Cycloaddition reactions of 3-fluorobutenone

Article abstract of DOI:10.1016/j.jfluchem.2009.03.004

3-Fluorobutenone (8) reacted as a dienophile with several dienes 9, 11, 13, 15, 17 to give cycloaddition products in moderate yields. The regio- and stereoselectivity of the reactions are given. Compound 8 is slightly less reactive than methyl vinyl keton

Full text of DOI:10.1016/j.jfluchem.2009.03.004

Journal of Fluorine Chemistry 130 (2009) 544–546
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Cycloaddition reactions of 3-fluorobutenone
*
Timothy B. Patrick , Hongli Li
Department of Chemistry, Southern Illinois University, Box 1652, Edwardsville, IL, USA
A R T I C L E I N F O
A B S T R A C T
Article history:
3-Fluorobutenone (8) reacted as a dienophile with several dienes 9, 11, 13, 15, 17 to give cycloaddition
products in moderate yields. The regio- and stereoselectivity of the reactions are given. Compound 8 is
slightly less reactive than methyl vinyl ketone.
Received 4 March 2009
Received in revised form 5 March 2009
Accepted 16 March 2009
Available online 27 March 2009
ß 2009 Elsevier B.V. All rights reserved.
Keywords:
Cycloaddition
X-ray structure
Stereoselectivity
Diels–Alder reaction
Secondary orbital effects
1. Introduction
cyclopentadiene. Percy and co-workers [5] demonstrated the facile
cycloaddition of a monofluoro vinyl carbamate (7).
Research into the use of fluorovinyl and
a-fluoro-a,b-enones
and esters-compounds as fluorodienophiles is of special interest
with regard to using these materials in synthetic protocol [1].
Recently, Haufe [2] has reviewed his work and theory on Diels–
Alder reactions of vinyl fluorides with dienes and indicates that
fluorinated alkenes are less reactive than the non-fluorinated
counterpart. For example alpha-(1) and beta-fluorostyrene (2)
decrease the cyclization rate by approximately 30 and 10 times,
respectively, with respect to styrene. Haufe concludes that simple
vinyl fluorides are poor dienophiles in normal Diels–Alder
reactions but are useful in inverse electron demand reactions. In
2. Results and discussion
We recently reported the preparation and synthetic utility of
3-fluorobutenone (8) in the Heck reaction [6] and in conjugate
addition reactions [7]. Dienophile 8 is a fluorinated analog of
methyl vinyl ketone. Now we report our results on cycloaddition
chemistry with 8 with cyclopentadiene (9), furan (11), 2,3-
dimethyl-1,3-butadiene (13), 1,3-diphenylisobenzofuran (15)
and 4-bromo-2H-pyran-2-one (17).
addition
a-fluoro-a,b-unsaturated carbonyl compounds, such as
fluoromaleic anhydride (3) and 2-fluorooct-1-ene-3-one (4), are
versatile dienophiles that react with preferred exo-selectivity.
We observed that monofluorinated butenolide 5 reacts slowly
in Diels–Alder reactions, but the non-fluorinated analog reacts well
[3]. Taguchi and co-workers [4] found enhanced reactivity and exo-
selectivity in the addition of fluoroacrylic acid derivatives (6) to
The cycloaddition of 8 with cyclopentadiene is kinetically
controlled and provides exo/endo products (10a, 10b) in a ratio of
3:1. These results are very similar to the results found by Haufe [2]
and by Taguchi and co-workers [4]. The assignment of endo and exo
structures is based on 19F NMR results reported by Taguchi. This
* 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.2009.03.004

T.B. Patrick, H. Li / Journal of Fluorine Chemistry 130 (2009) 544–546
545
reaction occurred easily at room temperature in CDCl3 or without
solvent.
is observed as a singlet at
d
À166.5 ppm (CFCl3 reference). This
observation aided in confirming the exo/endo structures for the
other compounds reported here as the exo isomer shows its 19F
shift at lower field that the endo isomer.
A competition reaction between 3-fluorobutenone (8) and
methyl vinyl ketone (MVK) for cyclopentadiene showed that MVK
is 8.5 times faster than 8 in agreement with Haufe [2] in showing
that the fluorine atom decreases the reactivity of the dienophile.
