Cycloaddition reactions of diethyl (E)-2-fluoromaleate

Article abstract of DOI:10.1016/j.jfluchem.2012.04.015

Diethyl E-2-fluoromaleate has been prepared in a pure state in 89% yield by a Horner-Wadsworth-Emmons Wittig procedure. The E configuration was determined by NMR spectroscopy. Diethyl E-2-fluoromaleate undergoes [3+2] cycloadditions with a series of aroma

Full text of DOI:10.1016/j.jfluchem.2012.04.015

Journal of Fluorine Chemistry 143 (2012) 109–111
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
[
3+2] Cycloaddition reactions of diethyl (E)-2-fluoromaleate
Timothy B. Patrick *, Mehrdad Shadmehr, Akbar H. Khan, Rajiv K. Singh, Bethel Asmelash
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:
Diethyl E-2-fluoromaleate has been prepared in a pure state in 89% yield by a Horner–Wadsworth–
Emmons Wittig procedure. The E configuration was determined by NMR spectroscopy. Diethyl E-2-
Received 17 February 2012
Received in revised form 13 April 2012
Accepted 26 April 2012
fluoromaleate undergoes [3+2] cycloadditions with a series of aromatic
nitrones. The yields of purified cyclic products ranged from 65 to 80%.
a-iminoesters and aromatic
Available online 16 May 2012
ß 2012 Elsevier B.V. All rights reserved.
Keywords:
E-2-Fluoromaleate
Fluorinated pyrrolidine
Proline
Fluorinated isoxazolidines
Iminoester
Nitrone
[
3+2] Cycloaddition
1
. Introduction
The concept of [3+2] cycloaddition reactions was reviewed in
963 by Huisgen [5]. Many new materials with widespread
1
Cycloaddition reactions of fluorinated alkenes represent an
important new methodology for the preparation of fluorinated
carbocycles [1,2] and fluorinated heterocycles. [3].
biological use have been prepared by this cycloaddition method.
We thus felt that the use of 1 in cycloadditions could be very useful
for the preparation of a wide variety of fluorinated heterocyclic
compounds with applications in biological sciences.
Following our studies of Diels–Alder reactions of fluoroalkenes
[
4], we now extend our research to include [3+2] cycloadditions.
Although Huisgen’s methodology is long known [5], very little is
reported on the preparation of ring-fluorinated heterocycles by
2. Results and discussion
[
3+2] cyclizations [2]. We chose to focus on reactions of
For this study we have used aromatic a-imines, 2a and 2b,
azomethine ylides [6] and nitrones [7,8] with fluoromaleate (1).
We recently developed a new and convenient preparation of 1 in
obtained from the condensation of glycine methyl or ethyl ester
hydrochlorides with aromatic aldehydes following the method of
Longmire [6]. Aromatic nitrones, 3a, 3b, 3c and 3d, were obtained
by condensation of methyl hydroxylamine with aromatic
aldehydes.
8
9% yield by the reaction of ethyl glyoxylate in the Horner–
Wadsworth–Emmons reaction with triethyl 2-fluoro-2-phos-
phoethanoate as shown in equation (1).
(1)
*
Corresponding author Tel.: +1 618 650 3582.
E-mail address: tpatric@siue.edu (T.B. Patrick).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2012.04.015

1
10
T.B. Patrick et al. / Journal of Fluorine Chemistry 143 (2012) 109–111
Cyclization of 1 with the
a-imines (2) was accomplished in 65
and 77% yield by refluxing the components in toluene with silver
acetate catalyst to give 4a and 4b.
Fig. 2. Proposed mechanism for nitrone cyclization.
The protons H
atom (J = 26.0 Hz) and establish that the H and F atoms are cis to
each other. The COSY spectrum shows that H and H are adjacent
to each other and confirms the regiochemistry of the cycloaddition.
The absence of any NOE between H and H indicates that these
two atoms are trans to each other, as shown in 4a and 4b.
The regioselectivity observed between 1 and the
be explained as shown by the proposed mechanism in Fig. 1. In the
cyclization the imine bears a partial negative charge which adds to
the carbon alpha to the fluorine atom.
