Fluorocyclization of norbornenecarboxylic acids with F-TEDA-BF4

Article abstract of DOI:10.1070/MC2002v012n03ABEH001564

The reactions of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) with cis-5-norbornene-endo-2,3-dicarboxylic acid, its monomethyl ester and 5-norbornene-endo-2-carboxylic acid in acetonitrile lead to the formation of corres

Full text of DOI:10.1070/MC2002v012n03ABEH001564

Mendeleev Commun., 2002, 12(3), 115–117
Fluorocyclization of norbornenecarboxylic acids with F-TEDA-BF4
Yurii A. Serguchev,* Lyudmila F. Lourie, Galina V. Polishchuk and Alexander N. Chernega
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 02094 Kiev, Ukraine.
Fax: +38 044 573 2043; e-mail: serg@mail.kar.net
10.1070/MC2002v012n03ABEH001564
The reactions of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) with cis-5-norbornene-endo-
2,3-dicarboxylic acid, its monomethyl ester and 5-norbornene-endo-2-carboxylic acid in acetonitrile lead to the formation of
corresponding fluorinated γ-lactones.
Lactones are synthesised by electrophilic heterocyclization of
F
unsaturated carboxylic acids using various agents, such as halo-
gens, metal salts, sulfenyl chlorides, acids and peroxy acids.1–3
Traditional fluorinating electrophiles (F2, XeF2, CF3OF, RCOOF
etc.), were never employed in these reactions because of their
high reactivity, which considerably hampers the control of addi-
tion and cyclization stages. However, the fluorocyclization of
unsaturated carboxylic acids seems to be a very alluring direct
single-step preparative approach to fluorinated lactones structur-
ally related to biologically important fluorinated carbohydrates.4–6
The electrophilic fluorocyclization of norbornenecarboxylic acids
is of particular interest owing to structural similarity of the com-
pounds to naturally occurring terpenes.
Here, we report the fluorocyclization of cis-5-norbornene-
endo-2,3-dicarboxylic acid 1a, its monomethyl ester 1b and
5-norbornene-endo-2-carboxylic acid 4 by a soft electrophilic
fluorinating agent, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo-
[2.2.2]octane bis(tetrafluoroborate) known as F-TEDA-BF4.†
On heating with F-TEDA-BF4 in acetonitrile under reflux, 1a
and 1b are transformed mainly into corresponding exo-fluoro-
γ-lactones 2a,b (Scheme 1).
7
H
N
BF4
BF4
4
3
5
9
∆
COOR
2
H
MeCN
6
1
N
CO2H
8
CH2Cl
1a R = H
1b R = Me
F
COOR
F
H
H
COOR
H
CO2H
H
O
O
53%
2a
2b 58%
traces
3a
3b 8%
Scheme 1
The exo-arrangement of the fluorine atom in compounds 2a,b
was inferred from the correlation of their NMR spectra with
those previously reported for exo-fluoronorbornanes7–9 and from
†
General procedure. A mixture of appropriate acid 1a,b or 4 (5 mmol)
and F-TEDA-BF4 (6 mmol) in acetonitrile (20 ml) was heated at reflux and
stirred for 37–48 h. The precipitate formed was separated by filtration,
and the filtrate was evaporated to leave a solid residue, which was washed
with water and extracted with dichloromethane (2×15 ml). The extract
was washed with water and 10% aqueous NaHCO3, dried (Na2SO4),
concentrated, and separated by column chromatography on silica gel using
diethyl ether–hexane (2:1) as an eluent. The 1H, 13C and 19F NMR spectra
were taken on a Varian VXR-300 spectrometer at 299.9, 75.3 and
282.2 MHz, respectively, using TMS and CCl3F as internal standards.
The IR spectra were measured on a Specord IR-75 spectrophotometer in
KBr disks. The mass spectra were measured on a MAT 8200 instrument
at 70 eV. TLC was carried out on Silufol UV-254 plates (eluent: diethyl
ether–hexane 6:1). Single crystals of 2b were grown from ethyl acetate.
