The Search For Innovative Fragrant Molecules: B 2008 Verlag Helvetica Chimica Acta Ag, Zdrich
The Search For Innovative Fragrant Molecules: B 2008 Verlag Helvetica Chimica Acta Ag, Zdrich
The Search For Innovative Fragrant Molecules: B 2008 Verlag Helvetica Chimica Acta Ag, Zdrich
5 (2008) 1083
An overview of the recent research subjects in the perfumery field and, more precisely the synthesis
of novel compounds for the hesperidic family of odorants, is presented. The new derivatives possess very
different structures; nevertheless, they all share an aldehydic odor, but with diverse nuances, which make
them all attractive for different purposes.
Scheme 1
then further reduced to the alcohols 1. Following this reaction scheme, alcohols 1b and
1c were obtained, using vinylmagnesium bromide and isopropenylmagnesium bromide,
respectively (Scheme 2).
Scheme 2
However, this elegant synthesis was not so easy to perform. It was essential to avoid
methods involving Hg to obtain the intermediate vinyl ethers, and the alternative
methods with Pd catalysts required well-purified alcohols 2. Unfortunately, whereas the
Grignard reactions proceeded cleanly with total conversion, the purification by
distillation happened to be difficult, leading to by-products (presumably due to
polymerization of the allylic alcohols), lowering the yield dramatically. At that point, it
was actually found that the alcohols 1 were not very interesting, possessing only slightly
sandalwood or vague woody odors. However, the intermediate aldehydes 3 were found
to be far more interesting, emanating intense aldehydic, floral, non-woody odors.
It was, therefore, necessary to investigate this substance class further, and to
prepare other aldehydes of that kind, but other routes needed to be developed to
CHEMISTRY & BIODIVERSITY – Vol. 5 (2008) 1085
achieve an easy access to the differently substituted target molecules. Finally, two
rather simple routes with possible industrial scale-up were found interesting to obtain
the desired compounds. The first one of them involved a Wittig reaction, and the first
compound prepared that way was aldehyde 3b (FleurenalH ; Scheme 3). The ylide of
phosphonium salt 4, easily obtained from commercially available 4-chlorobutanenitrile,
was condensed with campholenic aldehyde to provide intermediate nitrile 5b, as a 9 : 1
(Z)/(E)-mixture. The nitrile 5b was further reduced by diisobutylaluminum hydride
(DIBAL-H) to furnish aldehyde 3b in 36% overall yield. Compound (þ)-3b has also
been prepared from (þ)-(R)-campholenic aldehyde with a similar yield, without
significant change in the power or character of the odor.
Scheme 3
Half-hydrogenated nitrile 5’b and its corresponding aldehyde 3’b, derived from
hydrogenated campholenic aldehyde were also prepared with similar yields. Starting
from the same phosphonium salt 4, the methylated aldehyde 3c was prepared in a
similar manner. Prior to the Wittig reaction, phosphonium salt 4 was alkylated with
MeI, and 3c was obtained as a 1 : 1 (Z)/(E)-mixture in 30% overall yield (Scheme 4).
Scheme 4
The alternative pathway consisted in preparing fully hydrogenated nitriles 5’’ via
malonic ester synthesis with cyanoacetic acid and a suitable carbonyl compound 6,
obtained by aldolization from campholenic aldehyde (Scheme 5). Prior to reduction
with DIBAL-H to the target aldehydes, the intermediate diene nitriles were fully
1086 CHEMISTRY & BIODIVERSITY – Vol. 5 (2008)
Scheme 5
reduced to 5’’. Thus were obtained saturated aldehydes 3’’ in overall yields between 20
and 25%.
Starting from aldehydes 3, a variety of other derivatives were also prepared. Thus,
diethyl acetals 7b and 7’’d (see below) were obtained from 3b and 3’’d, respectively.
Aldehyde 3’’c was methylated by known methods to give 3’’e [8], and ketone 8 was
synthesized by reacting MePh3PBr with nitrile 5b (Scheme 6) [9].
Scheme 6
Finally, although we did not achieve an interesting sandalwood odorant, this project
afforded many new molecules, from nitriles to aldehydes and their acetals, with a wide
odor range, from typically aldehydic odorants to derivatives with floral, marine, or even
animalic aspects (see Table 1).
well as the design of new phosphine ligands, allow relatively mild reaction conditions
and provide excellent chemo- and regioselectivities in this highly atom-efficient
process. Thus, the terminal C¼C bond of 9 should undergo hydroformylation with
introduction of a valuable CHO function.
Hence, 5,7-dimethylocta-1,6-diene (9) was treated under a CO/H2 atmosphere in
the presence of a Rh catalyst and a suitable ligand to give a mixture of aldehydes 10
(NoreenalH ) and 11 (Scheme 7).
