Selective fluorination of (1S,4R)-(-)-camphanic acid with sulphur tetrafluoride: Preparation of new fluorinated optically active derivatives of camphor and 1,2,2-trimethylcyclopentane

Article abstract of DOI:10.1016/S0022-1139(99)00035-4

Treatment of (1S,4R)-(-)-camphanic acid (1) with sulphur tetrafluoride affords (1R,4S)-(-)-3-oxa-4-(trifluoromethyl)camphor (2) as a main product together with small amounts of (1S,4R)-camphanoyl fluoride (3), (1R)-3-(trifluoromethyl)camphonenoyl fluoride (4) and (1R)-3,4-dehydrocamphoroyl difluoride (5). Reduction of 2 with LiAlH₄ gives the diol, (1R,3S)-(+)-3-hydroxy-1,2,2-trimethyl-3-trifluoromethyl-1-cyclopentanemethanol (6), which when heated with KHSO₄ readily dehydrates to (1R,4S)-(-)-3-oxa-4-(trifluoromethyl)bornane (7). Acylation of the diol 6 proceeds regioselectively at the primary hydroxyl group to give exclusively monoacylated derivative 8.

Full text of DOI:10.1016/S0022-1139(99)00035-4

Journal of Fluorine Chemistry 97 (1999) 97±100
Selective ¯uorination of (1S,4R)-( )-camphanic acid with sulphur
tetra¯uoride: preparation of new ¯uorinated optically active
derivatives of camphor and 1,2,2-trimethylcyclopentane
Wojciech Dmowski*, Krystyna Piasecka-Maciejewska
Institute of Organic Chemistry, Polish Academy of Sciences, 01-224 Warsaw, Poland
Received 5 October 1998; received in revised form 9 November 1998; accepted 9 November 1998
Dedicated to Prof. Yoshiro Kobayashi on his 75th birthday
Abstract
Treatment of (1S,4R)-( )-camphanic acid (1) with sulphur tetra¯uoride affords (1R,4S)-( )-3-oxa-4-(tri¯uoromethyl)camphor (2) as a
main product together with small amounts of (1S,4R)-camphanoyl ¯uoride (3), (1R)-3-(tri¯uoromethyl)camphonenoyl ¯uoride (4) and
(1R)-3,4-dehydrocamphoroyl di¯uoride (5). Reduction of 2 with LiAlH4 gives the diol, (1R,3S)-(‡)-3-hydroxy-1,2,2-trimethyl-3-
tri¯uoromethyl-1-cyclopentanemethanol (6), which when heated with KHSO4 readily dehydrates to (1R,4S)-( )-3-oxa-4-(tri¯uor-
omethyl)bornane (7). Acylation of the diol 6 proceeds regioselectively at the primary hydroxyl group to give exclusively monoacylated
derivative 8. # 1999 Elsevier Science S.A. All rights reserved.
Keywords: Camphanic acid; Fluorination; Sulphur tetra¯uoride; (1R,4S)-( )-3-Oxa-4-(tri¯uoromethyl)camphor; 3-Hydroxy-1,2,2-trimethyl-3-tri¯uoro-
methyl-1-cyclopentanemethanol; (1R,4S)-( )-3-Oxa-4-(tri¯uoromethyl)-bornane
1. Introduction
phanic acid (1) readily available from camphoric acid [3],
and related chemistry.
In the preceding paper [1] it has been reported that a
sulphur tetra¯uoride ¯uorination of commercially available
(1R,3S)-(‡)-camphoric acid proceeds selectively to give,
besides two minor compounds, (1R,3S)-(‡)-3-(tri¯uoro-
methyl)camphonanoyl ¯uoride as a main product. The
expedient isolation of the latter as (1R,3S)-(‡)-3-(tri¯uor-
omethyl)camphonanic acid has also been later described [2].
