Reactions of carboxyl derivatives of camphor with sulphur tetrafluoride

Article abstract of DOI:10.1016/S0022-1139(00)00242-6

Treatment of a mixture of endo- and exo-(1R)-3-camphorcarboxylic acid (1) with sulphur tetrafluoride gave initially, (1R)-3-(fluoroformyl)camphor (2) and (1R)-2,2-difluoro-3-(fluoroformyl)bornane (3) but after prolonged reaction time, a mixture of endo- and exo-(1R)-3-(trifluoromethyl)camphor (4) was obtained, albeit in low yield. Carboxylic groups in (1S)-ketopinic and (1R)-trans-isoketopinic acids (5) and (9) were found to be resistant towards SF₄ such that at ambient temperature only corresponding acid fluorides (6) and (10) were obtained but under forced conditions fluorination of the carbocyclic ring carbonyl group occurred affording, respectively, (1S)-2,2-difluoro-1-fluoroformyl-7,7-dimethylbicyclo[2,2,1]heptane (7) and (1R)-2,2-difluoro-trans-7-fluoroformyl-1,7-dimethylbicyclo[2,2,1]heptane (11). Hydrolysis of 7 and 11 gave the corresponding acids 8 and 12.

Full text of DOI:10.1016/S0022-1139(00)00242-6

Journal of Fluorine Chemistry 104 (2000) 273±276
Reactions of carboxyl derivatives of camphor
with sulphur tetra¯uoride
Wojciech Dmowski*, Krystyna Piasecka-Maciejewska
Institute of Organic Chemistry, Polish Academy of Sciences, 01-224 Warsaw, Poland
Received 15 February 1999; received in revised form 14 February 2000
Abstract
Treatment of a mixture of endo- and exo-(1R)-3-camphorcarboxylic acid (1) with sulphur tetra¯uoride gave initially, (1R)-3-
(¯uoroformyl)camphor (2) and (1R)-2,2-di¯uoro-3-(¯uoroformyl)bornane (3) but after prolonged reaction time, a mixture of endo- and exo-
(1R)-3-(tri¯uoromethyl)camphor (4) was obtained, albeit in low yield. Carboxylic groups in (1S)-ketopinic and (1R)-trans-isoketopinic
acids (5) and (9) were found to be resistant towards SF4 such that at ambient temperature only corresponding acid ¯uorides (6) and (10)
were obtained but under forced conditions ¯uorination of the carbocyclic ring carbonyl group occurred affording, respectively, (1S)-2,2-
di¯uoro-1-¯uoroformyl-7,7-dimethylbicyclo[2,2,1]heptane (7) and (1R)-2,2-di¯uoro-trans-7-¯uoroformyl-1,7-dimethylbicyclo[2,2,1]hep-
tane (11). Hydrolysis of 7 and 11 gave the corresponding acids 8 and 12. # 2000 Elsevier Science S.A. All rights reserved.
