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Journal of the Chilean Chemical Society

versión On-line ISSN 0717-9707

J. Chil. Chem. Soc. v.48 n.2 Concepción jun. 2003 

J. Chil. Chem. Soc., 48, N 2 (2003)


Miguel Zárraga O., Alberto Miranda M.

Faculty of Chemical Sciences, Department of Organic Chemistry, University of Concepcion, Casilla 160-C, Concepción, Chile.
(Received: January 1, 2003 - Accepted: March 12, 2003)


The modification of camphor at C(3) by an aldolization reaction using decanal followed by oxidation of the alcohols mixture was studied. The oxidation of the alcohols mixture with sodium hypochlorite in pure ethanoic acid produces only 3-a-chloro-3-exo-decanoyl-1,7,7-trimethyl bicyclo[2.2.1]heptan-2-one.


Camphor is an important terpene for organic synthesis, characteristics such as chirality, crystallinity, and its abundance in nature, has attracted the attention of the organic chemists for some decades.1 It is possible to find several functionalities at C(3), C(5), C(8), C(9) and C(10); some other interesting building blocks for asymmetric synthesis can be obtained breaking the bonds between C(1)/(C2) y C(2)/C(3).2,3 Recent studies using metal complexes with chiral amino alcohols derived from camphor have shown good catalytic activities and high performance for asymmetric reduction of ketones4 and alkylation of aldehydes5. These kind of compounds are promissory tools for asymmetric synthesis. Recent studies show that the aldol reaction products of camphor with aromatic aldehydes at C(3) have shown to be good chiral auxiliaries for asymmetric synthesis6. This study concerns on the syntheses and subsequent oxidation of new alcohols derived from camphor as a model for a latter synthesis of chiral ligands such as 2 and 3 types. These alcohols were obtained by an aldol reaction on C(3) of racemic camphor with some aliphatic aldehydes.

Figure 1


Reactions were carried out in THF dried over sodium and benzophenone. Diisopropylamine was dried over NaOH and distilled before use. Column chromatography was carried out in silicagel (merck, 60G, particle size 40 mesh). 1H and 13C NMR spectra were recorded on a Bruker AC 250 spectrometer (250 MHz for 1H and 62.4 MHz for 13C) in CDCl3 and TMS as internal standard. Chemical shifts are expressed in delta units (ppm) and coupling constants in Hertz (Hz). FT-IR spectra were recorded on a Nicolet 550 IR spectrometer. Mass spectra were recorded on a HP 7952 GC-MS.

Endo and exo adducts of camphor with decanal

Aldolization procedure

Lithium diisopropylamide (LDA) was prepared from diisopropylamine (12.4 mL, 92.1 mmol) with n-butyllithium (51.4 mL of a 1.6 M solution in hexane, 82.24 mmol) in 30.0 mL of dry THF at -78°C. The solution was stirred for 30 min. and then a solution of camphor (12.0 g, 78.9 mmol) in dry THF (52.0 mL) was added dropwise. After the addition, the solution was stirred for 2.5 h, treated with freshly distilled aldehyde (79.0 mmol) and stirred for an additional 20 min. the reaction was quenched at -78°C with a saturated aqueous solution of NH4Cl (200 mL). The cold bath was then removed and the mixture extracted with ethyl ether (3 x 100 mL). The combined organic layers were washed with an aqueous NaCl solution, dried over Na2SO4, and concentrated in vacuum to afford the adduct mixture. The products were purified by liquid column chromatography and the adducts ratio obtained was quantified by 1H-NMR.

Oxidation with NaClO/ CH3CO2H

0.16 g (0.52 mmol) of the alcohols mixture was stirred for 12 h at 50° C with 1M (2.5 mL) aqueous solution of sodium hypochlorite and pure ethanoic acid (4mL). The products were extracted with ethyl ether (3 x 40 mL) and the organic phase was washed with distilled water and dried with anhydrous sodium sulfate. The organic fractions obtained were concentrated and the products were purified in a liquid column chromatography.

3-exo-1-hydroxydecyl-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one. (4)

1H-NMR: 4.15(1H, s), 3.90(1H, m), 2.04(1H, m), 1.97-1.91 (2H, m), 1.76-1.26 (26H, s), 0.94 (3H, s), 0.91 (3H, s), 0.88(3H, s), 0.85 (3H, s). 13C-NMR: 223.6, 73.30, 59.56, 57.84, 46.01, 36.17, 31.90, 29.61-29.31 (7CH2), 24.76, 22.67, 21.67, 20.44, 14.05, 9.04. Anal. Calcd. for C20H36O2 ; C, 77.87; H, 11.76. found. C, 77.90; H, 11, 79.