This result showed that in camphoric acid only the less
sterically hindered carboxylic group at the position 3 can be
converted into the CF3 group while the reaction with the
second, sterically more crowded carboxylic group at the
position 1, stops at the stage of an acyl ¯uoride. This rather
rare case of selective ¯uorination of carbonyl functions with
SF4 stimulated further studies on ¯uorination of polyfunc-
tional substrates, particularly derivatives of terpenes, aiming
in the preparation of new tri¯uoromethyl derivatives with the
de®nite con®guration. The present paper reports a sulphur
tetra¯uoride ¯uorination of the lactone, (1S,4R)-( )-cam-
2. Results and discussion
A prolonged treatment of camphanic acid (1) with sulphur
tetra¯uoride at ambient temperature (ca. 208C) resulted in a
mixture consisting mostly (84 GLC%) of a bicyclic lactone,
(1R,4S)-( )-3-oxa-4-(tri¯uoromethyl)camphor (2), together
with small amounts of the intermediate bicyclic acyl ¯uoride
3 and the lactone opening products 4 and 5, although the
structures of these side products were tentatively assigned
based on GC±MS analyses.
It is known that esters and lactones are much less reactive
towards sulphur tetra¯uoride than free carboxylic acids [4],
and in compound 1 the reactivity of lactone moiety should
be lowered by steric crowdness due to the neighbouring
methyl groups in positions 4 and 7; this explains high
selectivity of the ¯uorination.
Treatment of the crude reaction mixture with aqueous
potassium hydroxide effectively removed acyl ¯uorides 3±5
leaving compound 2 unchanged and thus enabling its ef®-
cient isolation. Reduction of 2 with LiAlH4 gave the diol 6 in
*Corresponding author. Tel.: +48-22-632-3221; fax: +48-22-632-6681;
e-mail: dmowski@ichf.edu.pl
0022-1139/99/$ ± see front matter # 1999 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 0 3 5 - 4

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W. Dmowski et al. / Journal of Fluorine Chemistry 97 (1999) 97±100
high yield. Dehydration of diol 6 with anhydrous KHSO4 at
1808C afforded the bicyclic ether, (1R,4S)-( )-3-oxa-4-
(tri¯uoromethyl)bornane (7). The hydroxy groups in the
diol 6 showed quite different reactivities. Thus, acetylation
with a ®ve-fold excess of acetyl chloride proceeded regio-
selectively at the primary hydroxyl group to give exclu-
sively monoacetylated product 8. Compounds 2 and 6±8
retain the absolute con®guration of the starting acid 1 on
both asymmetric carbon atoms. The bicyclic compounds 2
and 7 also retain the negative sign of the optical rotation
coef®cient [ꢀ] while this coef®cient for the monocyclic
compounds 6 and 8 showed the opposite sign (positive).
Further chemistry of compounds 2±8 is being investigated.
trometer and IR spectra with a Perkin-Elmer 1640 instru-
ment. Optical rotations were measured at ambient
temperature as 5% solutions in methanol with a JASCO
DIP-360 polarimeter using a 100 mm cell.
(1S,4R)-( )-camphanic acid (1) was synthesised by fol-
lowing the literature procedure [3].
3.1. Reaction of (1S,4R)-( )-camphanic acid (1) with
sulphur tetrafluoride
(1S,4R)-( )-camphanic acid (1) (20 g, 0.1 mol) was
placed in a 250 ml capacity stainless steel autoclave ®tted
with a needle valve, the autoclave was cooled in an acetone-
3. Experimental
dry ice bath, evacuated, then sulphur tetra¯uoride (32 g,
0.3 mol) was condensed into it. The autoclave was left at
ambient temperature (20±228C) for 14 days (shaken occa-
sionally). After completion of the reaction, gaseous pro-
ducts were let off (SF4, SOF2, HF) and a brown oily residue
was washed out with CH2Cl2 (180 ml) into a polyethylene
container, sodium ¯uoride (30 g) was added and the mixture
was stirred overnight to remove HF. Precipitates were
®ltered off and the ®ltrate was concentrated on a rotary
evaporator affording a yellow oily residue containing some
solid material (elemental sulphur). This mixture was stirred
with hexane (200 ml) for half an hour and ®ltered. The GC±
MS analysis of the hexane solution revealed the presence of
compound 2 as the main component (84%) together with a
number of minor components of which the most abundant
Melting points were determined in capillaries and boiling
points were measured during distillation; both are uncor-
1
rected. H and 19F NMR spectra were recorded in CDCl3
with a Varian Gemini 200 spectrometer at 200 and
188 MHz, respectively. Chemical shifts are quoted in
ppm from internal TMS for H (positive down®eld) and
from internal CFCl3 (positive up®eld). Crude mixture of
products were analysed with a Shimadzu GC-14A Chro-
matograph using a 3.5 mÂ2 mm column packed with 5%
silicone oil SE-52 on Chromosorb G. GS±MS analyses were
performed with a Hewlett-Packard 5890 apparatus using a
30 m capillary column coated with a HP5 oil. Mass spectra
of pure compounds were obtained with an AMD-604 spec-
1

W. Dmowski et al. / Journal of Fluorine Chemistry 97 (1999) 97±100
99
were 3 (4.5%), 4 (2%) and 5 (6.5%). A 5% aqueous solution
of KOH (100 ml) was added and the two phases were
vigourously mixed together for 2 h. The organic layer
was separated, washed with water (3Â50 ml) and dried
over MgSO4. Compounds 3, 4 and 5 were not detected
by GLC. The solvent was distilled off on a water bath and
the residue was vacuum distilled to afford 2 as a white waxy
material (solidi®es in a water condenser) possessing mild
camphor like smell.