Keywords: 3-Camphorcarboxylic acid; Ketopinic acid; Isoketopinic acid; Fluorination; Sulphur tetra¯uoride; (1R)-3-(Tri¯uoromethyl)camphor; (1S)-2,2-
di¯uoro-7,7-dimethylbicyclo[2,2,1]heptane-1-carboxylic acid; (1R)-2,2-di¯uoro-1,7-dimethylbicyclo[2,2,1]heptane-trans-7-carboxylic acid
1. Introduction
camphor-carboxylic acid (1) was less successful. Treatment
of 1 (endo/exoˆca. 3:1) with SF4 at ambient temperature for
24 h resulted mostly in conversion of the carboxylic group
into a ¯uoroformyl group and, to much less extent in
¯uorination of the carbonyl group; a mixture of (1R)-3-
(¯uoroformyl)camphor (2) and (1R)-2,2-di¯uoro-3-(¯uoro-
formyl)bornane (3) in a 10:1.6 ratio was formed almost
quantitatively. When the reaction was run for a prolonged
time (7 days) a dark oily tar was formed from which, after
treatment with aqueous alkaline solution a mixture of endo-
and exo-(1R)-3-(tri¯uoromethyl)camphor (4) was isolated
but only in ca. 18% yield. The endo/exo ratio of 4 was
roughly the same as that of the starting acid 1 thus con-
®rming retention of the con®guration at the carbon atom C-3
during the ¯uorination reaction. The endo and exo con®g-
urations of the CF3 group in 4 (and of the COOH group in 1)
Terpenes are versatile, chiral and enantiopure staring
materials in natural product synthesis [1]. In the preceding
papers we reported that a sulphur tetra¯uoride ¯uorination
of (1R,3S)-(‡)-camphoric acid [2,3] and (1S,4R)-( )-cam-
phanic acid [4] proceeds selectively, i.e. only sterically less
hindered carboxyl groups were converted into tri¯uoro-
methyl groups: (1R,3S)-(‡)-3-(tri¯uoromethyl)-camphona-
nic acid and (1S,4R)-( )-3-oxa-4-(tri¯uoromethyl)-
camphor were obtained, respectively, in good yields. These
compounds were converted into a number of new tri¯uor-
omethyl derivatives with the de®ned steric con®guration.
The present paper reports results of the continued study on
¯uorination of carboxyl derivatives of camphor.
1
were unambiguously assigned from their H NMR spectra:
2. Results and discussion
in the endo form a coupling between H-3 and H-4 protons
appears which is absent in the exo form. The coupling
constants (Jˆ4.6 and 0 Hz, respectively) are in agreement
with values obtained by semiempirical modelling (MOPAC
6, PCMODEL).
In contrast to the earlier reported reactions of camphoric
and camphanic acids with SF4 which gave good yields of
tri¯uoromethyl derivatives [2±4], ¯uorination of (1R)-3-
The long reaction time did not gave detectable amount of
penta¯uorobornane which should result from the ¯uorina-
tion of both carboxylic and keto groups; probably steric
crowding in compound 3 prohibits further ¯uorination.
* Corresponding author. Fax: ‡48-22-632-66-81.
E-mail address: dmowski@icho.edu.pl (W. Dmowski)
0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 0 ) 0 0 2 4 2 - 6

274
W. Dmowski, K. Piasecka-Maciejewska / Journal of Fluorine Chemistry 104 (2000) 273±276
It appears that carboxylic groups in acids 5 and 9 are even
less reactive towards SF4 than the carbonyl group at the
highly sterically crowded position 2 of the bornane mole-
cule. In both above cases the carboxylic groups are bound
to tertiary carbon atoms. Similarly low reactivity was
previously reported for a-branched aliphatic acids, e.g.
trimethylacetic, isobutyric and others [5,6].
3. Experimental
Melting points were determined in capillaries and boiling
points were measured during distillation; both are uncor-
rected. 1H and 19F NMR spectra were recorded with a Varian
Gemini 200 spectrometer at 200 and 188 MHz, respectively.
Chemical shifts are quoted in ppm from internal TMS for 1H
(positive down®eld) and from internal CFCl3 (positive
up®eld). The crude mixture of products was analysed with
a Shimadzu GC-14A Chromatograph using a 3.5 mÂ2 mm
column packed with 5% silicone oil SE-52 on Chromosorb
G. GC-MS analyses were performed with a Hewlett-Pack-
ard 5890 apparatus using a 30 m capillary column coated
with a HP-5 oil. Mass spectra of pure compounds were
obtained with an AMD-604 spectrometer and IR spectra
with a Perkin-Elmer Spectrum 2000 instrument. Optical
rotations were measured at ambient temperature with a
JASCO DIP-360 polarimeter using a 100 mm cell.
Interestingly, introduction of the CF3 group into a cam-
phor molecule drastically changes its physical properties. In
contrast to unsubstituted camphor, which is a high melting
crystalline solid (mp ca. 1808C), 3-(tri¯uoromethyl)cam-
phor (4) is at room temperature a viscous oil.