By tuning the catalyst or the ligand, the ratio of linear vs. branched aldehyde (10/11
ratio) could be modified, and using, for instance, bis-(h4-cycloocta-1,5-diene)di-m-
methoxydirhodium(I) as catalyst and XantphosH as ligand, under 30 bars of syngas
(equimolar CO/H2 mixture) at 70 – 808, gave almost exclusively the linear derivative
10 in 75% yield. This aldehyde has a very intense aldehydic odor in the mandarin
range.
1088 CHEMISTRY & BIODIVERSITY – Vol. 5 (2008)
Scheme 7
When using monophosphine ligands such as Ph3P, the selectivity towards the linear
products was reduced, and a mixture enriched in 11 was obtained. Fine distillation
furnished purely the branched isomer 11, which was found greener in smell, reminiscent
of citronella and parsley. Other derivatives were then prepared from NoreenalH (10)
and its hydrogenation product 10’ (obtained in 96% yield by hydrogenation over Pd/C),
including alcohols, esters, and acetals (Scheme 8). Thus, alcohols 12 and 12’ were
obtained by reduction of 10 and 10’, respectively, with NaBH4 in 73 and 54% yield.
Scheme 8
CHEMISTRY & BIODIVERSITY – Vol. 5 (2008) 1089
Compounds 12 and 12’ were further esterified to provide in 76% the acetates 13a and
13’a, respectively, and the propanoate 13b was prepared from 12 in 71% yield. The
different acetals 14 and 14’ were also obtained in good yields from 10 and 10’,
respectively. The saturated acetals 14’ have also been prepared by hydrogenation of the
corresponding acetals 14 in quantitative yields.
Similarly, derivatives of the branched aldehyde 11 were synthesized, such as 2,5,7-
trimethyloct-6-en-1-ol and 2,5,7-trimethyloct-6-en-1-yl acetate [11]. All those novel
derivatives possess various interesting and nice aldehydic odors, with green, floral, or
fruity aspects as compiled in Table 2.
So, this project gave also birth to unexpected interesting aldehydic odorants with
green or fruity aspects. These derivatives have a major advantage over the common
aldehydes perfumery raw materials: they are less fragile than the latter.
1090 CHEMISTRY & BIODIVERSITY – Vol. 5 (2008)
Scheme 9
In conclusion, the aldehydic family of odorants has been enriched with new
interesting compounds possessing very different structures – a valuable benefit to the
field of perfumery. These compounds are likely to find their way into many different
applications, as, furthermore, their novel nuances make them very attractive in
enhancing floral, marine, or fruity compositions.
Experimental Part
General. All reagents and solvents were commercially available, and were used without any further
purification, unless otherwise mentioned. GC: HP 6890 with a polar DBWAX-FF column. IR Spectra:
Biorad fts-155 spectrophotometer. NMR Spectra: Bruker 200 MHz instrument in CDCl3 . MS: Normag
quadrupole RIO-IC spectrometer.
6-(2,2,3-Trimethylcyclopent-3-enyl)hex-4-enenitrile (5b). A suspension of (3-cyanopropyl)triphenyl-
phosphonium chloride (365.8 g, 1 mol; readily prepared by reaction between Ph3P and 4-chlorobuta-
nenitrile), K2CO3 (276 g, 2 mol), commercial campholenic aldehyde (180 g, 1.02 mol), and a cat. amount
of PhCOOH (6.1 g, 0.05 mol) in toluene (1.5 l) was refluxed for 24 h. The mixture was then cooled down
and filtered. The filtrate was washed twice with warm H2O, dried (MgSO4 ), and the solvents were
evaporated to afford an oily crude product, which was triturated with t-BuOMe to precipitate most of the
phosphine oxide. After filtration, the solvents were evaporated, and the crude oil was distilled.
Compound 5b (136 g, 0.67 mol, 67%) was obtained as a 9 : 1 (Z)/(E)- mixture of isomers. B.p. 98 – 1008/
0.76 – 0.79 Torr. IR (neat): 798m, 1013w, 1360m, 1444m, 1463m, 1653w, 2246w, 2835m, 2866s, 2895s, 2930s,
2956s, 3013w, 3035w.
CHEMISTRY & BIODIVERSITY – Vol. 5 (2008) 1091
Data of (Z)-5b: 1H-NMR (CDCl3 ): 0.83 (s, 3 H); 1.03 (s, 3 H); 1.6 – 1.65 (m, 3 H); 1.75 – 1.95 (m,
2 H); 1.95 – 2.4 (m, 3 H); 2.4 – 2.55 (m, 4 H); 5.2 – 5.3 (m, 1 H); 5.35 – 5.7 (m, 2 H). 13C-NMR (CDCl3 ):
13.02; 17.93; 20.13; 23.76; 26.28; 28.32; 35.93; 47.15; 50.66; 119.82; 212.99; 125.57; 133.51; 148.83.
