Exaltone Synthesis Essay

1H NMR spectra were obtained with a GE-Nicolet QE-Plus 300 MHz and Bruker Avance DRX 300 MHz spectrometers, using CDCl3 as solvent and TMS as internal standard, unless otherwise specified. IR spectra were obtained with a Nicolet 20DBX FT-IR instrument. Non-deuterated solvents were dried and distilled before use. The cyclic allenes 1, 7 and 11 can readily be synthesized from the corresponding cycloalkenes by the two-step protocol according to Moore and Ward, as well as Skattebol’s method by dibromocarbene addition followed by treatment of the adduct with methyllithium at −20 °C. All three cyclic allenes used in this study were previously reported in literature.30 For the dibromocarbene additions, we used the Makosza method employing a two-phase system using a phase-transfer catalyst.31 Full details for the two-step protocol are described below.

General Procedure for the Synthesis of Allenes

  1. Dibromocarbene additions: To an ice-cold solution of 20 mmol of cycloalkene, bromoform (15 g, 60 mmol), 145 mg of benzyltriethylammonium chloride (aka TEBA) and 1 mL of ethanol was added dropwise a 50% aqueous KOH solution (from 10 g KOH) was added dropwise, with efficient mechanical stirring (Hershberg-stirrer). After stirring the brown mixture for 12 hours, 100 mL of H2O was added, and the product extracted with n-hexane (5×30 mL). The combined organic extracts were washed with 30 mL of brine, dried over anhydrous Na2SO4, and the solvent rotaevaporated. The residue was purified by Kugelrohr distillation. Yields: 9,9-dibromobicyclo[6.1.0]nonane (90%), 11,11-dibromo[8.1.0]undecane (76%), 13,13-dibromobicyclo[10.1.0]tridecane (84%).

  2. Treatment of the diboromocarbene adducts with MeLi. To a solution of 20 mmol of the diboromocarbene adduct in 40 mL of anhydrous ether was added dropwise 27 mL of MeLi (38 mmol, 1.4 M) at −78 °C under a dry nitrogen atmosphere. After stirring the 15 min, the solution was allowed to warm to room temperature (22 °C). Water (40 mL was added dropwise, and the ether layer was separated, washed once with saturated NaHCO3 solution, twice with brine (each 20 mL) and dried over anhydrous Na2SO4. The solvent was rotoevaporated and the product isolated by Kugelrohr distillation.

1,2-Cyclononadiene (11, 72%), 1H NMR (300 MHz, CDCl3) δ 5.26 (m, 2H), 2.20 (m, 4H), 1.2–1.9 (m, 8H).

1,2-Cycloundecadiene (7, 68%), 1H NMR (300 MHz, CDCl3) δ 5.25 (m, 1H), 1.8–2.2 (m, 4H), 1.2–1.8 (m, 12H) ppm.

1,2-Cyclotridecatriene (1, 82%) 1H NMR (300 MHz, CDCl3) δ 5.13 (m, 2H), 2.1 (m, 4H), 1.0–1.7 (m, 16H) ppm.

Dichloroketene Additions

In a 250 mL two-necked flask equipped with a reflux condenser carrying a drying tube, and a 50 mL pressure-equalizing dropping funnel was placed a solution of 0.01 mol of cyclic 1,2-diene in 50 mL dry ether, and 1.71 g of zinc dust was added. The suspension was partially submerged in a Branson B-321 ultrasonic cleaner (50/60 Hz, 117 Volt) filled 95% with water in a place that produced maximum agitation. To this suspension, 3.05 g (0.017 mol) of freshly distilled trichloroacetyl chloride in 25 mL dry ether was added dropwise within 30 min while sonication continued. Ice was added occasionally to the water bath to maintain the bath temperature between 15–20 °C. After the completion of the reaction (ca. 60 min), it was quenched with wet ether (10 mL) and the reaction mixture suction-filtered through Celite. The filtrate was washed successively with water (2×20 mL), saturated aqueous bicarbonate (5×20 mL) and brine solution (2×20 mL). After drying the ether solution over Na2SO4, the solvent was evaporated in vacuo, and the product isolated by column chromatography on silica gel, eluting with petroleum ether/CH2Cl2 (90:10).