3-endo-1-hydroxydecyl-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one. (5)

1H-NMR: 3.92(1H, s), 3.74(1H, m), 2.34 (1H, m), 2.10 (1H, s), 1.77-1.69 (2H, m), 1.47-1.39 (4H, m), 1.27(8CH2, s), 0.98(3H, s), 0.92(3H, s), 0.88(3H,s), 0.85(3H, s). 13C-NMR: 223.90, 73.23, 70.89, 65.77, 59.38, 57.76, 54.88, 46.84, 45.86, 36.05, 34.82, 31.52, 29.56, 29.24, 24.67, 20.81, 19.54, 18.53, 15.20, 9.24

3-decylidene-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one. (7)

1H-NMR: 3.06 (1H5a, ddd, J = 18.2, 8.2, 6.8 Hz); 2.87 (d, 1H, J = 4.0 Hz), 2.41 (H5, ddd, b, J = 18.2, 7.95, 6.27); 0.98 (3H, s), 0.88 (3H, s), 0.79 (3H, s), 0,53 (3H, s) 2.10-1.75 (2H, m), 1.48-1.70 (2H, m). 13C-NMR: 211.0, 198.6, 75.1, 57.9, 49.5, 45.3, 36.9, 31.8, 31.6, 29.3, 29.2, 28.9, 24.0, 22.6, 20.0, 14.0, 9.8. IR (cm-1): 2927.0, 2866.3, 1754.9, 1722.7, 1458.0, 1379.5, 1115.6, 1009.3, 764.6. EM (m/z) 312, 297, 277, 188, 186, 171, 155, 143, 95, 83, 55. Anal. Calcd. for C20H36O2; C, 82.69; H, 11.80. found. C, 82.71; H, 11, 76.

3-chloro-3-decanoyl-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one. (8)

1H-NMR : 6.36 (1H, dd, J= 7.76, 7.67 Hz), 2.16-2.08 (2H, m, 1.73-1.60 (2H, m), 1.37 (2H, m, 1.26 (8CH2, s), 0.96 (6H,s), 0.90 (t, J= 8 Hz), 0.78 (s, 3H). 13C-NMR: 207.1, 142.7, 130.5, 57.7, 47.5, 45.9, 31.8, 30.3, 29.3, 28.7, 28.6(2CH2), 26.4, 22.5, 20.4, 18.2, 14.0, 9.1. MS: 186 (base peak), 312, 297,155, 83, 55. Anal. Calcd. for C20H33ClO2; C, 70.46; H, 9.76. found. C 70.42; H, 9.77.


Early literature indicates that camphor alkylation and aldol reactions give the exo (4) product mainly7. Some previous studies show that exo/ endo ratio is influenced by steric hindrance to the approach of electrophiles, produced by the 5-endo hydrogen of the lithium enolate. That fact induces an electrophilic attack to the most favored exo face. On the other hand, when the aldol reaction is carried out using 5,6-dehydrocamphor an opposite result is obtained and the observed endo/ exo ratio is near to 12:1. That confirms that H5 plays an important role in the selectivity found in the targeted reaction. Products obtained with the aliphatic substituted camphor derivatives (methyl, ethyl, 2-methylpropyl) show an exo/endo ratio lower than the found for the aromatic derivatives (3:1 and 11:1 respectively). Also kinetic factors play an important role to induce the production of the exo adducts, which can equilibrate with the endo form at the thermodynamic equilibrium.

The endo/exo ratio calculated from the integrals on the 1H-NMR spectra for the aldol reaction of camphor with decanal was equal to 2.8:1, with an overall alcohols yield of 80%. The structure of the alcohols was determined utilizing different NMR techniques and the information previously reported by other authors.7 According to the literature7, a coupling constant JH4H3a near to 1 Hz is evidence for an exo-structure (4); while a coupling constant J H4H3b of 4 Hz suggests the endo-structure (5) for the aldol reaction products. Two different JH4H3a were found in the 1H-NMR for the products of the reaction studied here; a J H4H3b equal to 4.5 Hz and 2.0 Hz for JH4H3a. These results are assigned to the endo and exo isomers respectively. To determine the absolute configuration of C3 is difficult. It is generally accepted7, 8 that the internal hydrogen bond generates two possible structures for the 3-exo isomers. Thus the stereochemistry for C1' can be partially determined according to the coupling constant J H3aH1'. Then a coupling of 7-12 Hz suggests a threo arrangement due to the anti position of the two hydrogens (4). A coupling constant of 0-4 Hz due to the erythro configuration is assigned to a gauche relationship (6). In this study the found coupling constants between H3 and H1' were 10.2 Hz for the anti threo isomer (4) and 4.5 Hz for the erythro isomer (6).