Data of (E)-5b: 1H-NMR (CDCl3 ; selected data): 0.80 (s, 3 H); 1.01 (s, 3 H). 13C-NMR (CDCl3 ):
18.14; 28.81; 33.69; 50.41; 122.08; 126.41; 134.25; 148.89. EI-MS (70 eV): 203 (10, M þ ), 188 (100), 171
(38), 160 (19), 147 (35), 133 (19), 121 (31), 109 (83), 108 (91), 107 (26), 105 (24), 95 (26), 94 (31), 93
(44), 91 (44), 81 (19), 79 (40), 77 (33), 55 (36), 53 (27), 41 (72), 39 (26). Odor description: slightly
woody (cedarwood), floral.
(þ)-6-[(1R)-2,2,3-Trimethylcyclopent-3-enyl]hex-4-enenitrile ((þ)-5b). Prepared from (þ)-(R)-
campholenic aldehyde (152 g, 1 mol) in 62% yield as described for 5b. [a]D ¼ þ 1.92 (neat).
6-(2,2,3-Trimethylcyclopentyl)hex-4-enenitrile (5’b). Prepared from 2H-dihydrocampholenic alde-
hyde (25 g, 0.163 mol) in 56% yield as described for 5b. The product was obtained as a 9 : 1 (Z)/(E)-
mixture. B.p. 828/0.02 Torr. IR (neat): 1367m, 1388w, 1428m, 1453m, 1465m, 1660w, 1710w, 1727w, 2247m,
2870s, 2955s, 3013m.
Data of (Z)-5’b: 1H-NMR (CDCl3 ): 0.53 (s, 3 H); 0.82 (d, J ¼ 6.7, 3 H); 0.88 (s, 3 H); 1.05 – 1.25 (m,
2 H); 1.25 – 1.55 (m, 2 H); 1.55 – 1.90 (m, 3 H); 2.05 – 2.25 (m, 1 H); 2.27 – 2.47 (m, 4 H); 5.20 – 5.40 (m,
1 H); 5.45 – 5.65 (m, 1 H). 13C-NMR (CDCl3 ): 13.82; 14.33; 17.47; 23.24; 25.60; 28.13; 28.27; 29.85; 44.97;
50.89; 119.34; 124.67; 133.30.
Data of (E)-5’b: 1H-NMR (CDCl3 , selected data): 0.50 (s, 3 H); 0.84 (s, 3 H). 13C-NMR (CDCl3 ):
12.54; 17.67; 19.65; 25.80; 27.84; 28.01; 33.69; 35.45; 50.18; 50.52; 119.34; 125.05; 133.03. EI-MS (70 eV):
205 (1, M þ ), 190 (7), 188 (4), 162 (8), 148 (13), 134 (8), 120 (6), 111 (72), 109 (18), 95 (24), 84 (33), 70
(22), 69 (100), 67 (25), 55 (38), 41 (41). Odor description: not powerful, floral (HelionalH,
FloralozoneH ).
4-Methyl-6-(2,2,3-trimethylcyclopent-3-enyl)hex-4-enenitrile (5c). To a suspension of (3-cyanopro-
pyl)triphenylphosphonium chloride (180 g, 0.49 mol) in THF (0.6 l) was added portionwise t-BuOK
(60.8 g, 0.54 mol). After stirring at r.t. for 30 min, the mixture was cooled down (ice bath) before slowly
adding MeI (34 ml, 0.54 mol). The mixture was stirred for a further h, and another equiv. of t-BuOK
(60.8 g, 0.54 mol) was added portionwise. After stirring at r.t. for another h, campholenic aldehyde (97 g,
0.55 mol) was added, and the mixture was further stirred overnight. The mixture was poured into 1 : 1
H2O/t-BuOMe (600 ml). The separated aq. layer was acidified and extracted three times with t-BuOMe
(200 ml). The combined org. layers were washed twice with H2O (200 ml), then with sat. aq. NaHCO3
(250 ml) and with brine (250 ml). After drying (MgSO4 ), the solvents were evaporated, and the crude
product was purified by distillation. B.p. 104 – 1068/0.7 – 0.8 Torr. Compound 5c was obtained as a 1 : 1
(Z)/(E)-mixture (52 g, 42%). IR (neat): 799m, 1013w, 1356m, 1382w, 1445m, 1462m, 1691w, 2246w,
2835m, 2866m, 2930s, 2956s, 3036w. 1H-NMR (CDCl3 ): 0.79 (s, 3 H); 0.99 (s, 3 H); 1.58 – 1.63 (m, 3 H);
1.63 – 2.53 (m, 12 H); 2.41 (s, 3 H); 5.2 – 5.25 (m, 1 H); 5.25 – 5.38 (m, 1 H). 13C-NMR (CDCl3 ): 12.57;
15.64/15.84; 16.31/22.72; 19.68; 25.84/25.87; 27.56; 28.36/28.5; 35.07; 35.48/35.52; 46.68; 50.34/50.53;
119.47/119.52; 121.56/121.69; 127.43/128.48; 130.79/130.9; 148.41/148.49. EI-MS (70 eV): (Z)-5c: 217 (12,
M þ ), 202 (19), 185 (13), 146 (12), 122 (45), 121 (93), 109 (100), 108 (93), 107 (83), 95 (31), 93 (48), 91
(48), 81 (63), 79 (54), 77 (35), 67 (76), 55 (37), 53 (34), 41 (66), 39 (23). (E)-5c: 217 (15, M þ ), 202 (27),
185 (5), 146 (10), 122 (54), 121 (100), 109 (99), 108 (100), 107 (90), 95 (33), 93 (48), 91 (50), 81 (64), 79
(53), 77 (35), 67 (75), 55 (35), 53 (33), 41 (61), 39 (22). Odor description: slightly anisic, fruity.