2 4
and H in 4a couple equally with the fluorine
3
.2. Diethyl (E)-2-fluoromaleate (1)
5
4
A three necked 100-mL flask fitted with a magnetic stirrer was
5
4
flamed dried and kept under nitrogen atmosphere. Triethyl 2-
fluoro-2-phosphonethonate (4.6 g, 1.7 mmol) in 20 mL of anhy-
drous tetrahydrofuran was injected into the flask. The solution was
cooled to À788 with a dry ice–acetone bath. n-Butyllithium (1.6 M,
a
À imines can
1
2.5 mL in hexane) was gradually added to the flask. The bright
yellow solution was stirred for 20 min, and ethyl glyoxylate
5.15 g, 5.0 mmol) was added by syringe. The mixture was stirred
The cyclization of 1 with the nitrones (3) to give 5a–5d was
accomplished by refluxing the materials in toluene for 20 h. The
cycloadducts were formed in 70–78% yield.
(
at À788 C for 1 h and then allowed to warm to room temperature.
The solution was quenched with 80 mL of cold water. The contents
The regiochemistry and stereochemistry of 5a–5b were
1
4
were extracted three times (20 mL) of ether and dried with MgSO .
established also by H NMR. Protons H
3
and H
4
are adjacent to
is
1
The solvent was removed to give 3.18 g (89%) of 1. H NMR data
each other by COSY, but do not show a NOE effect. Proton H
4
1
9
˙
were fully consistent with reported values [9]. F NMR
d
À112 3
coupled with F into a doublet (J = 22.6 Hz), and F shows no further
coupling. The selectivity in the reaction of the nitrones with 1 is
explained from calculations which show that the reaction is
controlled by the HOMO of the nitrone and the LUMO of 1. This
interaction predicts that the oxygen of the nitrone will add to the
carbon of 1 that has the F atom. (Fig. 2).
This methodology is simple and regioselective and opens new
avenues for the preparation of fluorinated heterocycles that have
potential use in medicinal chemistry.
1
9
(
d, J = 15.7 Hz) [lit. 9
d
F À109 J = 15.7 Hz].
3.3. The a-imines were prepared by standard literature procedures by
condensing glycine ester hydrochlorides with aromatic aldehydes [6]
1
Benzylideneamino acetic acid methyl ester (2a): 77%, H NMR
d
3
3
.74 (s, 3H, CH ), 4.38 (s), 7.4–7.8 (m, 5H, aromatic) 8.3 (s, 1H, CH).
1
3
C NMR
CH), 170.8 (C 55 O).
-Chlorobenzylidineamino acetic acid ethyl ester (2b): 65%,
NMR 1.95 (t, 3H, CH , J = 5 Hz), 4.24 (s, 2H, CH
aromatic, 4H), 8.24 (s, CH, 1H). C NMR d 14.3 (CH
27.9–139.7 (aromatic), 164.2 (CH), 170.1 (C 55 O).
d
52.33 (OCH
3
), 62.2 (CH
2
), 127.9–140.8 (aromatic), 165.7
(
1
4
H
3
. Experimental procedure
d
3
2
), 7.2–7.8 (m,
), 61.3 (OCH ),
1
3
3
2
3.1. General
1
1
H NMR data were recorded at 300.0 MHz with tetramethylsi-
d = 0.00 ppm) as internal reference. C NMR spectra were
3.4. Nitrones (3a–3d)
13
lane (
recorded at 75.5 MHz with deuterated chloroform (CDCl
3
The nitrones were prepared by heating at reflux a mixture of
N-methylhydroxylamine and the aromatic aldehyde for 18 h. The
19
d
= 77.0 ppm) as internal reference. F NMR spectra were recorded
at 282.3 MHz with trifluoroacetic acid (TFA = 0.00 ppm) as
Deuterated
d
nitrones were purified by flash chromatography.
1
external reference, and are corrected to CFCl
3
.
N-methylphenylnitrone (3a): H NMR
d
3.8 (CH
3
, 3H), 7.31 (m,
chloroform was the solvent in all cases.
5
H, aromatic) 8.09 (m, 1H, CH). N-methyl-4-methoxyphenylni-
1
The mixtures were purified by flash column chromatography on
silica gel with hexane/ethyl acetate mixtures as the eluent
solvents.
trone (3b): H NMR
aromatic), 8.1 (m, 1H, CH). N-methyl-4-chlorophenylnitrone
3
d 3.8 (s, CH ) 3.9 (CHN), 6.9–7.3 (m, 4H,
1
(
7
3
3c): H NMR
d
3.8 (s, 3H, CH
.08 (s,1H, CH). N-methyl-2-furanylnitrone (3d): H NMR
H, CH ), 6.5, 7.4–7.7 (m, 3H, furan), 7.8 (m, 1H CH).