The reaction of 8 with furan (11) gave the exo product (12a)
predominantly with exo/endo selectivity of 9:1 in moderate yield.
Cycloaddition of fluorinated dienophiles with furan is rare but has
been accomplished with 8 with exo/endo selectivity of approxi-
mately 8:1.
Halogenated 2(H)-pyran-2-ones are interesting dienes with
much synthetic potential for natural products [8–10]. Computa-
tional predictions for the regio- and stereoselectivity of several
halogenated 2(H)-pyran-2-ones are known from the work of
Afarinkia et al. [8]. We studied the cycloaddition of 8 with 5-
bromo-2(H)-pyran-2-one (17). The only regio isomer observed
contains the fluorine and acyl groups in the 5-position, as predicted
by Afarinkia. The ratio of exo/endo isomers is 2:1 with the exo
isomer being the major product. Fluorine coupling with C-4 and H-
4 established the regiochemistry.
2,3-Dimethyl-1,3-butadiene (13) gave a pure cycloaddition
product (14) with 8 by heating in ethyl acetate at 160 8C overnight
in 17% yield. Attempts to improve the yield using longer reaction
times or the use of Lewis acid catalysts were unsuccessful.
The propensity for obtaining exoisomers in Diels–Alderreactions
when fluorinated dienophiles are used is well documented [2,4,5]
and alsoobserved hereinthechemistryof8. Theoreticalcalculations
by Haufe and co-workers [11] have shown that the stereoselectivity
is kinetically controlled rather than thermodynamically controlled
but the calculations do not resolve the problem. A somewhat
qualitative approach to the selectivity can be obtained by applying
the endo rule of Diels–Alder chemistry [12]. Secondary orbital
3-Fluorobutenone (8) underwent cycloaddition with the highly
reactive 1,3-diphenylisobenzofuran (15) to give products 16a (exo)
and 16b (endo) with exo/endo ratio of 2:1. Nice white crystals were
obtained for X-ray analysis (Fig. 1) for exo 16a. The F NMR for the
interactions between the dienophile substituents and the
p orbitals
of the diene control the stereoselectivity of the reaction. Fig. 2 shows
two alternative transition states possible: transition state A has an
endo fluorine and transition state B has an endo acetyl group.
Fluorine is unusual in that it contains a low anti-bonding sigma
exo isomer shows a singlet at
d
À155.6 ppm while the endo isomer
orbital (À13.5 eV) that can interact with the diene
The anti-bonding orbitals of the carbonyl group are somewhat
higher at +0.8 eV [14]. Thus the interaction with the endo fluorine
p system [13].
p
p
atom is favored and places the fluorine in the endo position and the
acetyl in the exo position, as in observed (transition state A). Thus,
because the fluorine interaction with the diene is greater that the
interaction of the acetyl with the diene, the fluorine atom
determines the stereoselectivity, and the observation is consistent
with the endo rule.
3. Experimental procedure
3.1. General
1H NMR data were recorded at 300.0 MHz with tetramethylsi-
lane (
d
= 0.00 ppm) as internal reference. 13C NMR spectra were
Fig. 2. Secondary orbital interactions.
Fig. 1. ORTEP representation of the X-ray crystal structure of 16a (exo).

546
T.B. Patrick, H. Li / Journal of Fluorine Chemistry 130 (2009) 544–546
recorded at 75.5 MHz with deuterated chloroform (CDCl3
= 77.0 ppm) as internal reference. 19F NMR spectra were recorded
at 282.3 MHz with trifluoroacetic acid (TFA = 0.00 ppm) as
3.5. Exo-5-fluoro-7-oxo-5-exo-acetyl-1, 3-diphenyl-2, 3-
d
benzobicyclo[2.2.1]-2-heptene (16a, 16b)
d
external reference, and are corrected to CFCl3. Deuterated chloro-
form was the solvent in all cases.
The exo/endo ratio of 2:1 was determined from integration of
the 19F spectrum. Recrystallization of the solid reaction mixture
from ethyl acetate gave the pure exo-16a product as white needles,
mp 170–172 8C. The ORTEP diagram for 16a is shown in Fig. 1.