4-Methyl-6-(2,2,3-trimethylcyclopentyl)hexanenitrile (5’’c). 2-Methyl-4-(2,2,3-trimethylcyclopent-3-
enyl)but-2-enal (83 g, 0.43 mol) was reacted at r.t. with CNCH2COOH (36.7 g, 0.43 mol) in the presence
of 2,6-lutidine (4.6 g, 0.043 mol) and ammonium acetate (2 g, 0.026 mol) to provide 4-methyl-6-(2,2,3-
trimethyl-cyclopent-3-enyl)hexa-2,4-dienenitrile (76% crude yield). After removal of the less-volatile
by-products, a soln. of 4-methyl-6-(2,2,3-trimethylcyclopent-3-enyl)hexa-2,4-dienenitrile was hydro-
genated in EtOH under H2 pressure (P(H2 ) ¼ 20 bars; r.t.) over 5% Pd/C (10 g) to provide 5’’c (55 g,
55%). B.p. 958/0.07 Torr. IR (neat): 1365m, 1385w, 1427w, 1465m, 2246w, 2869s, 2955s. 1H-NMR
(CDCl3 ): 0.49 (s, 3 H); 0.82 (d, J ¼ 6.7, 3 H); 0.85 (s, 3 H); 0.91 (2d, J ¼ 6.3, 3 H); 1.0 – 1.8 (m, 13 H); 2.25 –
2.42 (m, 2 H). 13C-NMR (CDCl3 ): 13.91/14.43; 14.93/15.0; 18.77/19.06; 25.68/25.72; 27.5/27.69; 28.24/
28.38; 30.13; 32.1/32.27; 32.55; 35.35/35.65; 42.32; 45.24; 50.85/51.17. EI-MS (70 eV): 221 (3, M þ ), 206
1092 CHEMISTRY & BIODIVERSITY – Vol. 5 (2008)
(6), 204 (9), 178 (18), 84 (100), 83 (26), 70 (56), 69 (83), 55 (58), 41 (45). Odor description: Sweet,
gourmand, not powerful.
4-Ethyl-6-(2,2,3-trimethylcyclopentyl)hexanenitrile (5’’d). Prepared as described for 5’’c, from 2-
ethyl-4-(2,2,3-trimethylcyclopent-3-enyl)but-2-enal (41 g, 0.2 mol, prepared from campholenic aldehyde
and propanal). Compound 5’’d was obtained as a 7 : 3 mixture of isomers (20 g, 40%). B.p. 1128/0.03 Torr.
IR (neat): 1118w, 1244w, 1367m, 1384w, 1461m, 1738w, 2247w, 2869s, 2956s. 1H-NMR (CDCl3 ; common
signals): 0.46 (s, 3 H); 0.7 – 0.9 (m, 9 H); 0.9 – 1.5 (m, 12 H); 1.5 – 1.85 (m, 3 H); major isomers: 2.27 (t, J ¼
7.4, 2 H); minor isomers: 2.54 (t, J ¼ 7.2, 2 H). 13C-NMR (CDCl3 ): Major isomers: 10.18/10.52; 13.73/
13.76; 14.27; 14.52/14.66; 24.72/25.16; 25.54/25.58; 27.0/27.27; 28.19/28.23; 28.58/28.83; 29.97/30.04; 31.31/
31.39; 38.05/38.25; 42.12/42.15; 45.08/45.11; 50.93/51.14; 119.89; minor isomers (selected data): 10.55/
10.88; 25.46/25.92; 26.97/27.05; 30.68/31.02; 39.12/39.23; 50.99. EI-MS (70 eV): 235 (1, M þ ), 220 (3), 192
(10), 84 (162), 83 (26), 70 (67), 69 (89), 55 (49), 41 (43). Odor description: orris, carrot, powdery, plastic.