(E)-11,11-dichlorobicyclo[7.2.0]undec-8-en-10-one (12)

(77%); mp 62–64 °C (from pet. ether). Though this compound had been described by Brady et al., its 1H NMR was recorded on a lower resolution instrument. Below, high resolution NMR spectra of 12 and its IR data are described : 1H (300 MHz, CDCl3) δ 6.73 (ddd, J= 2.8, 6.9, 9.6 Hz, 1H), 3.43 (dm, J= 12.0 Hz, 1H), 2.2–2.5 (m, 3H), 2.1 (m, 1H), 1.7 (m, 2H), 1.3–1.6 (m, 6H) ppm; 13C NMR (CDCl3, TMS, 75 MHz) δ 187.0, 146.2, 141.7, 88.5, 58.8, 31.0, 29.3, 26.5, 25.9, 25.7, 22.6 ppm; FT-IR (KBr): 2930, 2860, 1772.5, 1660, 1457, 911, 747 cm−1.

(E)-13,13-Dichlorobicyclo[9.2.0]tridec-10-en-12-one (8)

82%; 1H NMR (CDCl3, TMS): δ 6.8 (m, 1H), 3.5 (m, 1H), 2.1–2.5 (m, 4H), 1.3–1.7 (m, 8H) ppm; FT-IR (film): 2928, 2859, 1774, 1658, 1455, 1442, 910, 751 cm−1; Anal. Calcd. for C13H18Cl2O: C 59.78; H 6.95; Cl 27.15. Found: C 59.76; H 6.94; Cl 26.96.

(E)-15,15-Dichlorobicyclo[11.2.0]pentadec-12-en-14-one (2a)

79%; 1H NMR (300 MHz, CDCl3) δ 6.8 (ddd, J= 2.9, 6.1, 10.3 Hz, 1H); 3.57 (m, 1H); 2.22 (m, 2H); 1.97 (m, 1H); 1.8 (m, 1H); 1.2–1.7 (m, 16H); 13C NMR (75 MHz, CDCl3) δ 186.3, 143.5, 142.4, 87.7, 55.9, 29.9, 27.9, 26.4, 26.1, 25.9, 25.83, 25.81, 24.6, 24.5, 24.2 ppm; FT-IR (film): 2932, 2860, 1774, 1655, 1463 and 1446 cm−1; Anal. Calcd. for C15H22Cl2O; C 62.29; H 7.67; Cl 24.51. Found C 62.26; H 7.66; Cl 24.46.

(Z)-15,15-Dichlorobicyclo[11.2.0]pentadec-12-en-14-one (2b)

11%; 1H NMR (300 MHz, CDCl3) δ 6.35 (ddd, J 2.1, 5.1, 11.6 Hz), , 3.15 (m, 1H), 3.0 (m, 1H), 2.1 (m, 2H), 1.95 (m, 1H), 1.2–1.75 (m, 16H); 13C NMR (75 MHz, CDCl3), δ 188.0, 146.5, 143.5, 86.8, 55.8, 31.0, 30.5, 27.1, 26.8, 26.2, 25.3, 25.1, 24.8, 23.7, 23.0 ppm; Anal. Calcd. for C15H22Cl2O; C 62.29; H 7.67; Cl 24.51. Found C 62.28; H 7.64; Cl 24.58.

Reductive Dechlorination of Allene-DCK cycloadducts

To a solution of 0.1 mol of the DCK- allene cycloadduct in 100 mL of methanol (previously saturated with NH4Cl) 2 g of zinc dust was added, and the mixture was stirred at room temperature overnight. The solid was removed by suction filtration, the filter cake washed with 50 mL of ether. To the filtrate, another 150 mL of ether was added, and the solution transferred to a separatory funnel and extracted sequentially with each 200 mL of water, 200 mL of brine and 100 mL of saturated aqueous NaHCO3 solution, respectively. The ethereal solution was then dried over MgSO4, and the solvent rotaevaporated to give a yellowish oil that was purified by flash chromatography (20% EtOAc/petroleum ether) on silica gel.