3
), 7.4 (d, J = 2 Hz) and 8.2 (d, J = 2 Hz),
1
d 3.8 (s,
3
3.5. Cyclization of 1 with 2a and 2b to produce pyrrolidines 4a and 4b
3,4-Diethyl 2-methyl 3-fluoro-5-phenylpyrrolidine-2,3,4-tri-
carboxylate (4a). To a mixture of imine 2(88 mg, 0.45 mmol) and
silver acetate (2.3 mg) in 2 mL of dry toluene was added 1 (90 mg,
0.68 mmol) and diisopropylamine (8 mL) in 3 mL of dry toluene.
The reaction was heated at reflux for 20 h. The mixture was
concentrated and chromatographed (hexane/EtOAc, 3/1) to give
1
Fig. 1. Proposed mechanism for
a-imine cyclization.
pure 4a (65%). H NMR
d
0.88 (t, 3H, CH
3
, J = 5 Hz), 1.2 (t, 3H, CH
3
,

T.B. Patrick et al. / Journal of Fluorine Chemistry 143 (2012) 109–111
111
J = 5 Hz), 3.7 (s, 3H, OCH
J = 5 Hz), 4.4 (d, H2, J = 2 Hz), 4.6 (d, 1H, J = 4 Hz, H5), 7.2–7.5 (m,
3
), 3.8 (t, 2H, CH
2
, J = 5 Hz), 4.2 (t, 2H, CH
2
,
61.8 (d, J = 25 Hz, C4), 76.1 (C3), 117.1 (d, JCF = 300 Hz, CF), 130.1
19
(m, aromatic) 135, 137 (aromatic), 164 (CFC 55 O), 167.2 (C 55 O).
NMR
F
1
3
5
6
1
3
H, aromatic). C NMR
d
13.8 (d,) 53.2 (OCH
3
), 58.5 (C5) 61.0 (C2),
d
À97.5. m/z calcd for 359.09: found: 359.079.
2.0, (CH ), 101.4 (C3, d, JCF = 289 Hz), 128–140 (Aromatic), 164,
71, 171.7 (C 55 O). F NMR
2
Diethyl 3-(p-methoxyphenyl)-5-fluoro-2-methylisoxazoli-
19
d
À155.2. m/z calcd. 367.140: found:
dine-4,5-dicarboxylate (5c).
1
67.142.
H NMR
d
1.2 (t, 3H, CH
3
), 1.39 (t, 3H, CH
3
), 2.7 (s, 3H, NCH
), 4.35 (q, 2H,
), 43.5 (NCH ),
), 61.9 (d, J = 27 Hz, C4), 76.8 (C3), 118.1 (d, CF, JCF
3
), 3.8
Triethyl 5-(p-chlorophenyl)-3-fluoropyrrolidine-2,3,4-tri-
carboxylate (4b) was prepared in 77% yield as described for 4a:
(s, 3H, OCH
3
), 3.9 (dd, H3, H4, 2H), 4.2 (q, 2H, CH
2
1
3
CH
55.5 (OCH
300 Hz), 130, 138, 139 (aromatic), 164 (CFC 55 O) 167 (C 55 O).
NMR
À97.9. m/z calcd. For 355.141: found: 355.134; Calcd. For
355.141.
Diethyl 5-fluoro-3-(2-furanyl)-2-methylisoxazolidine-4,5-
dicarboxylate (5d).
2
), 6.8–7.3 (m, 4H, aromatic). C NMR
d
14.2 (CH
3
3
1
H NMR
.2 (m, CH
HH = 2 Hz, aromatic). C NMR
8.6 (CH ), 59.5 (CH ), 62.0 (CH
several singlets, aromatic), 168.0, 172.4, 172.7 (three C 55 O of
d
1.3 (m 6H, CH
3
of ethyl), 3.8–4.0 (m, 3H, CH
3
of 3-ethyl),
3
=
9
1
4
J
2
of 2,3-diethyl 6H), 4.6 (d, 1H, H5), 7.2–7.9 (dd, 4H,
F
13
d
14.8 (3 s, CH
3
), 50.2 (C2), 54.3 (C5),
d
5
(
2
2
2
), 102 (d, JCF = 290 Hz), 128–141.0
19
esters). F NMR
found 401.797.