4-Methyl-6-(2,2,3-trimethylcyclopentyl)hex-3-enenitrile. (5’’’c). Prepared as described for 5’’c from 2-
methyl-4-(2,2,3-trimethylcyclopentyl)butanal (60 g, 0.306 mol, obtained from 2-methyl-4-(2,2,3-trime-
thylcyclopent-3-enyl)but-2-enal by hydrogenation (5% Pd/C, EtOH, 40 bars H2 )). Compound 5’’’c was
obtained as a 4 : 6 mixture of isomers (31.5 g, 47%). B.p. 958/0.03 Torr. IR (neat): 920w, 1049w, 1366m,
1386m, 1418w, 1453m, 1466m, 1669w, 1754w, 2250w, 2869s, 2954s. 1H-NMR (CDCl3 ): 0.49 (s, 3 H); 0.75 –
0.9 (m, 6 H); 0.9 – 1.4 (m, 5 H); 1.4 – 1.6 (m, 2 H); 1.6 – 2.1 (m, 3 H); 1.65 (s, 3 H); 3.03 (d, J ¼ 6.9, 2 H);
5.1 – 5.2 (m, 1 H); minor isomer (selected data): 1.73 (d, J ¼ 1.3, 3 H). 13C-NMR (CDCl3 ): Major isomer:
13.82; 14.37; 16.16; 16.39; 25.56; 28.04; 28.46; 30.05; 38.4; 42.25; 45.11; 50.29; 111.11; 118.63; 142.96.
Minor isomer: 13.82; 14.37; 16.02; 16.39; 23.13, 28.15; 28.25; 28.46; 31.13, 38.4; 42.31; 45.19; 50.61; 111.72;
118.63; 143.09. EI-MS (70 eV): Major isomer: 219 (1, M þ ), 204 (5), 179 (8), 124 (9), 109 (26), 95 (16), 84
(67), 83 (32), 81 (17), 70 (44), 69 (100), 67 (26), 55 (40), 41 (49); minor isomer: 219 (1, M þ ), 204 (7), 124
(15), 109 (69), 95 (23), 84 (49), 83 (26), 82 (36), 81 (20), 70 (35), 69 (100), 67 (30), 55 (39), 41 (48).
Odor description: Woody (sandalwood), lactonic, a bit animalic.
6-(2,2,3-Trimethylcyclopent-3-enyl)hex-4-enal (3b, FleurenalH ). A 1m soln. of DIBAL-H in toluene
(355 ml, 0.355 mol) was added dropwise to a soln. of 5b (60 g, 0.295 mol) in toluene (100 ml) at such a
rate that the temp. remained under 408. After complete addition, the soln. was heated at 808 for 2 h. The
hydrolysis was carefully performed pouring the reaction soln. into a mixture of AcOH (60 g) and ice
(400 g). The aq. layer was extracted twice with t-BuOMe (200 ml), and the combined org. layers were
washed twice with H2O (250 ml), with sat. aq. NaHCO3 (250 ml), and finally with brine (250 ml). After
drying (MgSO4 ), the solvents were evaporated to furnish a crude oil, which was purified by bulb-to-bulb
prior to conventional distillation (42% yield). B.p. 76 – 788/0.2 Torr. IR (neat): 798m, 1013w, 1360m,
1384w, 1409w, 1444m, 1463m, 1727s, 2719w, 2833m, 2866m, 2894s, 2930s, 2955s, 3010m, 3035w. 1H-NMR
(CDCl3 ): (Z)-3b): 0.8 (s, 3 H); 1.1 (s, 3 H); 1.55 – 1.65 (m, 3 H); 1.65 – 2.6 (m, 9 H); 5.15 – 5.25 (m, 1 H);
5.25 – 5.55 (m, 2 H); 9.78 (t, J ¼ 1.5, 1 H). 13C-NMR (CDCl3 ): 12.58; 19.67; 20.11; 25.85; 27.77; 35.52;
43.76; 46.69; 50.31; 121.6; 127.2; 131.09; 148.49; 202.15. 1H-NMR (CDCl3 ): (E)-3b (selected data): 0.76 (s,
3 H); 0.97 (s, 3 H); 9.66 (m, 1 H). EI-MS (70 eV): 206 (8, M þ ), 191 (19), 173 (12), 147 (28), 121 (30), 109
(48), 108 (100), 107 (45), 105 (20), 97 (21), 95 (36), 93 (52), 91 (36), 81 (27), 79 (65), 77 (30), 69 (36), 67
(76), 55 (46), 53 (21), 43 (24), 41 (80), 39 (26). Odor description: floral (lily of the valley), green, very
powerful.
(þ)-6-[(1R)-2,2,3-Trimethylcyclopent-3-enyl]hex-4-enal ((þ)-3b). Prepared from (þ)-5b (35 g,
0.173 mol) in 48% yield, as described above for 3b. [a]D ¼ þ 2 (neat).
6-(2,2,3-Trimethylcyclopentyl)hex-4-enal (3’b). Prepared as described for 3b in 37% yield from 5’b
(14.5 g, 0.072 mol) as a 9 : 1 (Z)/(E)-mixture. IR (neat): 1366m, 1388m, 1409w, 1453m, 1466m, 1728s,
2719m, 2870s, 2955s, 3010m.
Data of (Z)-3’b: 1H-NMR (CDCl3 ): 0.51 (s, 3 H); 0.80 (d, J ¼ 6.7, 3 H); 0.86 (s, 3 H); 1.05 – 1.25 (m,
2 H); 1.25 – 1.90 (m, 5 H); 2.02 – 2.20 (m, 1 H); 2.25 – 2.52 (m, 4 H); 5.12 – 5.50 (m, 2 H); 9.74 (t, J ¼ 1.5,
1 H). 13C-NMR (CDCl3 ): 13.82; 14.24; 20.03; 25.60; 28.15; 29.87; 42.18; 43.74; 44.99; 50.97; 126.75;
131.28; 202.01.