(E)-Bicyclo[7.2.0]undec-8-en-10-one

1H NMR (300 MHz, CDCl3): δ 6.3 (m 1H), 3.1 (dd, J= 9.0, 17.1 Hz, 1H), 2.95 (m, 1H), 2.48 (dd, 4.8, 17.1 Hz, 1H), 2.3 (m, 1H), 2.0 (m, 1H), 1.3–1.7 (m, 10H); 13C NMR (75 MHz, CDCl3): δ 199.6, 153.4, 130.3, 51.6, 37.1, 33.25, 29.8, 28.9, 27.2, 26.2, 22.9 ppm; FT-IR (neat): 2923, 2861, 1750, 1669, 1450, 1120.4, 1049 cm−1; Anal. Calcd. for C11H16O; C 80.44; H 9.82. Found: C 80.48; H 9.86.

(E)-Bicyclo[9.2.0]tridec-10-en-12-one

1H NMR (300 MHz, CDCl3): δ 6.25 (ddd, 2.47, 3.48, 12 Hz, 1H), 3.15 (m, 1H), 3.0 (dd, 8.9, 16.9 Hz, 1H), 2.56 (dd, 4.72, 16.9 Hz, 1H), 2.35 (m, 1H), 2.1 (m, 1H), 1.2–1.7 (m, 14H); 13C NMR (CDCl3, TMS, 75MHz): δ 199.3, 151.4, 131.7, 49.1, 35.1, 32.4, 26.9, 26.7, 26.1, 26.0, 24.5, 23.6 ppm; FT-IR (neat): 2925, 2860, 1751, 1656, 1469, 1445, 1122 cm−1; Anal. Calcd. for C13H20O; C 81.20; H 10.48. Found: C 81.24; H 10.45.

(E)-Bicyclo[11.2.0]pentadec-12-ene-14-one (3)

mp 39–40 °C, 1H NMR (300 MHz, CDCl3): δ 6.25 (ddd, J= 2.5, 5.4, 9.4 Hz, 1H), 3.2 (m, 1H), 3.0 (dd, J= 9.4, 17.4 Hz, 1H), 2.7 (dd, J= 5.4, 17.4 Hz, 1H), 2.15 (m, 2H), 1.9 (m, 1H), 1.2–1.7 (m, 16H); 13C NMR (75 MHz, CDCl3): δ 199.2, 150.8, 132.1, 48.6, 33.8, 31.3, 26.8, 26.7, 26.5, 26.0, 24.7, 24.6, 24.4, 23.0 ppm; FT-IR: 2927, 2856, 1749, 1663 cm−1; Anal. Calcd. for C15H24O; C 81.76; H 10.98. Found: C 81.73; H 10.94.

General procedure for the catalytic hydrogenations of the α,β-unsaturated cyclobutanones

A solution of 0.1 mol of unsaturated compound obtained by reductive dechlorination of the DCK-adduct was dissolved in 25 mL of ethyl acetate, and hydrogenated over 0.1 g of Pd/C. The progress of hydrogen uptake was monitored by means of a burette. After filtration of the catalyst, the solvent was rotaevaporated to give the fully saturated bicyclic cyclobutanone as a mixture of cis-trans isomers. Though for the TMSI-promoted cyclobutanone ring opening it was not necessary to isomerize the cis-trans mixtures to the more stable trans isomers, small amounts were subjected to base-catalyzed isomerization for characterization purposes.

General Procedure for the base-catalyzed isomerization of the cis-trans mixtures to the trans isomers

Bicyclic cyclobutanone (0.01 mol) dissolved in 5 mL of methanol was added dropwise to a solution of 0.5 g of KOH in 10 mL of methanol at 0 °C. The solution was stirred at room temperature for 30 min, then 50 mL water and 20 mL of ether were added, the payers separated, the aqueous layer extracted with two 20 mL portions of ether, the combined ether extracts dried over MgSO4 and the solvent rotaevaporated. The residue was purified by preparative TLC, eluting with 15% EtOAc/hexane.

