Syntheses in the isocamphane series XLII [1]. Synthesis and odour of 5-exo-hydroxycamphene (isonojigiku alcohol)

Article abstract of DOI:10.1007/PL00013494

The synthesis of the title compound is described. Hydroxylation of the endocyclic double bond of 2-acetyl-3,3-dimethylnorborn-5-ene furnished a mixture of nojigiku alcohol and the title compound. A shorter route leads from 2,5-norbornadiene solely to the desired camphoraceous smelling new hydroxy derivative to which the name isonojigiku alcohol is assigned.

Full text of DOI:10.1007/PL00013494

Monatshefte fuÈr Chemie 129, 865±870 (1998)
Syntheses in the Isocamphane Series
XLII [1]. Synthesis and Odour of 5-exo-
Hydroxycamphene (Isonojigiku Alcohol)
Ã
and Andreas Wachter
Gerhard Buchbauer , Helmut Spreitzer, Ursula Koller, Irmtraud Bauer,
Institute of Pharmaceutical Chemistry, University of Vienna, A-1090 Vienna, Austria
Summary. The synthesis of the title compound is described. Hydroxylation of the endocyclic double
bond of 2-acetyl-3,3-dimethylnorborn-5-ene furnished a mixture of nojigiku alcohol and the title
compound. A shorter route leads from 2,5-norbornadiene solely to the desired camphoraceous
smelling new hydroxy derivative to which the name isonojigiku alcohol is assigned.
Keywords. 2-Acetyl-3,3-dimethylnorborn-5-ene; Bicyclo[2.2.1]heptane derivatives; Fragrance
compounds; Nojigiku alcohol; Odour.
Synthesen in der Isocamphanreihe, 42. Mitt. [1]. Synthese und Geruch von
5-exo-Hydroxycamphen (Isonojigikualkohol)
Zusammenfassung. Die Synthese des bisher unbekannten 5-exo-Hydroxycamphens wird beschrie-
ben. Hydroxylierung der Doppelbindung in 2-Acetyl-3,3-dimethylnorborn-5-en fuÈhrt zu einem
Gemisch der beiden isomeren Camphenalkohole Nojigikualkohol und der Titelverbindung. Ein
kuÈrzerer Syntheseweg, ausgehend von 2,5-Norbornadien, fuÈhrt ausschlieûlich zur camphrig
riechenden Titelverbindung, die mit Isonojigikualkohol bezeichnet wird.
Introduction
In the preceding paper of this series [1] we have described the synthesis of 7-syn-
hydroxycamphene (1) which-on account of its warm, soft, and pleasant
camphoraceous odour-could be a valuable constituent in fragrance compositions,
especially of the woody type. Another hydroxycamphene compound, nojigiku
alcohol (6-exo-hydroxycamphene, 2) has been shown to be an important olfactory
component of ¯oral perfumes and fragrance compositions [2], especially because
of its ``good aroma'' [3]. Besides its odour qualities, 2 was also found to be a
suitable starting compound for the preparation of ꢀ-campholenic aldehyde (3) [4]
from which many important synthetic sandalwood odorants can be obtained [5].
Therefore, it is not surprising that an economic synthesis of 2 has already been
Ã
Corresponding author

866
G. Buchbauer et al.
developed [6]. However, not only 1 and 2 are valuable for perfumery purposes, but
also 1-hydroxycamphene (4) has been said to impart a pleasant fresh note to a
perfume on account of its camphoraceous odour [7, 8]. Finally, also the synthesis
of 4-hydroxy-camphene (5) has been described, but no olfactive properties given
[9, 10]. Therefore, it seems logical to synthesize the ``missing link'' in the series of
hydroxycamphenes, the hitherto unknown 5-exo-hydroxycamphene (6) to which
we want to assign the name isonojigiku alcohol and to evaluate its olfactive
properties.
Results and Discussion
2-Acetyl-3,3-dimethylnorborn-5-ene as starting substance
The easy access of 2-acetyl-3,3-dimethylnorborn-5-ene (7) by a Diels-Alder
reaction of mesityl oxide and cyclopentadiene [11] and the versatility of this
synthon for the preparation of a lot of biologically active compounds like fragrants
(e.g. Ref. [12]), fungicides (e.g. Ref. [13]), or pharmaca (e.g. Ref. [14]) prompted
us to use 7 in the synthesis of the target compound 6 as well. However, several
attempts to prepare 5-hydroxycamphene (6) via hydroxylation of the endocyclic
double bond of 7 followed by the already established reaction sequence to
transform the side chain of 7 into the exocyclic double bond [1, 15] failed. An
unseparable 1:2 mixture of the corresponding 5-hydroxy- and 6-hydroxy-
dimethylnorbornane compounds was obtained using different hydroxyl protecting
groups (e.g. MEM ether [16], pivaloyl ester [17]. Attempts to remove the MEM
group from the corresponding MEM-camphene 8 furnished either 8 again or
destroyed the molecule [16]. Also, various attempts to obtain pure 2 and 6 by
chromatographical procedures proved to be useless. By HPLC, the 3,5-
dinitrobenzoate ester mixture of 2 ‡ 6 could be separated into its single esters
indeed, but only on an analytical scale [17]. Multifold TLC on silica gel coated
plates (0.25 mm) yielded only some mg of 2 but not the target molecule 6 [17].
Therefore, the idea to use synthon 7 for the preparation of this new terpenic alcohol
proved to be impracticable and had to be dismissed.