Data of (E)-3’b: 1H-NMR (CDCl3 ; selected data): 0.47 (s, 3 H); 0.97 (s, 3 H); 9.72 (t, J ¼ 1.6, 1 H).
13
C-NMR (CDCl3 ): 12.52; 13.24; 25.13; 25.79; 27.72; 35.48; 42.09; 43.41; 45.10; 50.28; 127.16; 130.99;
CHEMISTRY & BIODIVERSITY – Vol. 5 (2008) 1093
201.92. EI-MS (70 eV): 208 (1, M þ ), 193 (3), 124 (6), 111 (33), 109 (25), 95 (28), 80 (25), 79 (22), 69
(100), 67 (24), 55 (38), 41 (40). Odor description: powerful, floral (lily of the valley), green.
4-Methyl-6-(2,2,3-trimethylcyclopent-3-enyl)hex-4-enal (3c). Prepared from 5c (36 g, 0.176 mol) in
54% yield, as a 6 : 4 (Z)/(E)-mixture, as described for 3b.
Data of (Z)-3c. 1H-NMR (CDCl3 ): 0.77 (s, 3 H); 0.97 (s, 3 H); 1.55 – 1.65 (m, 3 H); 1.65 – 1.70 (m,
3 H); 1.70 – 2.05 (m, 4 H); 2.05 – 2.25 (m, 2 H); 2.25 – 2.55 (m, 3 H); 5.15 – 5.25 (m, 2 H); 9.77 (t, J ¼ 1.7,
1 H). 13C-NMR (CDCl3 ): 12.57/19.67; 23.09; 24.28; 25.86; 28.31; 35.60; 42.25; 46.66; 50.66; 121.63; 126.41;
132.67; 148.50; 202.28.
Data of (E)-3c: 1H-NMR (CDCl3 ; selected data): 1.57 – 1.60 (m, 3 H); 9.74 (t, J ¼ 1.9, 1 H).
13
C-NMR (CDCl3 ): 12.57/19.67; 16.13; 25.88; 28.45; 31.96; 35.53; 42.13; 46.66; 50.51; 121.68; 125.35;
132.74; 148.50; 202.61. Odor description: floral (lily of the valley), LilialH, LyralH.
4-Methyl-6-(2,2,3-trimethylcyclopentyl)hexanal (3’’c). Prepared from 5’’c (44 g, 0.2 mol) in 88% yield
as described for 3b. IR (neat): 1365w, 1387w, 1465m, 1729s, 2714w, 2869s, 2931s, 2955s. 1H-NMR (CDCl3 ):
0.49 (s, 3 H); 0.74 – 0.91 (m, 6 H); 0.82 (d, J ¼ 6.7, 3 H); 0.91 – 1.56 (m, 10 H); 1.56 – 1.85 (m, 4 H); 2.35 –
2.53 (m, 2 H); 9.78 (t, J ¼ 1.9, 1 H). 13C-NMR (CDCl3 ): 13.92/14.42; 19.29/19.6; 25.71/25.74; 27.66/27.85;
28.28/28.42; 28.69/29.21; 30.17; 32.68/32.93; 35.8/36.08; 41.71/41.83; 42.31; 45.27; 50.95/51.26; 203.04. EI-
MS (70 eV): 224 (2, M þ ), 207 (6), 163 (9), 110 (20), 109 (36), 95 (34), 85 (33), 84 (70), 83 (34), 81 (29),
70 (79), 69 (100), 67 (23), 57 (19), 55 (66), 43 (22), 41 (55). Odor description: slightly woody, green,
lactonic (wax), plastic.
4-Ethyl-6-(2,2,3-trimethylcyclopentyl)hexanal (3’’d). The crude material was obtained from 5’’d
(15 g, 0.064 mol) as described for 3b. Purification by column chromatography (CC) provided pure 3’’d
(8.8 g, 0.037 mol, 58%) as a 1 : 1 mixture of isomers. IR (neat): 1051m, 1103m, 1367m, 1385m, 1461s,
1728s, 2715w, 2869s, 2955s. 1H-NMR (CDCl3 ): 0.45 (s, 3 H); 0.7 – 0.95 (m, 9 H); 0.78 (d, J ¼ 6.7, 3 H);
0.95 – 1.35 (m, 12 H); 1.35 – 1.65 (m, 3 H); 1.65 – 1.85 (m, 3 H); 2.34/2.38 (2td, J ¼ 1.7/1.5, 7.8/7.6, 2 H); 9.73
(t, J ¼ 1.9, 1 H). 13C-NMR (CDCl3 ): 10.45/10.77; 13.78; 14.30; 24.93/25.68; 25.24; 25.58; 27.19/27.21; 28.24;
30.03; 31.87/31.90; 38.55/38.68; 41.20/41.42; 42.18; 45.14; 51.07/51.11; 202.98. EI-MS (70 eV): 238 (1, M þ ),
223 (4), 209 (4), 177 (6), 123 (8), 110 (20), 109 (27), 99 (19), 95 (27), 84 (66), 83 (37), 81 (26), 70 (79), 69
(100), 67 (23), 57 (19), 55 (81), 43 (30), 41 (65). Odor description: sweet (furaneol), animalic (costus,
goat), a bit metallic.