On cooling the reaction mixtures were concentrated by blowing
a stream of nitrogen gas over the solution. The remaining mixtures
were purified by flash column chromatography on silica gel with
hexane/ethyl acetate mixtures as the eluent solvents. Yields are
reported with the equations. A complete material balance was not
achieved but minor amounts of 8 were observed in crude NMR
spectra and some polymeric residues were observed (carbon,
hydrogen and fluorine analysis were satisfactory for the exo
isomers).
1H NMR:
of CH2, 1H), 7.0–7.8 (m, aromatic, 14H); 13C NMR
d
2.05 (s, CH3, 3H), 2.20 m (CH of CH2, 1H), 3.0 (m, CH
27.0 (s, CH3),
d
46.8 (d, CH2, J = 8.24 Hz, 3-C), 74.9 (s, 4-C;) 91.4 (d, C, J = 25.0 Hz, 1-
C), 119.2 (d, C, J = 10.0 Hz), 112.2–148.6 (aromatic peaks) 205 (d,
CO, J = 26.9 Hz); 19F NMR
d
À155.6 (m, CF). The endo isomer 16b
showed 19F À165.7 (m, CF, endo).
3.6. Exo-8-acetyl-6-bromo-8-fluoro-2-oxa-bicyclo[2.2.2]oct-5-en-
3.2. (Exo.endo)-1-(2-Fluorobicyclo[2.2.1] hept-5-en-2-yl)ethanone
3-one (18a)
(10a, 10b)
Column chromatography on silica gel with hexane/ethyl acetate
(exo-10a) 1H NMR
J = 2.4 Hz, 3H), 2.24 (m, 4-CH, 1H) 3.08 (d, 1-CH, J ꢀ 0.1 Hz, 1H), 5.8
(m, 5-CH, 1H), 6.3 (m, 6-CH, 1H); 113C NMR
26.3 (s, CH3), 39.0 (m,
d
1.1–2.2 (m, 3-CH2, 7-CH2, 4H), 2.22 (d, CH3,
eluent gave the pure exo isomer 18a. 1H NMR:
d 2.4 (d, J = 2.2 Hz,
CH3, 3H), 2.42 (m, CH of CH2, 1H), 2.85 (m, CH of CH2, 1H), 3.8 (d,
J = 4 Hz, CH next to CO, 1H), 5.3 (m, CH next to O, 1H), 6.4 (m, vinyl-
CH, 1H); 13C NMR:
d25.3 (d, CH3, J = 3.3 Hz), 29.9 (m, 7-CH2), 40.6 (d,
4-CH, J = 7.5 Hz), 68.0(s, 1-CH), 96.8(d, 8-C, J = 196.5 Hz), 126.0 (s, 6-
CH), 131.9 (s, 5-CH), 166.0 (s, CO of lactone), 204.5 (d, J = 31 Hz, CO of
d
3-CH2), 42.3 (s, 4-CH), 50.6 (7-CH2), 51.08 (d, 1-CH, J = 7 Hz), 107.2
(d, J = 193 Hz, 2-C), 132.5 (5-CH), 142.3 (6-CH), 209.5(d, CO,
J = 35.1 Hz); 19F NMR
d
À149.7 (m).
(endo-10b) (obtained from impure sample) 1H NMR
d
1.2–2.2
ketone); 19F NMR:
d
À148.6 (exo). The endo isomer was observed in
(m, 3-CH2, 7-CH2, 4H), 2.2 (m, 4-CH, 1H), 2.38 (d, CH3, J = 2.4 Hz,
3H), 3.0 (d, 1-CH, J = 0.5 Hz, 1H), 6.1 (m, 5-CH, 1H) 6.5 (m, 6-CH,
the mixture but not obtained pure. It showed 19F NMR at À154.3
(endo). The exo/endo ratio determined from integration of the 19F
NMR spectrum of the mixture was 2:1.
1H); 13 C NMR (not obtained); 19F NMR
d
À157.2 (m). An exo/endo
ratio of 3:1 was obtained from 19F analysis of the crude reaction
mixture.