The carboxylic groups in ketopinic acid (5) and isoke-
topinic acid (9) were found to be unexpectedly unreactive
towards SF4. Thus, treatment of the acid 5 with SF4 at room
temperature overnight gave ketopinoyl ¯uoride (6) almost
quantitatively and as the only product. When the reaction
time was prolonged to 10 days a complex mixture was
formed with 2,2-di¯uoro-1-¯uoroformyl-7,7-dimethylbicy-
clo[2,2,1]heptane (7) being the main product (GC-MS
identi®cation). The latter was isolated, after hydrolysis,
as 2,2-di¯uoro-7,7-dimethylbicyclo-[2,2,1]heptane-1-car-
boxylic acid (8).
3.1. Starting materials
Sulphur tetra¯uoride was a technical grade commercial
product (Air Products, USA).
(1R)-3-camphorcarboxylic acid (1) was synthesizsed
from (1R)-(‡)-camphor by following the literature proce-
dure [7]; according to the 1H NMR analysis a 3:1 mixture of
endo and exo forms was obtained, mp 124±1268C (Lit.
1288C for the endo form [7]); [a]Dˆ‡41.2 (cˆ10, MeOH).
(1S)-(‡)-ketopinic acid (5) was prepared by oxidation of
(1S)-(‡)-10-camphorsulphonyl chloride [8]; mp 232±
2338C (Lit. 237±2408C [9]); [a]Dˆ‡26.1 (cˆ10, MeOH),
in agreement with literature data [10].
(1R)-trans-isoketopinic acid (9) was prepared in six
stages from (1R)-(‡)-camphor. Camphor was brominated,
®rst to endo-3-bromocamphor then to 3,8-dibromocamphor
which was debrominated to 8-bromocamphor [11]. The next
three steps involved a conversion of 8-bromocamphor to 8-
acetylcamphor followed by hydrolysis to 8-hydroxycam-
phor [12,13] and oxidation of the latter [13]; mp 252±2558C
(Lit. 257±2588C [14]).
Isoketopinic acid (9) appears to be even less reactive than
ketopinic acid (5); the reaction conducted for 6 days at room
temperature gave isoketopinoyl ¯uoride (10) and 2,2-
di¯uoro-7-¯uoroformyl-1,7-dimethylbicyclo[2,2,1]heptane
(11) in a 3.5:1 ratio. In contrast to 5, which when reacted at
elevated temperatures produced only black tar, acid 9 was
successfully ¯uorinated at 1008C to give acid ¯uoride (11)
almost quantitatively. Hydrolysis of the crude reaction
mixture afforded 2,2-di¯uoro-1,7-dimethylbicyclo[2,2,1]-
heptane-7-carboxylic acid (12) in a 86 % yield.
3.2. Reactions of carboxylic acids with sulphur
tetrafluoride
3.2.1. General procedure
An acid was placed in a 30 ml capacity stainless steel
autoclave ®tted with a needle valve, the autoclave was

W. Dmowski, K. Piasecka-Maciejewska / Journal of Fluorine Chemistry 104 (2000) 273±276
275
cooled in an acetone-dry ice bath, evacuated, then sulphur
tetra¯uoride was condensed into it. The autoclave was
mechanically agitated at ambient temperature (ca. 208C)
for the required time. After completion of the reaction,
gaseous products were let off (excess SF4, SOF2, HF), the
residue was dissolved in CH2Cl2, agitated overnight with
dry sodium ¯uoride (removal of HF) then the solvent was
removed on a rotary evaporator to give a crude mixture of
products.
exo-(1R)-3-(tri¯uoromethyl)camphor (4b): 1H NMR
(200 MHz, in CDCl3) d: 0.90 (s, CH3); 0.96 (s, CH3);
3
0.99 (s, CH3); 1.45±1.9 (m, 4H); 2.43 (d, JHHˆ4.1 Hz,
1H); 2.72 (q, 3JHFˆ11.3 Hz, 1H) ppm. 19F NMR (188 MHz,
3
in CDCl3) d: 60.8 (d, JHFˆ11.3 Hz, CF3). GC-MS: iden-
tical with endo isomer.