3-Methyl-6-(2,2,3-trimethylcyclopentyl)hexanal (3’’a). The crude material was obtained from 5’’a
(10.3 g, 0.046 mol) as described for 3b. Purification by CC provided pure 3’’a (3.3 g, 0.0147 mol, 32%). IR
(neat): 1127w, 1367m, 1384m, 1464s, 1728s, 2712m, 2869s, 2954s. 1H-NMR (CDCl3 ): 0.47 (s, 3 H); 0.80 (d,
J ¼ 6.7, 1 H); 0.83 (s, 3 H); 0.94 (2d, J ¼ 6.6, 1 H); 1.0 – 1.55 (m, 10 H); 1.55 – 1.85 (m, 2 H); 2.03 (d, J ¼ 6.5,
1 H); 2.18/2.24 (td, J ¼ 2.2, 7.7, 2 H); 2.34/2.42 (td, J ¼ 2, 5.8, 2 H); 9.74 (t, J ¼ 2.2, 1 H). 13C-NMR (CDCl3 ):
13.85; 14.31; 19.86/20.05; 25.63; 26.14/26.22; 28.12/28.25; 28.21; 30.12; 30.47/30.58; 37.28/37.39; 42.20;
45.19; 20.79/50.85; 50.99/51.17; 202.99/203.02. EI-MS (70 eV): 224 (1, M þ ), 109 (13), 95 (21), 84 (61), 83
(28), 81 (22), 70 (86), 69 (100), 67 (18), 55 (52), 43 (23), 41 (51). Odor description: marine, ozonic,
transparent (MelonalH ).
2,4-Dimethyl-6-(2,2,3-trimethylcyclopentyl)hexanal (3’’e). Aldehyde 3’’c (10 g, 0.045 mol) was
alkylated according to [8] with MeI (9.6 g, 0.068 mol) via its diisobutylenamine, obtained with (i-
Bu)2NH (5.8 g, 0.045 mol) by azeotropic removal of H2O with toluene (30 ml). The obtained product
was purified by CC to give recovered 3’’c (12%) and pure 3’’e (4.6 g, 0.019 mol, 43%) as a mixture of
isomers, two observable groups in NMR, ratio 6 : 4, composed each of two diastereoisomers. IR (neat):
1367w, 1380w, 1464m, 1709m, 1729s, 2704w, 2870s, 2956s. Major isomers: 1H-NMR (CDCl3 ): 0.48 (s, 3 H);
0.80 (d, J ¼ 6.7, 3 H); 0.83 (s, 3 H); 0.87 (d, J ¼ 6.5, 3 H); 0.92 – 1.51 (m, 10 H); 1.06 (d, J ¼ 6.9, 3 H); 1.51 –
1.87 (m, 3 H); 9.55 (d, J ¼ 1.6, 1 H); 9.57 (d, J ¼ 1.5, 1 H). 13C-NMR (CDCl3 ): 13.85; 14.10/14.26; 14.35;
19.66/19.99; 25.64; 27.63; 28.20; 30.10; 30.51/30.95; 35.73/36.02; 38.17/38.51; 42.24; 44.13; 45.20; 50.83/
51.17; 205.40. Minor isomers: 1H-NMR (CDCl3 ; selected data): 0.88 (d, J ¼ 6.6, 3 H); 1.05 (d, J ¼ 7.0, 3 H);
9.59 (2d, J ¼ 2.0, 1 H). 13C-NMR (CDCl3 ): 13.24/13.38; 13.85; 14.35; 19.10/19.43; 25.68; 27.42; 28.34;
30.10; 30.41/30.60; 36.40/36.67; 37.33/37.92; 42.24; 44.23; 45.20; 50.88/51.14; 205.35. EI-MS (70 eV): 238
(M þ ), 223 (1), 180 (6), 125 (15), 109 (32), 99 (22), 97 (22), 95 (27), 84 (62), 83 (37), 81 (21), 71 (20), 70
(73), 69 (100), 57 (21), 55 (72), 43 (39), 41 (57). Odorless.
1094 CHEMISTRY & BIODIVERSITY – Vol. 5 (2008)
(CDCl3 ): 17.87; 21.25; 24.74; 25.73; 27.29; 32.30; 32.46; 37.69; 52.42; 52.49; 104.5; 129.59; 131.47. EI-MS
(70 eV): 214 ( < 1, M þ ), 182 (12), 135 (11), 109 (11), 107 (10), 97 (33), 95 (23), 84 (26), 83 (64), 81 (12),
75 (100), 71 (20), 69 (13), 67 (13), 55 (32), (41 (20). Odor description: green (peas), grapefruit.