For 2a: white crystals, yield 53%, Rf 0.35, mp 131–132.5 °C. 1H NMR
characteristic values of the coupling constants JFH.
To verify the spectral identification of these products, we
performed single-crystal X-ray diffraction analysis of fluoro-
γ-lactone 2b and established unequivocally the exo-orientation
For 3a (not isolated): 19F NMR ([2H6]DMSO) d: –211.8 (dd, CHF,
2JFH 54.7 Hz, 3JFH 7.3 Hz).
For 3b: white crystals, yield 8%, Rf 0.72, mp 134–135 °C. H NMR
1
(CDCl3) d: 2.61–2.71 (m, 2H, 2-H, 3-H), 3.20–3.28 (m, 2H, 1-H, 4-H),
2
3.70 (s, 3H, Me), 5.42 (d, 1H, 7-H, JFH 58.2 Hz), 6.24 (m, 2H, 5-H,
6-H), 7.5 (br. s, 1H, COOH). 13C NMR (CDCl3) d: 43.90 (d, 2-C, J
5.2 Hz), 44.12 (d, 3-C, J 5.3 Hz), 47.8 (d, 1-C, 4-C, J 17.8 Hz), 52.19
(Me), 101.47 (d, 7-C, J 199.7 Hz), 133.08 (5-C), 133.28 (6-C), 172.51
(9-C), 178.33 (8-C). 19F NMR (CDCl3) d: –211.3 (dd, CHF, 2JFH 58.1 Hz,
3JFH 6.5 Hz). IR (n/cm–1): 1740 and 1700 (COO). MS, m/z (%): 214 (18)
[M+], 183 (45) [M+ – MeO], 155 (28) [M+ – COOMe], 111 (16) [M+ –
– COOMe – CO2], 98 (20), 79 (11), 66 (100), 59 (13), 39 (21). Found
(%): F, 8.78. Calc. for C10H11FO4 (%): F, 8.87.
([2H6]DMSO) d: 1.67 (m, 1H, 7-Hanti, 2JHH 11.4 Hz), 1.85 (m, 1H, 7-Hsyn
,
2JHH 11.4 Hz), 2.77–2.83 (m, 2H, 1-H and 2-H), 3.17 (m, 1H, 3-H, 3JHH
3
3
11.1, 5.5 Hz), 3.34 (m, 1H, 4-H, JHH 6.0 Hz), 4.72 (dd, 1H, 6-H, JHF
20.7 Hz, 3JHH 5.1 Hz), 5.07 (d, 1H, 5-H, 2JHF 50.4 Hz), 11.98 (br. s, 1H,
COOH). 13C NMR ([2H6]DMSO) d: 33.29 (7-C), 40.81 (1-C), 44.83 (d,
4-C, J 24.8 Hz), 47.00 (2-C), 47.30 (d, 3-C, J 13.6 Hz), 83.85 (d, 6-C,
J 26.4 Hz), 94.42 (d, 5-C, J 183.1 Hz), 172.99 (8-C), 177.42 (9-C).
19F NMR ([2H6]DMSO) d: –183.4 (dd, CHF, 2JFH 51.1 Hz, 3JFH 20.3 Hz).
IR (n/cm–1): 1750 and 1700 (COO). MS, m/z (%): 200 (3) [M+], 155 (10)
[M+ – COOH], 141 (56), 111 (34) [M+ – COOH – CO2], 97 (83), 79 (100),
59 (81), 39 (70), 27 (42). Found (%): C, 53.72; H, 4.57; F, 8.90. Calc. for
C9H9FO4 (%): C 54.00; H, 4.53; F, 9.49.