d
À155.8 (CF, J = 27.8 Hz). m/z calcd for 401.810:
1
H NMR
s, NCH ), 4.1 (q, CH
7.4 (furan). C NMR
C4), 63.5 (OCH ), 76.1 (C3), 115 (d, J = 300 Hz, CF), 116,.0 143.2,
39.0, 145.5 (furanyl), 164.1 (d, C3, C 55 O, J = 7 Hz), 166.3 (d, C4,
d
1.2 (t, 3H, CH
) 4.21 (m, H3, H4, 2H), 4.4 (q, CH
14.1 (CH ), 43.5 (NCH
3
, J = 5 Hz), 1.38 (t, 3H, CH
3
, J = 5 Hz), 2.8
(
3
2
2
), 6.2, 6.5, 7.2,
1
3
3.6. Cyclization of 1 with nitrones 3a–3d to produce isoxazolidines
d
3
3 2
), 55.5 (OCH ), 62.0 (d,
5
a–5d
2
1
1
9
Diethyl 5-fluoro-2-methyl-3-phenylisoxazolidine-4,5-dicar-
boxylate (5a). Nitrone 3a (1 mmol) and diethyl (E)-2-fluoromale-
ate (1) were allowed to reflux in toluene (4 mL) for 20 h. The
C 55 O). F NMR
d
À97.5. m/z calcd for 315.113: found. 315.121.
References
toluene was removed under vacuum and the product was
1
[1] G. Haufe, in: V.A. Soloshonok (Ed.), Vinyl Fluorides in Cycloaddition in Fluorine
Containing Synthons, ACS Symposium Series 911, 2005, Ch 5.
chromatographed on silica gel to give pure 5a (76%): H NMR
d
1
3
7
6
.3, 1.8 (two triplets, 6H, CH
3
, of ester, Js = 5 Hz), 2.7 (s, NCH
, of ethyl), 7.3–
of ethyls), 43.4 (NCH ),
1 (C4), 76.1 (C3), 117 (d, CF, J = 300 Hz), 128.4 (m, aromatic) 135,
3
, 3H),
[2] Y.-H. Lam, S.J. Stanway, V. Gouverneur, Tetrahedron 65 (2009) 9905.
[3] W.R. Dolbier, in: M. Hudlicky, A.E. Pavlath (Eds.), Cycloadditions Forming Five- and
Six-Membered Rings in Chemistry of Organic Fluorine Compounds II, ACS,
Washington DC, 1995, , ACS Monograph 187.
[4] T.B. Patrick, J. Neuman, A. Tatro, Journal of Fluorine Chemistry 132 (2011) 779.
[5] R. Huisgen, Angewandte Chemie International Edition^pV 2 (1963) 565.
.84–3.96 (dd, H4, H5, Js = 3 Hz), 4.1 and 4.3 (q, CH
2
13
.5 (m, 5H, aromatic). C NMR
d
14.0 (CH
3
3
1
9
(aromatic), 164 (d, CFC 55 O, J = 6 Hz), 167.0 (C 55 O). F NMR
d
À97.6.
[
6] J.M. Longmire, B. Wang, X. Zhang, Journal of American Chemical Society 124 (2002)
3400.
m/z calcd for 325.130: found: 325.136.
1
Diethyl 3-(p-chlorophenyl)-5-fluoro-2-methylisoxazolidine-
[7] A. Brandi, F. Cardona, S. Cicchi, F. Cardero, A. Goti, Chemistry: A European Journal
15 (2009) 7808.
4
,5-dicarboxylate (5b).
1
[8] R.C.F. Jones, J.N. Martin, in: A. Padwa, W.H. Pearson (Eds.), Synthetic applications of
,3-dipolar cycloaddition chemistry toward heterocycles and natural products,
H NMR
d
1.2 (t, 3H, CH
3
), 1.38 (t, 3H, CH
3
), 2.7 (s, 3H, NCH
), 4.3 (q, 2H, CH
of ethyl), 43.3 (NCH
3
), 3.8
1
(dd, H3 and H4, 2H, Js = 4 Hz)), 4.2 (q, 2H, CH
2
2
),
Wiley, New York, NY, 2002, pp. 1–81.
13
7
.4–7.6 (dd, aromatic). C NMR
d
14.1 (CH
3
3
)
[9] J. Cousseau, P. Albert, Bulletin de la Soci e´ t e´ Chimique de France 6 (1986) 910.