trans-Bicyclo[7.2.0]undecan-10-one (13), 1H NMR (300 MHz, CDCl3) δ 3.0 (ddd, J= 2.1, 8.1, 16.8 Hz, 1H), 2.95 (m, 1H), 2.65 (ddd, J= 2.1, 9.3, 16.8 Hz, 1H), 2.15 (m, 1H), 2.08 (m, 1H), 1.85 (m, 1H), 1.25–1.7 (m, 12H); 13C NMR (75Hz, CDCl3) δ 199.6, 68.5, 52.6, 37.4, 35.3, 28.4, 27.9, 26.7, 26.6, 26.0 ppm; FT-IR (film): 2919, 2860, 1784, 1476, 1448, 1136 cm−1; this compound has previously been prepared by Ghosez et al.18.

trans-Bicyclo[9.2.0]tridecan-12-one (9), 1H NMR (300 MHz, CDCl3) δ 3.1 (ddd, J= 2.6, 8.8, 17.5 Hz, 1H), 2.9 (m, 1H), 2.65 (ddd, J= 2.8, 7.2, 17.5 Hz, 1H), 2.18 (m, 1H), 1.9 (2H), 1.2–1.65 (m, 16H); 13C NMR (75 MHz, CDCl3) δ 212, 66.2, 51.4, 35.3, 32.5, 27.1, 26.6, 26.2, 25.9, 25.7, 24.9, 22.9 ppm; FT-IR (film): 2929, 2859, 1778, 1459, 1445, 1160 cm−1. a cis-trans mixture of this compound has previously been reported by an alternate route, see ref. 31.

trans-Bicyclo[11.2.0]pentadecan-14-one (4), 1H NMR (300 MHz, CDCl3) δ 3.05 (ddd, J= 2.8, 8.7, 17.6 Hz, 1H), 2.85 (m, 1H), 2.6 (ddd, J= 3.3, 7.2, 17.6 Hz, 1H), 2.0 (m, 1H), 1.8 (m, 2H), 1.1–1.7 (m, 20H); 13C NMR (75 MHz, CDCl3) δ 65.3, 50.3, 36.5, 31.3, 28.2, 27.2, 26.1, 25.8, 25.7, 25.5, 25.4, 25.1, 23.9 ppm; FT-IR (film): 2930, 2861, 1779, 1462, 1450 1150 cm−1. Anal. Calcd. for C15H26O: C 81.02; H 11.79. Found: C 81.06; H 11.77.

General Procedure for the Synthesis of the cyclic enones

Cyclobutanone (1mmol) was dissolved in 2 mL of CCl4 and 150 mg of Hg was added. The mixture was kept under an argon atmosphere while freshly distilled TMSiI (0.6 g, 3 mmol) was added, and the mixture stirred for 2 hr. The mixture was then diluted with 25 mL of ether, and washed with 5% Na2SO3, followed by 5 mL of NaHCO3, dried and the solvent rotaevaporated. The βiodocycloalkanone was dissolved in 10 mL of dry CH2Cl2 and 1 mmol of DBU was added dropwise at 0 °C. The solution was stirred for 30 min at room temperature, then 10 mL of H2O was added, the organic layer washed successively with 5% HCl and NaHCO3, the solution dried over MgSO4, the filtrate rotaevaporated, and the residue purified by column chromatography on silica gel (15%EtOAc/hexane) to give the macrocyclic enone. During the TMSI promoted ring opening reaction of 9, a small aliquote was isolated and analyzed by 1H NMR spectrum. The β-iodocyclotridecanone derivative was clearly discernible in the spectrum due to the caharacteristic 3° β-hydrogen at 4.3 ppm (m, 1H), and the α-CH2 group exhibting an AB system at 2.7 (dd, J= 9.2, 17.2 Hz, 1H) and 2.15 (dd, J= 7.0, 17.2 Hz, 1H).