1H NMR: 0.85 (s, CH3); 1.01 (q, 5JHFˆ2.6 Hz, CH3); 1.06
(s, CH3); 1.52±1.83 (m, 2H); 1.92±2.12 (m, 1H); 2.18±2.34
(m, 1H); 3.30 and 3.60 (AB system, JABˆ10.7 Hz, CH2O);
4.18 (brs, OH); 6.24 (brs, OH) ppm. 19F NMR: 74.4 (s) ppm.
‡
MS (70 eV) m/e (rel.int., ion): 226 (<1, M ); 208 [<1,
‡
‡
ꢀM H2O† ]; 194 [23, (23, ꢀM CH2OH2† ]; 177 [100,
‡
‡
ꢀM H2O CH2OH† ]; 163 (54, C8H10F3 ) 135
‡
‡
‡
ꢀ18; C6H6F3 †; 109 ꢀ12; C8H13†; 96 ꢀ26; C7H12†; 83
‡
‡
‡
ꢀ71; C6H11†; 71 ꢀ20; C4H7O †; 69 (12, CF3 ); 67 (15,
‡
‡
‡
‡
(1R,4S)-( )-3-oxa-4-tri¯uoromethylcamphor (2): Yield:
10.7 g (48.2%). GLC purity: 98.5%. B.p. 928C/5 Torr; 65±
C5H7 ); 55 (49, C4H7 ); 43 (22, C3H7 ); 41 (31, C3H5 ).
668C/2 Torr. M.p.ˆ38±408C. IR (CCl4) (cm 1): 1807.8 (vs,
3.3. (1S,4R)-( )-3-Oxa-4-(trifluoromethyl)bornane (7)
22
C=O). ‰ꢀŠ ˆ 1.4 (cˆ5, MeOH). Analysis: Found: C, 54.0;
D
H, 6.05; F, 25.7%. C10H13F3O2 (222.21) requires: C, 54.05;
The diol 6 (1.1 g, 5 mmol) and potassium hydrogen
sulphate (5.0 g, 37 mmol) freshly dried at 2008C were
ground together, then placed at the bottom of a glass tube
(ꢁˆ20 mm, lˆ200 mm) and covered by a layer of potas-
sium hydrogen sulphate (3.5 g). The tube was sealed and
slowly heated on an oil bath to 1808C and then kept at the
same temperature for 3 h. A liquid product condensed at the
upper, cooler part of the tube. After cooling to ambient
temperature, ether was added (20 ml), and the solid material
was ®ltered off, then the solid material was washed with
ether (5 ml). The GC±MS analysis of the combined ether
solutions revealed a single component. The solvent was
distilled off on a water bath and the residue was vacuum
distilled to afford a white low melting crystalline solid
possessing a mild terpenic smell. Yield: 0.76 g (73%).