3.2.3. Reactions of (1S)-(‡)-ketopinic acid (5) with SF4
3.2.3.1. Preparation of (1S)-ketopinoyl fluoride (6). (1S)-
(‡)-ketopinic acid (1.82 g, 10 mmol) and SF4 (7 g,
65 mmol) were reacted at ambient temperature for 20 h
and worked up as in Section 3.2.1. Evaporation of the
solvent gave a colourless and odourless crystalline
product. GLC analysis showed basically one component.
Yield: 1.73 g (95%). GLC purity>92%. IR (CCl4) (cm 1):
1831 (vs, COF); 1757.8 (vs, CO). MS (70 eV) m/e (rel. int.,
3.2.2. Reactions of (1R)-3-camphorcarboxylic acid (1)
with SF4
3.2.2.1. Preparation of compounds 2 and 3. The acid
(2.0 g, 10 mmol) was reacted with SF4 (3.5 g, 30 mmol)
at ambient temperature for 24 h and worked up as in Section
3.2.1. GC-MS analysis of the crude product (1.8 g, dark oil)
showed the presence of compounds 2 and 3 in a 10:1.6 ratio.
IR (film) n (cm 1): 1833.7 (vs, COF); 1755.3 (vs, CO).
(1R)-3-(¯uoroformyl)camphor (2): GLC yield: 78%. GC-
‡
‡
ion): 184 (86, M ); 169 [57, (M CH3) ]; 164 [100,
‡
‡
(M HF) ]; 141 [27, (M CO CH3) ]; 136 [41,
‡
(M HF CO) ].
‡
MS m/z (rel. int., ion): 198 (trace, M ); 152 [35,
‡
‡
(M COF) ]; 109 (50, C8H13 ); 108 (30); 95 (100,
‡
3.2.3.2. Preparation of (1S)-(‡)-2,2-difluoro-7,7-
dimethylbicyclo[2,2,1]heptane-1-carboxylic acid (8).
(1S)-(‡)-ketopinic acid (1.82 g, 10 mmol) and SF4 (7 g,
65 mmol) were reacted at ambient temperature for 10 days
and worked up as in Section 3.2.1 to give a dark oil (2.2 g).
GC-MS analysis revealed the presence of eight components
with highest m/e ions: 208 (C10H15F3O, one minor
component), 206 (C10H13F3O, two compounds), 246
(C10H12F6, two compounds), 228 (C10H13F5, two
compounds) and 278 (probably C10H12F6S). The oil was
dissolved in n-hexane (20 ml) and agitated with 5% aqueous
KOH for 2 h. GC-MS showed the disappearance of one
component with molecular ion 206 (compound 7, the
most abundant one). The aqueous layer was separated,
boiled for a few minutes with charcoal and filtered.
Acidification with concentrated hydrochloric acid gave a
white±gray precipitate which was filtered off and
recrystallised from n-hexane/CHCl3 (2:1) to give
colourless crystals. Yield: 0.27 g (13%). Mp ca. 2608C
(subl.). IR (nujol) (cm 1): 1708.6 (vs, CO). [a]Dˆ‡ 8.8
(cˆ1.4, MeOH).
‡
‡
‡
C7H11 ); 83 (C6H11 ); 81 (C6H9 ); 67 (50, C5H7 ); 55
‡
‡
(45, C4H7 ); 41 (75, C3H5 ).
(1R)-2,2-di¯uoro-3-(¯uoroformyl)bornane (3): GLC
‡
yield: 11%. GC-MS m/z (rel. int., ion): 220 (10, M );
‡
‡
200 [20, (M HF) ]; 153 [20, (M HF COF) ]; 132
‡
‡
‡
(30, C6H6F2O ); 117 (C5H3F2O ); 103 (100, C4HF2O );
‡
‡
‡
90 (40, C3F2O ); 77 (40, C3H3F2 ); 51 (20, CHF2 ).
