 mg
(2.01 mmol) of anthrone (3) and 18 mg of zinc chloride. The
reaction mixture was heated for 3 h at 110 8C in a silicon oil bath.
J = 21 Hz, CH2), 96.1 (d, J = 187 Hz, CFH), 117.0, 123.7, 131.2, 155.4
(aromatic), 208.6 (d, J = 27 Hz, CO).
3-Fluoro-4-(4-hydroxy-2,6-dimethyl-phenyl)-butan-2-one
(13) mp 105–109 8C, 1H NMR
d
2.29 (d, J = 5 Hz, CH3, 3H), 2.30 (s,
CH3, 6H), 3.10 (m, CH2, 2H), 4.41 (dm, JHF = 50 Hz, CHF, 1H), 4.73
(OH), 6.54 (s, aromatic, 2H) 13C NMR)
20.6 (t, J = 3 Hz, 2CH3), 26.0
d

T.B. Patrick, U.P. Dahal / Journal of Fluorine Chemistry 130 (2009) 470–473
473
(d, J = 3 Hz, CH3), 31.4 (d, J = 21 Hz, CH2),
d
96.4 (d, J = 187 Hz, CHF),
Acknowledgment
118.0, 118.5 123.5, 139.8, (s, aromatic), 154.3 (s, COH),
d
208.4 (d,
J = 26 Hz, CO).
This research was supported by the NSF-RUI program.
3-Fluoro-4-(4-hydroxy-naphthalen-1-yl)butan-2-one
raspberry odor, 1H NMR
(15)
References
d
2.20 (d, J = 5 Hz, CH3, 3H), 3.5 (dm,
CH2 2H), 5.06 (dm, JHF = 50 Hz, CHF) 6.75–8.35 (m, aromatic, 6H);
13C NMR (CDCl3, TMS) 26.5 (s, CH3), 35.5 (d, J = 21 Hz, CH2), 96.7 (d,
J = 159 Hz, CHF), 108.9, 122.1, 123.3, 124.0, 126.3, 128.0 133.5
(aromatic), 152.0 (s, COH), 210 (d, J = 26 Hz, CO).
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