1
For 5: white crystals, yield 27%, Rf 0.60, mp 166–167 °C. H NMR
(CDCl3) d: 1.59–1.70 (m, 2H, 3-Hendo, 7-Hanti), 1.99–2.10 (m, 2H, 3-Hexo
,
3
7-Hsyn), 2.55 (m, 1H, 2-H, JHH 11.1, 4.5 Hz), 2.66 (m, 1H, 4-H), 3.22
2
3
(m, 1H, 1-H), 4.50 (d, 1H, 5-H, JHF 49.8 Hz), 4.64 (dd, 1H, 6-H, JHF
3
20.4 Hz, JHH 5.4 Hz). 13C NMR (CDCl3) d: 30.13 (d, 3-C, J 9.8 Hz),
33.33 (7-C), 37.72 (2-C), 41.58 (d, 4-C, J 21.2 Hz), 44.28 (1-C), 83.77
(d, 6-C, J 28.1 Hz), 95.79 (d, 5-C, J 189.4 Hz), 179.28 (8-C). 19F NMR
(CDCl3) d: –179.2 (dd, CHF, 2JFH 50.5 Hz, 3JFH 20.6 Hz). MS, m/z (%):
156 (49) [M+], 128 (12) [M+ – CO], 112 (20) [M+ – CO2], 97 (64), 79
(73), 66 (100) [M+ – CO2 – CHF=CH2], 59 (53), 39 (31), 27 (19). Found
(%): C, 60.76; H, 5.92. Calc. for C8H9FO2 (%): C, 61.53; H, 5.81.
For 6: oil, yield 37%, Rf 0.58. 1H NMR (CDCl3) d: 1.64–1.79 (m, 2H,
3-Hendo, 5-Hendo), 1.97–2.07 (m, 1H, 3-Hexo), 2.28–2.39 (m, 1H, 5-Hexo),
2.46–2.52 (m, 1H, 4-H), 2.54–2.62 (m, 1H, 2-H), 3.18–3.24 (m, 1H, 1-H),
For 2b: white crystals, yield 58%, Rf 0.39, mp 89–91 °C. 1H NMR
(CDCl3) d: 1.70 (m, 1H, 7-Hanti, ,
2JHH 11.4 Hz), 2.14 (m, 1H, 7-Hsyn
2JHH 11.4 Hz), 2.85 (dd, 1H, 2-H, 3JHH 10.6, 4.5 Hz), 2.88–2.92 (m, 1H,
3
1-H), 3.12 (m, 1H, 3-H, JHH 10.6, 5.1 Hz), 3.34–3.38 (m, 1H, 4-H),
3.73 (s, 3H, Me), 4.71 (dd, 1H, 6-H, 3JHF 20.4 Hz, 3JHH 5.1 Hz), 5.19 (d,
1H, 5-H, 2JHF 49.8 Hz). 13C NMR (CDCl3) d: 33.58 (7-C), 41.30 (1-C),
44.73 (d, 4-C, J 22.8 Hz), 46.80 (2-C), 47.52 (d, 3-C, J 9.1 Hz), 52.91
(Me), 84.08 (d, 6-C, J 28.1 Hz), 93.38 (d, 5-C, J 186.9 Hz), 170.95
(9-C), 179.91 (8-C). 19F NMR (CDCl3) d: –184.7 (dd, CHF, 2JFH 49.9 Hz,
3JFH 21.2 Hz). IR (n/cm–1): 1790 and 1730 (COO). MS, m/z (%): 214 (4)
[M+], 183 (13) [M+ – MeO], 155 (83) [M+ – COOMe], 127 (21) [M+ –
– COOMe – CO], 111 (59) [M+ – COOMe – CO2], 98 (94), 79 (69), 66
(35), 59 (100), 39 (62), 27 (35). Found (%): C, 55.83; H, 5.11; F, 9.05.
Calc for. C10H11FO4 (%): C, 56.07; H, 5.18; F, 8.87.
3
2
5.03 (dd, 1H, 6-H, JHH 6.8, 4.5 Hz), 5.07 (m, 1H, 7-H, JHF 56.1 Hz).