5-exo-Hydroxycamphene
867
8: R ˆ MEM
2,5-Norbornadiene as starting substance
Because of the dif®culties concerning the separation of the isomeric hydroxy
derivatives, a strategy introducing the hydroxyl function selectively at C5 had to be
developed. For this purpose, the commercially available bicyclo[2.2.1]heptadiene
(9) proved to be the ideal starting material, because it could easily be transformed
into the hydroxy ketone 11 via the 2,5-bis-exo-diol 10 with already correct
positions of the functional groups at C2 and C5 [18, 19]. Hydroboration of 9 [20]
with subsequent careful Jones oxidation furnished 5-exo-hydroxynorbornan-2-one
(11). Before the next step, the geminal dimethylation, the hydroxyl group had to be
protected which was performed using dihydropyrane, thus affording the
tetrahydropyranyl ether 12. This protecting group permits the application of basic
conditions and can be removed without dif®culties [21]. Geminal dimethylation in
position 3 of the bicyclus using CH3I/lithium cyclohexyl-isoproylamide/THF
furnished a mixture of mono- and (mainly) dialkylated norbornanone derivative
after 18 h of re¯ux which could be separated by preparative DC. By transformation
of the keto function of 13 into the exocyclic methylene group using Tebbe's reagent
[22], a titanium-aluminum complex especially suited for sterically hindered
ketones [23], we obtained the hydroxy derivative 14. Cleavage of the tetrahydro-
pyranyl ether with PPTS/EtOH [21] ®nally yielded isonojigiku alcohol (6).
6 possesses a not markedly pronounced camphoraceous odour with dry
woody notes, not comparable with the warm, soft, and pleasant odour of 7-syn-
hydroxycamphene (1) or with its isomer 6-exo-hydroxycamphene (nojigiku
alcohol, 2).
Experimental
1H NMR spectra: Bruker AM 400 WB (400.13 MHz) and Bruker AC-80 (80 MHz), TMS, ꢁ in ppm;
13C NMR spectra: Bruker AM 400 WB (100.61 MHz); IR spectra: Perkin Elmer-237, Perkin Elmer