In addition, NOESY experiments supports the two structures for 3-(endo,exo)-1'-hydroxydecyl-1,7,7 trimethylbicyclo[2.2.1]heptan-2-one.

Figure 3 confirms the structure endo for (5) by the presence of a NOE effect between H3 (d 2,3 ppm), H1' (d 3.9 ppm) and the angular methyl C7 (d 0.85 ppm).

Figure 3. NOESY spectrum of 3-endo-1-hydroxydecyl-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one. (5).

To obtain b-diketones, several oxidation reactions were studied on the b-ketoalcohols using oxidation agents such as chromic acid and sodium hypochlorite in pure ethanoic acid. Swern and Collin's oxidations were also tried. However, only hypochlorite oxidation in pure ethanoic acid gives good yields of the b-diketones (80 %). When chromic acid was used compound (7) was the only product obtained.

Under the reaction conditions studied the oxidation of the alcohols mixture with hypochlorite in pure ethanoic acid gives only product (8).

Compound (8) is a colorless liquid and the IR spectrum shows two bands at n 1754,9 cm-1 and n 1722,7 cm-1 for the carbonyl groups stretching of this compound. The 1H-NMR spectrum (Figure 6) and the 1H-1H-COSY shows two groups of signals for the H5 methylenes; at d 3.15 (1H, ddd, J= 7.8, 7.6, 3.9 Hz) for H5-endo and the signal for H5-exo at d 2.51 (1Hb, ddd, J= 7.8, 7.6, 6.5 Hz). The signals d 198.8 and d 212.0 in the 13C-NMR spectrum assigned to the two carbonyls support structure (8). Moreover the DEPT (135) experiment shows a new chemical shift at d 72.2, while the signal at d 75.77 for the methine (C3) disappears. The HETCOR, DEPT and 13C-NMR experiments help to the signals assignment for all of the carbons of the bicyclic ring and a part of the lateral aliphatic chain. Thus C2 at d 36.9 show coupling with the two signals for the diasterotopic hydrogens which signals appear at d 3.15 and 2.51. Besides the protons of the syn methyl group at C9 are shielded (d 0.62), because of the proximity to exo carbonylic group at C1'. The signals for the protons at C5 and C6 are very close, H5a and H6a are at d 2.03 and H5b and H6b at d 1.73. The incorporation of a chlorine atom on the alpha face was postulated due to both the shield induced on protons of one methyl at C7 and the chemical shift of H5a and H6a to lower field due to the fact that they are on the same face with respect to the chlorine.

Figure 6. 1H-NMR of 3-chloro-3-decanoyl-1,7,7 trimethylbicyclo[2.2.1]heptan-2-one.

The GC-MS spectrum helps to support the structure (8) for the new compound found. A peak at m/z 186-188 (base peak) with isotopic abundance of 100/32.5 which is assigned to fragment (a) and in addition, a peak with m/z 155 (M-186) assigned to fragment (b) shown in Figure 7 are conclusive evidences of this structure.

A probable explanation for the formation of compound (8) lies on the fact that an acidic solution of sodium hypochlorite has a certain concentration of Cl2 at the thermodynamic equilibrium (figure 8). Chlorine can add to the double bond of the enol structure of the oxidation products. It is expected that the attack by the chlorine is on the most exposed alpha face of the enol structure, producing the intermediate showed in Figure 8. This intermediate can quickly rearrange to the more stable compound (8).

4H+(ac) + 2 Cl - + 2 ClO -(ac) = 2 Cl2(g) + 2 H2O (l)

Figure 8


The aldolization reaction of camphor is high in yield under the reaction conditions of this study. However the oxidation of the ketoalcohols with strong acids produces mainly the dehydroalkyl camphor derivative. On the other hand, good yield to 3-chloro-3-decanoyl-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (8) is obtained. Compound (8) could be an interesting intermediate to synthesize iminoketones with sustituent at C(3).


M. Zarraga O. gives special thanks to the Research Council of University of Concepcion for the support obtained through the project DIUC 97.023.013-1. A. Miranda M. thanks CONICYT for the PhD studies scholarship granted.


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