3.2.2.2. Preparation of endo- and exo-(1R)-3-
(trifluoromethyl)camphor (4). The acid (2.0 g, 10 mmol)
was reacted with SF4 (3.5 g, 30 mmol) at ambient
temperature for 7 days and worked up as in Section
3.2.1. A solution of crude product in CH2Cl2 was
decanted from NaF and vigorously shaken with saturated
aqueous Na2CO3, then with water and dried over MgSO4. A
dark residue obtained after removal of the solvent (1.4 g)
was vacuum distilled to give a colourless oil possessing a
1
irritant terpenic odour. This oil was found by GC-MS, H
and 19F NMR analyses to be a mixture of endo and exo
isomers of 4 in a ca. 3:1 ratio. Yield: 0.41 g (18.6%). Bp
788C/5 Torr. IR (film) n (cm 1): 1758.1 (vs, CO).
Analysis: Found, C, 58.6; H, 7.0; F, 18.6%. C10H14F2O2
20
D
1
‰aŠ ˆ‡28.2 (cˆ5, MeOH). Analysis: Found: C, 60.0; H,
(204.22) requires: C, 58.8; H, 6.9; F, 18.6 %. H NMR
7.0; F, 25.8%. Calculated for C11H15F3O (220.23): C, 59.99;
H, 6.86; F, 25.88%.
(200 MHz, in DMSO): 1.06 (s, CH3); 1.15 (d, 5JHFˆ2.5 Hz,
CH3); 1.28 (complex, 1H); 1.65±2.0 (complex, 5H); 2.28±
2.45 (complex, 1H); 12.55 (broad s, COOH) ppm. 19F NMR
(188 MHz, in DMSO): AB system centered at 83.5
(JABˆ225 Hz) ppm.
endo-(1R)-3-(tri¯uoromethyl)camphor (4a):1H NMR
(200 MHz, in CDCl3) d: 0.90 (s, CH3); 0.96 (s, CH3);
3
1.04 (s, CH3); 1.45±1.9 (m, 4H); 2.38 (t, JHHˆca.
‡
3
3
4.5 Hz, 1H); 3.14 (qdd, JHFˆ10.5 Hz, JHHˆ4.6 Hz,
5JHHˆ1.0 Hz, 1H) ppm. 19F NMR (188 MHz, in CDCl3)
d: 61.9 (d, 3JHFˆ10.5 Hz, CF3). GC-MS m/z (rel. int., ion):
MS (70 eV) m/e (rel. int., ion): 204 (<1, M ); 184 [72,
‡
‡
‡
‡
(M HF) ]; 169 [23, (M HF CH3) ]; 142 (41,
C7H7FO2 ); 141 [83, (M F CO2) ]; 140 [69,
‡
‡
‡
‡ ‡
220 (10, M ); 205 [1, (M CH3) ]; 192 [2, (M CO) ]; 177
(M HF CO2) ]; 139 [100, (M HF CO2H) ]; 125 [31,
‡ ‡ ‡
(M HF CO2 CH3) ]; 97 (52, C7H13 ); 83 (27, C6H11 );
‡
‡
‡
[25, (M Me CO) ]; 108 (20, C8H12 ); 95 (40, C7H11 );
‡
‡
‡
‡
‡
‡
83 (100, C6H11 ); 69 (90, CF3 ); 55 (80, C4H7 ); 41 (95,
‡
77 (25, C3H3F2 ); 55 (24, C4H7 ); 43 (18, C3H7 ); 41 (26,
‡
C3H5 ).
C3H5 ).