868
G. Buchbauer et al.
FT-IR-Spektrometer Spectrum 2000, ꢂ in cmꢀ1; mass spectra: Hewlett Packard MSD (GC: 5890;
MS: 5970); TLC: PSC-Fertigplatte Merck Art. Nr. 13793, silica gel 60 F254S with concentration
zone, 20 Â 20 cm, layer thickness 2 mm, concentration zone 4 Â 20 cm; DC aluminum foil,
Merck Art. Nr. 5717, silica gel 60 F254, 20 Â 20 cm, layer thickness 0.2 mm; for further details, see
Ref. [24].
5-exo-Hydroxybicyclo[2.2.1]heptan-2-one (11)
Compound 11 was prepared according to Ref. [18]. 9.20 g (100 mmol) bicyclo[2.2.1]hepta-2,5-diene
(9), 100 ml dry THF, 100 ml borane-THF complex (100 mmol), 40 ml of a 2 M NaOH solution in
water, 40 ml 30% H2O2; yield of 10: 12.1 g (94.5%), white crystals, m.p.: 183±184ꢁC (Ref. [18]:
183.5±184.5ꢁC), C7H12O2 (128.08). 0.50 g (3.89 mmol) 10, 50 ml acetone, 1.8 ml of a 2 M CrO3
solution in 30% H2SO4; puri®cation of crude 11: column chromatography on silica gel 60, solvent
system: diethyl ether/methanol (100 ml/10 drops); yield of 22: 0.23 g (46%), colourless oily liquid,
1
C7H10O2 (126.07). IR (NaCl, liquid ®lm): 3430, 2974, 1744 cmꢀ1; H NMR (80 MHz, CDCl3):
ꢁ ˆ 1.71 (m, 3H), 1.86 (br s, 1H), 2.00 (m, 3H), 2.52 (m, 2H), 4.02 (d, 1H) ppm; 13C NMR (CDCl3):
ꢁ ˆ 33.5 (CH2), 35.4 (CH2), 39.9 (CH2), 43.1 (CH), 48.9 (CH), 7.22 (CH), 217.2 (C ˆ O) ppm; MS:
‡
m/z (%) ˆ 126 (M ; 59), 108 (8), 97 (12), 82 (100), 79 (35), 70 (14).
5-(O-Tetrahydropyranyl)-bicyclo[2.2.1]heptan-2-one (12)
0.6 g (4.76 mmol) ketoalcohol 11 were dissolved in 33 ml dry dichloromethane und mixed slowly
with 0.65 ml (7.14 mmol) dried dihydropyrane at room temperature. After addition of 0.12 g
(0.48 mmol) PPTS and stirring for 6 h, the mixture was extracted with diethyl ether, followed by
washing the ether extracts with brine and drying over MgSO4. After evaporation of the solvent, 0.9 g
(90%) of 12 were obtained .
C12H18O3 (210.28); IR (NaCl, liquid ®lm): 2943, 1751 cmꢀ1 1H NMR (80 MHz, CDCl3):
;
ꢁ ˆ 1.56±1.94 (m, 13H), 2.74 (m, 1H), 3.45 (m, 1H), 3.86 (m, 2H), 4.63 (d, 1H) ppm; 13C NMR
(CDCl3): ꢁ ˆ 19.7 (CH2, C-40), 25.4 (CH2, C-50), 31.0 (CH2, C-30), 33.9 (CH2), 34.2 (CH2), 39.4
(CH, C-4), 40.4 (CH2, C-3), 48.7 (CH, C-1), 62.8 (CH2, C-60), 75.9 (CH, C-5), 97.5 (CH, C-20),
‡
215.1 (C, C-2) ppm; MS: m/z (%) ˆ 210 (M ; 2), 192 (1), 168 (1), 126 (3), 109 (13), 85 (100), 81
(25), 67 (17).
3,3-Dimethyl-5-(O-tetrahydropyranyl)-bicyclo[2.2.1]heptan-2-one (13)
0.38 ml (2.33 mmol) cyclohexylisopropylamide in 8 ml dry THF were slowly mixed with 1.4 ml
(2.24 mmol) of a 1.6 M suspension of n-butyllithium in n-hexane at ꢀ10ꢁC under argon and warmed
up to ambient temperature. Then, 0.27 g (1.36 mmol) 5-(O-tetrahydropyranyl)-bicyclo[2.2.1]heptan-
2-one (12) und 0.21 ml (3.41 mmol) methyliodide were added at room temperature and re¯uxed for
18 h. Subsequent hydrolyzation with saturated ammonium chloride solution, extraction with diethyl
ether, and drying over Na2SO4 was followed by evaporation of the solvent. The same procedure was
repeated in order to obtain a geminal methylation. Puri®cation: prep. TLC, solvent system. ligroin/
EtOAc ˆ 80/20, twofold development.
Yield: 0.4 g (90%); oily liquid; C14H22O3 (238.33); IR (NaCl, liquid ®lm): 2943, 1748,
1454 cmꢀ1; 1H NMR (80 MHz, CDCl3): ꢁ ˆ 1.02 (s, 3H), 1.03 (s, 3H), 1.48±1.85 (m, 12H), 3.44 (m,
13
1H), 3.81 (m, 2H), 4.58 (d, 1H) ppm; C NMR (CDCl3): ꢁ ˆ 19.4 (CH2, C-40), 21.2 (CH3, C-200),
23.4 (CH3, C-300), 25.5 (CH2, C-50), 31.2 (CH2, C-30), 33.1 (CH2), 37.4 (CH2), 43.2 (CH), 48.3 (CH),
61.5 (C, C-3), 63.3 (CH2, C-60), 78.1 (CH, C-5), 98.1 (CH, C-20), 219.4 (C, C-2) ppm; MS: m/z
‡
(%) ˆ 238 (M ; 1), 210 (1), 196 (1), 154 (4), 109 (9), 85 (100), 71 (5), 67 (15).