1
H, 5.9; F, 25.65%. H NMR: 1.07 (brs, 2ÂCH3); 1.12 (s,
CH3); 1.65±1.8 (m, 1H); 1.82±2.1 (m, 2H); 2.2±2.35 (m,
1H) ppm. 19F NMR: 73.45 (s, CF3) ppm. MS (70 eV) m/z
‡
‡
‡
(rel.int., ion): 222 (1, M ); 194 [47, (M±CO) ]; 179 [9,
‡
ꢀM CO CH3† ]; 163 [100, (M CO2 CH3† ]; 109 (21,
‡
‡
‡
‡
C8H13 ); 83 (78, C6H11 ); 82 (44, C6H10 ); 69 (17, CF3 );
‡
‡
‡
67 (18, C5H7 ); 55 (41, C4H7 ); 41 (35, C3H5 ).
(1R,4S)-camphanoyl ¯uoride (3): GC±MS m/z (rel.int.,
‡
‡
ion): 200 (<1, M ); 172 [80, (M±CO) ]; 141 [95,
‡
‡
ꢀM CO2 CH3† Š; 113 (70, C7H10F ); 109 (100,
‡
‡
‡
‡
C8H13 ); 83 (90, C6H11 ); 69 (33, CF3 ); 67 (35, C5H7 )
‡
‡
55 (80, C4H7 ); 41 (85, C3H5 ).
(1R)-3-(tri¯uoromethyl)camphonenoyl ¯uoride (4): GC±
‡
‡
MS m/z (rel.int., ion): 224 (5, M ); 196 [5, (M±CO) ]; 177
‡
‡
‡
[100, (M±COF) ]; 135 (15, C6H6F3 ); 127 (20, C8H12F ).
(1R)-3,4-dehydrocamphoroyl di¯uoride (5): GC±MS m/z
GLC purity: >99%. B.p. 648C/18 Torr. M.p.ˆca. 328C.
20
IR (CCl4): no OH absorption. ‰ꢀŠ ˆ 10.7 (cˆ5, MeOH).
D
Analysis: Found, C, 57.5; H, 7.3; F, 27.5%. C10H15F3O
‡
‡
(rel.int., ion): 202 (5, M ); 174 [8, (M±CO) ]; 155 [40, (M±
‡
‡
‡
1
COF) ]; 127 (100, (M±COF±CO) ]; 107 (55, C8H11); 91
‡
(208.22) requires: C, 57.7; H, 7.25; F, 27.4%. H NMR:
(30, C7H7 ).
0.89 (s, CH3); 1.00 (s, CH3); 1.03 (q, Jˆ1.3 Hz, CH3); 1.45±
2.18 (m, 4H); 3.57 and 3.73 (AB system, JABˆ7.0 Hz, CH2)
ppm. 19F NMR: 74.2 (s) ppm. MS (70 eV) m/e (rel.int., ion):
3.2. (1R,3S)-(‡)-3-Hydroxy-1,2,2-trimethyl-3-
trifluoromethyl-1-cyclopentanemethanol (6)
‡
‡
‡
208 (10, M ); 193 [4, ꢀM CH3† Š;193 [4, ꢀM CH3† ];
‡
‡
163 [11, ꢀM CH3 CH2O† Š; 96 (100, C7H12); 83 (50,
‡
‡
‡
A solution of (1R,4S)-( )-3-oxa-4-tri¯uoromethylcam-
phor (2) (6.3 g, 0.028 mol) in dry ether (30 ml) was added
dropwise (15 min) to a stirred suspension of LiAlH4 (1.4 g,
0.037 mol) in ether (150 ml) precooled to 2±38C under
nitrogen atmosphere (slightly exothermic reaction), then
the reaction mixture was stirred for 1 h at 5±88C after which
it was slowly (1 h) warmed up to ambient temperature.
Diluted hydrochloric acid (ca. 10%, 150 ml) was slowly
added and a two-phase mixture was stirred until the water
phase became fully transparent. The layers were separated,
the water phase was washed with ether (3Â50 ml). The
combined ether phases were washed with brine and dried
over MgSO4. Evaporation of the solvent gave a colourless
solid which was recrystallised from hexane to afford large
crystals possessing a mould like smell. Yield: 5.65 g
C6H11); 55 (15, C4H7 ); 41 (10, C3H5 ).