13C NMR (CDCl3) d: 28.84 (d, 3-C, J 6.7 Hz), 34.08 (d, 5-C, J 2.9 Hz),
36.02 (d, 2-C, J 7.3 Hz), 38.87 (d, 4-C, J 16.1 Hz), 48.36 (d, 1-C, J
19.2 Hz), 80.09 (6-C), 98.55 (d, 7-C, J 193.1 Hz), 179.28 (8-C). 19F NMR
(CDCl3) d: –204.1 (d, CHF, 2JFH 56.7 Hz). MS, m/z (%): 156 (38) [M+],
128 (61) [M+ – CO], 112 (13) [M+ – CO2], 97 (31), 79 (91), 66 (100)
[M+ – CO2 – CFH=CH2], 59 (29), 39 (31), 27 (20).
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Mendeleev Commun., 2002, 12(3), 115–117
O(3)
C(10)
7
4
C(9)
3
C(1)
5
F(1)
2
6
1
C(2)
O(4)
CO2H
8
C(7)
C(6)
4
C(5)
F–N X
C(4)
C(3)
F
F
C(8)
O(1)
O(2)
CO2H
CO2H
Figure 1 Molecular structure of 2b. Selected bond lengths (Å): O(1)–C(3)
1.458(7), O(1)–C(8) 1.358(7), O(2)–C(8) 1.190(7), C(1)–C(2) 1.524(5),
C(1)–C(5) 1.537(4), C(1)–C(7) 1.547(11), C(2)–C(3) 1.534(5), C(3)–C(4)
1.533(5), C(4)–C(5) 1.523(5), C(4)–C(6) 1.533(9), C(6)–C(7) 1.568(4),
C(6)–C(8) 1.510(5).
A
B
F
F
F
F
of its fluorine substituent (Figure 1).‡ All geometric parameters
of 2b are unexceptional.12 In particular, the bond lengths and
angles in the lactone chain C(3)O(1)C(8)O(2)C(6), in contrast
to dilactone bridged systems,13 are virtually the same as the
statistical X-ray data for γ-lactones.14 As expected, the lactone
group C–O–C(=O)–C in 2b is almost planar, and the torsion
angle C(3)–O(1)–C(8)–C(6) is as small as –1.7°.
The by-product, isolated in 8% yield in the reaction of mono-
ester 1b with F-TEDA-BF4, was identified as methyl hydrogen
cis-7-fluoro-5-norbornene-exo-2,3-dicarboxylate 3b. The posi-
tion of the fluorine atom in the bridge of 3b is evidenced from
close similarity between the 19F NMR spectra of this compound
and related fluorine-substituted norbornans.15 The presence of a
double bond in 3b is confirmed by 13C NMR spectra containing
signals at 133.08 and 133.28 ppm characteristic of sp2-hybridised
carbon atoms.
The fluorocyclization of 5-norbornene-endo-2-carboxylic acid
4 by F-TEDA-BF4 leads to the formation of two isomeric pro-
ducts, exo-fluoro-γ-lactone 5 and rearranged lactone 6 (Scheme 2).
Compound 5 is very similar to exo-fluoro-γ-lactones 2a and 2b
in spectral properties. The 19F NMR signal of 6 is downfield
as compared to that of 5, and the geminal spin–spin coupling
constants JFH in the 1H and 19F NMR spectra (56.1 and 56.7 Hz)
are characteristic of the fluorine substituent at the bridge carbon
atom in norbornane structures.15 The 13C NMR spectrum of 6 is
consistent with the structure proposed. The signals of the bridge-
head atoms 1-C and 4-C are split into doublets with similar
coupling constants (2JCF 19.2 and 16.1 Hz). For the remote atoms
2-C, 3-C and 5-C, the coupling with fluorine is markedly weaker
(3JCF 7.3, 6.7 and 2.9 Hz). The 6-C atom appears as a singlet, in
contrast to compound 5 where its signal is split into a doublet
with 2JCF 28.1 Hz on the fluorine at 5-C.