Acknowledgments
3.3. 1-(2-Fluoro-7-oxa-bicyclo [2,2,1] hept-5-en-2-yl)ethanone
This research was supported by the NSF-RUI program. The X-
ray data were obtained by Dr. Nigam Rath at the University of
Missouri, St. Louis, MO.
(12a, 12b)
exo-12a; 1H NMR;
2H), 4.9 (m, 4-CH, 1H), 5.05 (m, 1-CH, 1H), 6.1 (m, 5-CH, 1H), 6.3 (m,
6-CH, 1H); 13C NMR
26.2 (s, CH3), 31.0 (d, 3-C, J = 21.4 Hz), 64.0
(4-C), 69.0 (d, 1-CH, J = 9 Hz), 130 (d, J = 1 95.1, 2-C), 141 (s, 5-c),
142 (s, 6-C), 207.3 (d, CO, J = 25.9 Hz); 19F NMRTM À189.5 (m, CF).
endo-12b: 1H and 13C NMR data for the endo isomer were not
observed because of the trace amounts of 12b obtained but a 19F
peak at À194.0 (m, CF, endo) could be observed and was used to
calculate the exo/endo ratio of >20:1.
d 2.2 (d, J = 2.0 Hz, CH3, 3H), 3.2 (m, 3-CH2,
References
d
[1] J.M. Percy, Topics in Current Chemistry, in: R.D. Chambers (Ed.), Organofluorine
Chemistry. Techniques and Synthons, Springer-Verlag, Germany, 1997, p. 193.
[2] G. Haufe, in V. Soloshonok (Ed.), Fluorine Containing Synthons, ACS Symposium
Series, vol. 911, 2005 (Chapter 7).
[3] T.B. Patrick, C. Finau, E. Pak, K. Zaksas, B. Neal, J. Fluorine Chem. 127 (2006) 861.
[4] (a) H. Ito, A. Saito, T. Taguchi, Tetrahedron: Asymmetry 9 (1998) 1979;
(b) H. Ito, A. Saito, T. Taguchi, Tetrahedron: Asymmetry 9 (1998) 1989.
[5] P.J. Crowley, J.M. Percy, K. Stansfield, Tetrahedron Lett. 37 (1996) 8237.
[6] T.B. Patrick, T.Y. Agboka, K. Gorrell, J. Fluorine Chem. 129 (2008) 983.
[7] T.B. Patrick, U.P. Dahal, J. Fluorine Chem. (2009). doi:10.1016/j.jfluchem.2009.02.007.
[8] K. Afarinkia, M.J. Bearpark, A. Ndibwami, J. Org. Chem. 70 (2005) 1122.
[9] (a) C.G. Cho, J.S. Park, I.H. Jung, H. Lee, Tetrahedron 42 (2001) 1065;
(b) C.G. Cho, Y.W. Kim, Y.K. Lim, J.S. Park, J. Org. Chem. 67 (2002) 290.
[10] G.H. Posner, T.D. Nelson, Tetrahedron 46 (1990) 4573.
[11] M. Essers, C. Muck-Lichtenfeld, G. Haufe, J. Org. Chem. 67 (2002) 4715.
[12] K. Alder, G. Stein, Angew. Chem. 50 (1937) 510.
[13] K. Uneyama, Organofluorine Chemistry, Blackwell Publishing, UK, 2006(Chapter 1).
[14] A. Rauk, Orbital Interactions: Theory of Organic Chemistry, second ed., John Wiley
and Sons, New York, 2004, p. 124.
3.4. 1-(1-Fluoro-3,4-dimethylcyclohex-3-enyl)ethanone (14)
1H NMR:
d 1.6 (s, CH3, 3H), 1.7 (s, CH3, 3H), 2.3 (s, CH3, 3H), 1.7
À2.6 (m, CH2, 6H); 13C NMR:
d 24.8 (d, CH3, J = 3.0 Hz), 24.0 (3-
CH3), 24.3 (m, 4-CH3), 24.5 (s, 5-C), 36.7 (6-C), 37.6 (s, 2-C), 120.9 (s,
3-C), 125.1 (s, 4-C), 210.6 (d, CO, J = 30.2 Hz), quaternary carbon 1
not observed; 19F NMR:
d
À162.0 (m, CF).