(E)-Cycloundec-2-enone (14), (67%)

1H NMR δ 6.8 (dt, J= 7.8, 16.5 Hz, 1H), 6.15 (dt, J= 1.2, 16.5 Hz), 2.6 (t, J= 6.6 Hz, 2H), 2.25 (m, 2H), 1.66 (m, 4H), 1.3 (m, 12H); 13C NMR (75 MHz, CDCl3) δ 205.5, 149.1, 134.3, 37.3, 33.9, 28.1, 26.4, 26.1, 23.9, 23.0, 22.4 ppm; FT-IR (film): 2931, 2859, 1690, 1668, 1165, 1463,1445, 1212, 985 cm−1; see ref 33.

(E)-Cyclotridec-2-one (10)

75%; 1H NMR (300 MHz, CDCl3) δ 6.8 (dt, J= 7.5, 15.3 Hz, 1H), 6.15 (dt, J= 1.2, 15.3 Hz, 1H), 2.45 (m, 2H), 2.2 (m, 2H), 1.67 (m, 2H), 1.53 (m, 2H) 1.2–1.3 (m, 12H); 13C NMR (75 MHz, CDCl3) δ 204.1, 149.3, 132.8, 39.2, 33.4, 27.4, 27.3, 26.9, 26.7, 26.6, 26.1, 25.9, 25.8 ppm; FT-IR (film): 2972, 2924, 2865, 1689, 1659. 1622, 1464, 1442, 1387, 1350, 1119, 912.6, 740 cm−1; see ref. 34.

(E)-Cyclopentadec-2-one (5)

73%; All spectral data were identical to those reported in literature, see refs. 3, 35.

d,l-Muscone (6)

Dried CuI (2.8 g, 14.7 mmol) was placed in a 50 mL two-necked round-bottomed flask, equipped with a magnetic stir bar and a rubber septum. Dry ether (25 mL) was added to the flask and the mixture was cooled to ca. −25 °C under an argon atmosphere. To the stirred suspension was added MeLi (23 mL of a 1.18 M ethereal solution, 26.7 mmol) with stirring. The mixture was stirred for 30 min, a solution of enone 5 (1g, 45 mmol) in 10 mL of ether was added over a period of 25 min. The mixture was stirred for 1h at −25 °C, and 25 mL of H2O and 3N HCl were added. The mixture was extracted with 3×25 mL of ether, the combined extracts were washed washed with NaHCO3 solution, then Na2SO3 solution, and finally with brine. After drying over MgSO4, the solvent was rotaevaporated. The resulting yellowish oil was purified by column chromatography on silica gel, eluting with 15% EtOAc/pet.ether to give 1.1 g of d,l-muscone (85%), identical in all respects to an authentic sample.

Reaction of 12 with NaOMe

(E)-11,11-dichlorobicyclo[7.2.0]undec-8-en-10-one (1g, 4.3 mmol) was dissolved in 20 mL of MeOH. This solution was added dropwise to a NaOMe solution (preformed from 0.2g, 8.3 mmol of Na and 20 mL of MeOH) at 0 °C. Upon addition, the color of solution immediately turned red. The mixture was stirred at 0 °C for 30 min, then heated to 50 °C for 1h. It was poured onto 100 mL of ice-water, acidified with 10% HCl, extracted with 3×50 mL of ether,. the combined ether extracts were dried over MgSO4, the solvent rotaevaporated, and the yellowish waxy material was purified by column chromatography on silica gel (15%EtOAc/pet.ether) to give two products.

(E)-11,11-dimethoxybicyclo[7.2.0]undec-8-en-10-one (16), 13%

1H NMR (300 MHz, CDCl3) δ 6.6 (ddd, J= 2.9, 7.4, 9.6 Hz, 1H), 3.5 (s, 3H), 3.3 (s, 3H), 3.0 (m, 1H), 2.35 (m, 2H), 2.0 (m, 2H), 1.4–1.7 (m, 8H); 13C NMR (75 MHz, CDCl3) δ 194.0, 147.8, 138.3, 121.9, 52.9, 51.6, 51.2, 30.4, 29.6, 26.7, 26.5, 26.4, 22.5 ppm; Anal. Calcd. for C14H22O2: C 75.63; H 9.97. Found: C 75.60; H 9.95.