3.4. (1R,3S)-(‡)-1-acetoxymethyl-3-hydroxy-1,2,2-
trimethyl-3-(trifluoromethyl)cyclopentane (8)
A solution of acetyl chloride (4 g, 50 mmol) in CH2Cl2
(5 ml) was added dropwise to a stirred solution of the diol 6
(2.2 g, 10 mmol) and pyridine (4 g, 50 mmol) in CH2Cl2
(15 ml). An exothermic reaction occurred and ®ne precipi-
tate of C5H5N..HCl immediately formed. The reaction
mixture was stirred at ambient temperature for 1 h, then
poured into cold water (60 ml) and acidi®ed with hydro-
chloric acid (ca. 2 ml). The bottom organic layer was
separated, washed with water followed by 10% aqueous
NaHCO3 and again with water and dried over MgSO4.
Evaporation of the solvent gave a crystalline solid posses-
sing strong smell of acetic acid. The solid was mixed with
triethylamine (6 ml) and stirred at 40±508C for 1 h. The
homogeneous solution was poured into water (100 ml) to
(89.2%). GLC purity: 99.65%. M.p. 103±1058C. IR
22
(CCl4) (cm 1): 3338.4 and 3123.2 (br, OH). ‰ꢀŠ ˆ‡12.1
D
(cˆ5, MeOH). Analysis: Found, C, 53.2; H, 7.6; F, 25.1%.
C10H17F3O2 (226.24) requires: C, 53.1; H, 7.6; F, 25.2%.

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W. Dmowski et al. / Journal of Fluorine Chemistry 97 (1999) 97±100
‡
MS (70 eV) m/e (rel.int., ion): 268 (<1%, M ); 250
afford white precipitate which was ®ltered off and dried over
P4O10 in vacuo to give 8 (2 g, m.p. 109±1118C). Recrys-
tallization from hexane (ca. 40 ml) gave ®ne, odourless
crystals. Yield: 1.4 g (52%). GLC purity: >99%.
M.p.ˆ112±1148C. IR (CCl4) (cm 1): 1720.3(s) and
‡
‡
[6, ꢀM H2O† Š; 225 [8, ꢀM CH3O† Š; 208
‡
‡
[4,ꢀM CH3CO2H† ]; 195 [17,ꢀM CH3CO2CH2† Š; 177
‡
‡
‡
(100, C9H12F3 ); 96 (34, C7H14 ); 83 (28, C6H11 ); 71 (9,
‡
‡
‡
C4H7O ); 68 (10, C5H8 ); 55 (14, C4H7 ); 43 (60,
CH3CO ).
‡
1741.5(vs) (C=O); 3462.6 (broad, hydrogen bonded OH)
20
D
Analysis: Found: C, 53.6; H, 7.3; F, 21.25%. C12H19F3O3
and 3603.7 (sharp, free OH). ‰ꢀŠ ˆ‡9.5 (cˆ5, MeOH).
1
(268.28) requires: C, 53.7; H, 7.15; F, 21.25%. H NMR:
References
0.97 (s, CH3); 1.00 ꢀq;5 JHFˆ2.6 Hz, CH3); 1.04 (s, CH3);
1.45±1.8 (m, 1H); 1.85±2.0 (m, 1H); 2.08 (s, COCH3); 2.25±
2.4 (m, 2H); 3.95 and 4.48 (AB system, JABˆ11.0 Hz,
CH2O) ppm. The spectrum contains also two sharp signals
at 1.64 and 2.33 ppm which disappear on addition of a drop
of D2O and appear again after addition of H2O; they could
be assigned to a hydrogen bonded and free OH groups.
19F NMR : 75.3 (s) ppm.
[1] W. Dmowski, T. Kozøowski, J. Fluorine Chem. 83 (1997) 187.
[2] W. Dmowski, K. Piasecka-Maciejewska, Org. Prep. Proc. Int. 31
(1999) 207.
[3] H. Gerlach, D. Kappes, R.K. Boeckman Jr., G.N. Maw, Org.
Syntheses 71 (1993) 48.
[4] W. Dmowski, Introduction of Fluorine in Organic Compounds Using
Sulfur Tetrafluoride, in: Houben-Weyl: Methods in Organic
Chemistry, vol. E10 a, Stuttgart, 1999.