5-exo-Hydroxycamphene
869
3,3-Dimethyl-2-methylene-5-(O-tetrahydro-pyranyl)-bicyclo[2.2.1]heptane (14)
0.28 g (1.18 mmol) 13 were dissolved in 4 ml of dry THF and cooled to 0ꢁC. Then, 2.36 ml
(2.36 mmol) of a 0.5 M suspension of Tebbe's complex in toluene were added and stirred for 30 min
at 0ꢁC and 5.5 h at room temperature. Upon addition of 15 ml diethyl ether and 20 drops of methanol,
the solution reacts vigorously under precipitation of a yellow, viscous precipitate. This was ®ltered
through Celite1 and washed with about 60 ml of diethyl ether. Subsequent column chromatography
over Al2O3 with diethyl ether as eluent and ®nally evaporation of the solvent furnished 0.24 g (88%)
of crude 14 as a yellow residue which was puri®ed by prep. TLC. (ligroin/diethyl ether ˆ 90/10,
twofold development).
C15H24O2 (236.36); IR (NaCl, liquid ®lm): 3068, 2959, 1663, 877 cmꢀ1; 1H NMR (400.13 MHz,
CDCl3): ꢁ ˆ 1.00 (s, 6H), 1.45±1.90 (m, 12H), 3.43 (m, 1H), 3.82 (m, 2H), 4.13 (d, 1H), 4.43 (s, 1H),
13
4.67 (s, 1H) ppm; C NMR (CDCl3): ꢁ ˆ 20.0 (CH2, C-40), 25.5 (CH2, C-50), 25.52 (CH3), 29.4
(CH3), 31.4 (CH2, C-30), 34.1 (CH2), 39.1 (CH2), 40.1 (C, C-3), 44.8 (CH), 47.4 (CH), 62.9 (CH2, C-
60), 79.3 (CH, C-5), 97.3 (CH, C-20), 101.3 (CH2, C-100), 164.6 (C, C-2) ppm; MS: m/z (%) ˆ 236
‡
(M ; 1), 194 (1), 135 (5), 199 (2), 107 (11), 85 (100), 77 (5), 67 (11).
3,3-Dimethyl-2-methylene-bicyclo[2.2.1]heptan-5-ol (6) (5-exo-hydroxycamphene)
A solution of 0.1 g THP ether 14 in dry ethanol was mixed 0.01 g (0.04 mmol) of PPTS and stirred
for 3 h at 55ꢁC (external temperature). After evaporation of the solvent, the residue (0.104 g, 80%)
was puri®ed by sublimation.
White needles with a camphoraceous and dry woody odour; m.p.: 60±63ꢁC; C10H16O (152.31);
1
IR (NaCl, liquid ®lm): 3320, 3065, 2959, 877 cmꢀ1; H NMR (400.13 MHz, CDCl3): ꢁ ˆ 1.00 (s,
6H), 1.32±1.91 (m, 7H), 2.65 (s, C1-H), 4.55, 4.71 (2s, 2H, ˆ CH2), 3.73 (m, HC-OH) ppm; 13C
NMR (CDCl3): ꢁ ˆ 25.3 (CH3), 29.4 (CH3), 29.7 (CH2, C-7), 33.4 (CH2, C-6), 41.5 (C, C-3), 46.0
(CH), 56.1 (CH), 70.3 (CH, C-5), 100.1 (CH2, C-100), 160.0 (C, C-2) ppm; MS: m/z (%) ˆ 152
‡
(M ; 10), 137 (11), 121 (12), 108 (96), 93 (100), 77 (5).
Acknowledgements
È
The authors are grateful to Mr. W. Hoppner and Mr. V. Hausmann (chief perfumers of Dragoco,
Vienna) for the olfactoric evaluation of the target compound and to their company for the interest in
our work.
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Received January 30, 1998. Accepted (revised) March 16, 1998