(Z)-11,11-dimethoxybicyclo[7.2.0]undec-7-en-10-one (15), 65%

1H NMR (300 MHz, CDCl3) δ 5.73 (dd, J= 6.8, 10.5 Hz, 1H), 5.56 (ddt, J= 1.7, 6.2, 10.5 Hz, 1H), 3.85 (dd, J= 6.8, 10.8 Hz, 1H), 3.4 (s, 3H), 3.3 (s, 3H), 2.2 (m, 2H), 2.1 (m, 2H), 1.85 (5, 1H), 1.2–1.7 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 204.7, 133.1, 125.3, 58.5, 53.5, 50.4, 46.7, 27.5, 27.1, 26.6, 26.0, 21.8 ppm; FT-IR (film): 3012, 2931, 2861, 2834, 1785, 1445, 1256, 1210, 1125, 1078, 1044, 997, 909, 797, 727 cm−1; Anal. Calcd. for C14H22O2: C 75.63; H 9.97. Found: C 75.65; H 9.96.

Silvanone Supra (Givaudan): a mixture of cyclopentadecanone and cyclohexadecanone
Romanone Extra (ACL Aromatics)

synonyms: nor-muscone, apo-muscone

Natural identical (found in muskrat).

Not to be confused with Exaltenone or Exaltolide.

White crystals.

Warm, diffusive musky, extremely fine, faceted, powdery, animal, greasy, natural musk-like odour.

Quite similar in odour to muscone, but more powerful and animal.

Nitromusks are sometimes defined as “animal”. While I quite agree on the fact that they possess a musk deer facet (they are warm and powdery, but also radiant, with some musky floralness) they don’t possess a truely dirty, greasy character.

Exaltone strikes with its greasy, warm animal musky odour.

@10% it is less dirty, more nuanced, somewhat metallic and much more similar to his brother muscone, or to exaltolide.

@1% finer. Best dilution. Every facet blooms and one can fully appreciate its elegant details: quite powdery, sort of ‘metallic’ (in a way that it recalls me of exaltolide), but still quite greasy and softly animal.

It is quite pricey, but is worth its weight in gold. I definitely love this molecule. And actually it costs about 3 times more than muscone (about the price of a jasmine absolute). This is the most astounding musk odourant I’ve ever smelled.

It was first synthesized in the 20’s (1926 patent, Chuit & Naef, Firmenich today) by L. Ruzicka, in an attempt to find a good substitute for natural musk. Exaltone is chemically very close to muscone; it only has one methyl function less.

In the 1927 “Notice sur l’Exaltone et autres produits à odoeur de musc”, it is explained why the name ‘Exaltone’ was chosen:

L’effet produit par l’exaltone dans une composition est le même que celui provoqué par le musc : son odeur s’allie merveilleusement à celle des autres produits de la composition et, contrairement à ce qui se produit avec l’emploi du “musc artificiel”, le résultat forme un ensemble des plus harmonieux; c’est justement en raison de sa propriété heureuse non seulement d’affiner, mais également et surtout d’exalter le parfum des compositions, que nous lui avons donné le nom d’exaltone.

Exaltone is capable of ‘exalting’ a composition and this property seemed to make this product a valuable candidate for replacing natural musk.

Reading this booklet one could get the feeling that natural musk extracts were not much prized for their “animal” odour, they would also have introduced unwanted, ammoniacal, rotting notes. The interest was in the smoothing, exalting effect coming from their musky odourants (such as muscone or civettone). A feeling that I also get when working with civet. However I am convinced that animal, greasy, dirty notes are sometimes really wanted and synthetical musks wouldn’t suffice alone (I am thinking about cuir, leather fragrances, or old chypres).

Muscone and Exaltone seem at first quite different products, olfactively. The odour of muscone when pure is almost difficult to perceive (as many other musks). Exaltone, on the other hand, is a solid at room temperature and its odour when smelled pure is strongly musky, animal and greasy and quite powerful.

However, upon dilution the differences are smoothed down. They are quite similar, indeed. Muscone is rounder and, obviously, more true-to-nature. Exaltone, very similar to muscone, powdery, musky, rather sweet, has darker tones, a greasy accent and nice projection.

Interesting enough, Exaltone was eventually found in nature in the muskrat glands.

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