276
W. Dmowski, K. Piasecka-Maciejewska / Journal of Fluorine Chemistry 104 (2000) 273±276
3.2.4. Reactions of (1R)-trans-isoketopinic acid (9) with
SF4
and SF4 (3.5 g, 32 mmol) were reacted under conditions
as in Section 3.2.4.2. The solid product was dissolved in
ether (5 ml), the solution was added to 10% aqueous KOH
and a two-phase mixture was vigorously stirred overnight
then charcoal was added, the mixture was boiled for a while
and filtered while hot. Acidification of the filtrate gave a
white precipitate which was filtered off, washed with water
and dried under vacuo over P4O10. Analytical sample was
obtained by recrystallization from hexane. Yield: 0.38 g
3.2.4.1. Preparation of compounds 10 and 11. (1R)-trans-
Isoketopinic acid (0.9 g, 5 mmol) and SF4 (2 g, 20 mol)
were reacted at ambient temperature for 6 days and worked
up as in Section 3.2.1. A colourless crystalline product was
obtained. GC-MS analysis (in Et2O solution) showed two
components in a 3.5:1 ratio which were identified,
‡
respectively, as isoketopinoyl fluoride (10) [m/e 184 M ;
‡
(86%). Mp ca. 2208C (subl.). IR (nujol) n (cm 1): 1704.2
20
D
156 (M CO) ] and (1R)-2,2-difluoro-7-fluorocarbonyl-
‡
(vs, COOH). ‰aŠ ˆ 14.5 (cˆ5, MeOH).
1,7-dimethyl-bicyclo[2.2.1]heptane (11) [m/e 206 M ;
‡
Analysis: Found: C, 58.6; H, 6.2; F, 18.55%. C10H14F2O2
(204.22) requires: C, 58.8; H, 6.1; F, 18.6%. 1H NMR
(200 MHz, in DMSO-d6) d: 1.15 (d, Jˆ0.3 Hz, CH3);
1.18 (d, Jˆ2.3 Hz, CH3); 1.2±1.4 (complex, 1H); 1.4±1.9
(complex, 4H); 2.29 (m, 1H): 12.4 (broad, COOH) ppm.
19F NMR (188 MHz, in DMSO-d6) d: 89.0 and 107.3 (AB
system, JABˆ228 Hz, CF2) ppm. GC-MS (rel. int., ion): 282
186 (M HF) ]. IR (10 and 11 in CCl4) (cm 1): 1837.3
(vs, COF); 1755.0 (vs, CO). Total yield: 0.9 g (ca. 96%).
3.2.4.2. Preparation of (1R)-2,2-difluoro-7-fluorocarbonyl-
1,7-dimethylbicyclo- [2,2,1]heptane (11). (1R)-trans-
Isoketopinic acid (0.9 g, 5 mmol) and SF4 (3.5 g, 32 mmol)
were reacted at 1008C for 4 days (96 h) to give a yellow
crystalline solid which was shown by GLC to be 92%
pure 11. Analytical, colourless sample was obtained by
recrystallisation from acetone with charcoal added. Yield:
0.95 g (85%); 0.4 g (40%) after recrystal-lisation. Mp ca.
165±1708C (intense sublimation). IR (CCl4) n (cm 1):
1837.3 (vs, COF). Analysis: Found: C, 58.0; H, 6.5; F,
27.7%. C10H13F3O (206.21) requires: C, 58.25; H, 35; F,
27.64 %. 1H NMR (200 MHz, in CDCl3) d: 1.25 (t,
Jˆ1.5 Hz, CH3); 1.38 (d, Jˆ2.1 Hz, CH3); 1.4±2.0
(complex, 5H); 2.2±2.5 (complex, 2H) ppm. 19F NMR
(188 MHz, in CDCl3) d: 34.4 (d, Jˆ1.9 Hz, COF); 89.1
and 107.8 (AB system, JABˆ229 Hz, CF2) ppm. MS (70 eV)
‡
‡
‡
(3, M ); 263 [10, (M F) ]; 213 [100, (M CF3) ].
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‡
‡
‡
(M F) ]; 186 [100, (M HF) ]; 171 [22, (M HF CH3) ];
‡
‡
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‡
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‡
(M 3HF) ]; 139 [(M COF HF) ], 127 (63); 119 [77,
‡
‡
(M COF 2HF) ]; 111 (98); 77 (38, C3H3F2 ); 55 (22,
‡
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‡
C4H5 ); 41 (17, C3H5 ).
3.2.4.3. Preparation of (1R)-( )-2,2-difluoro-1,7-
dimethylbicyclo[2,2,1]heptan-trans-7-carboxylic acid
(12). (1R)-trans-isoketopinic acid (0.39 g, 2.17 mmol)
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