CO2H
O
O
C
D
O
O
5 27%
H
F
CO2H
O
O
6 37%
Scheme 2
philic agents from the exo- than from the endo-side,1,16 the
bulkiness of F-TEDA-BF4 can explain the highly selective exo-
addition of fluorine to the norbornenecarboxylic acids.
The formation of skeletal-rearrangement products 3b and 6 in
the fluorocyclization suggests the carbocationic reaction mecha-
nism, which is generally accepted in the reactions of norbornene
with electrophilic fluorinating agents such as [fluoro(organyl-
sulfonyloxy)iodo]benzenes,3 methoxyxenon fluoride,7 xenon
difluoride9,17–19 and F-TEDA-BF4.15 Taking into account the in-
ability of a fluorine atom to form three-membered cyclic cations,20
we may presume the intermediacy of open (or nonclassical)
fluorocarbocations in the reaction. With such an assumption,
the mechanism of the fluorocyclization of acid 4 can be re-
presented as shown in Scheme 2. The quantum-chemical calcu-
lations performed for 4 at the semiempirical PM3 level also
count in favour of the proposed mechanism.
In the interaction of F-TEDA-BF4 with the double bond in 4,
carbocations A and B are formed. Cation A is cyclised into
five-membered exo-fluoro-γ-lactone 5 with an activation energy
of 0.3 kcal mol–1. The cyclization of cation B into the six-mem-
bered lactone is unfavourable because of a high activation barrier
(29 kcal mol–1) of the process, and it is isomerised to carbo-
cation C (Ea = 25 kcal mol–1). Next, cation C is transformed,
via a series of hydride 1,2-shifts (Ea £ 14.5 kcal mol–1), into
cation D, which easily undergoes lactonization into 6 (Ea =
= 3 kcal mol–1).
It is remarkable that exo- rather than endo-γ-fluorolactones are
formed in the fluorocyclization. Because norbornene systems
are considered to be sterically much more accessible to electro-
‡
Crystallographic data for 2b: C10H11FO4, M = 214.19, orthorhombic,
space group P212121, a = 7.160(4), b = 9.656(12) and c = 13.739(9) Å,
V = 1456.1 Å3, Z = 4, dcalc = 1.498 g cm–3, m = 10.63 cm–1, F(000) = 449.7,
crystal size 0.16×0.28×0.33 mm. All data were collected using CuKα
radiation (l = 1.54178 Å) on an Enraf-Nonius CAD4 diffractometer,
Compound 3b is evidently formed in the reaction of 1b with
F-TEDA-BF4 through the deprotonation of a C-type intermediate
carbocation.
q
max = 70°, 293 K, 1497 reflections were collected (845 independent,
Rint = 0.017). An empirical absorption correction based on azimuthal scan
data was applied. The structure was solved by direct methods and refined
by a full-matrix least-squares technique in the anisotropic approximation
using the CRYSTALS program package.10 All hydrogen atoms were
located in the difference Fourier maps and included in the final refine-
ment with fixed positional and thermal parameters. Convergence was
obtained at R = 0.043 and Rw = 0.044, GOF = 1.189 [820 reflections with
I > 3s(I), 136 refined parameters; obs/variabl. 6.0, difference electronic
density 0.20 and –0.26 e Å–3]. The Chebyshev weighting scheme11 with
parameters of 9.74, 3.02, 10.40, 0.65, and 3.09 was used in the refine-
ment. Atomic coordinates, bond lengths, bond angles and thermal param-
eters have been deposited at the Cambridge Crystallographic Data Centre
(CCDC). For details, see ‘Notice to Authors’, Mendeleev Commun.,
Issue 1, 2002. Any request to the CCDC for data should quote the full
literature citation and the reference number 1135/107.
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– 117 –