6,8-Dimethylnon-7-enal Diethyl Acetal (14b). Obtained in 88% yield from 10 (33 g, 0.27 mol), EtOH
(120 g, 2.6 mol) and HC(OEt)3 (80 g, 0.54 mol) as described for 7b. B.p. 1068/5 Torr. 1H-NMR (CDCl3 ):
0.86 (d, J ¼ 6.7, 3 H); 1.12 – 1.37 (m, 6 H); 1.17 (t, J ¼ 7.1, 6 H); 1.47 – 1.65 (m, 2 H); 1.57 (d, J ¼ 1.1, 3 H);
1.65 (d, J ¼ 1.0, 3 H); 2.15 – 2.37 (m, 1 H); 3.36 – 3.75 (m, 4 H); 4.44 (t, J ¼ 5.7, 1 H); 4.83 (sept. d, J ¼ 1.3,
9.4, 1 H). 13C-NMR (CDCl3 ): 15.27; 17.84; 21.23; 24.87; 25.70; 27.28; 32.28; 33.55; 37.69; 60.66; 60.72;
102.90; 129.52; 131.48. EI-MS (70 eV): 242 ( < 1, M þ ), 197 (10), 196 (12), 151 (5), 135 (10), 129 (7), 111
(38), 109 (15), 107 (10), 103 (100), 98 (16), 96 (17), 95 (41), 85 (15), 83 (71), 81 (16), 75 (55), 69 (21), 67
(13), 57 (16), 55 (34), 47 (30), 43 (10).
2-(5,7-Dimethyloct-6-enyl)[1,3]dioxolane (14c). Obtained in 88% yield from 10 (45.5 g, 0.27 mol),
ethylene glycol (167.4 g, 2.7 mol) and HC(OEt)3 (80 g, 0.54 mol) as described for 7b. B.p. 678/0.7 Torr.
1
H-NMR (CDCl3 ): 0.86 (d, J ¼ 6.7, 3 H); 1.0 – 1.45 (m, 6 H); 1.45 – 1.7 (m, 2 H); 1.57 (d, J ¼ 1.1, 3 H); 1.64
(d, J ¼ 1.1, 3 H); 2.17 – 2.44 (m, 1 H); 3.75 – 3.87 (m, 2 H); 3.87 – 3.97 (m, 2 H); 4.79 – 4.88 (m, 1 H); 4.81 (t,
J ¼ 4.8, 1 H). 13C-NMR (CDCl3 ): 17.85; 21.20; 24.19; 25.70; 27.34; 32.25; 33.89; 37.65; 64.73; 104.61;
129.56; 131.45. EI-MS (70 eV): 212 (4, M þ ), 155 (7), 135 (8), 127 (14), 107 (9), 99 (43), 86 (13), 83 (69),
81 (6), 73 (100), 69 (9), 67 (9), 55 (32), 45 (14), 43 (7), 41 (16).
6,8-Dimethylnonanal Dimethyl Acetal (14’a). Obtained in 75% yield from 14a as described for 10’.
B.p. 708/1 Torr. 1H-NMR (CDCl3 ): 0.81 (d, J ¼ 6.7, 3 H); 0.82 (d, J ¼ 6.5, 3 H); 0.84 (d, J ¼ 6.7, 3 H); 0.88 –
1.13 (m, 3 H); 1.13 – 1.38 (m, 5 H); 1.38 – 1.51 (m, 1 H); 1.51 – 1.69 (m, 3 H); 3.30 (s, 6 H); 4.35 (t, J ¼ 5.7,
1 H). 13C-NMR (CDCl3 ): 19.72; 22.26; 23.40; 24.90; 25.18; 26.79; 30.15; 32.49; 37.26; 46.78; 52.49; 52.52;
104.52. EI-MS (70 eV): 216 ( < 1, M þ ), 185 (4), 97 (7), 83 (5), 75 (100), 71 (8), 69 (5), 55 (6), 43 (6), 41
(7). Odor description: fruity (apple, pineapple), green, hesperidic.
6,8-Dimethylnonanal Diethyl Acetal (14’b). Obtained in quant. yield from 14b as described for 10’.
B.p. 908/2 Torr. 1H-NMR (CDCl3 ): 0.79 (d, J ¼ 6.6, 3 H); 0.80 (d, J ¼ 6.4, 3 H); 0.83 (d, J ¼ 6.6, 3 H); 0.87 –
1.12 (m, 3 H); 1.18 (t, J ¼ 7.0, 6 H); 1.21 – 1.51 (m, 6 H); 1.51 – 1.70 (m, 3 H); 3.55 (m, 4 H); 4.46 (t, J ¼ 5.7,
1 H). 13C-NMR (CDCl3 ): 15.29; 19.71; 22.23; 23.37; 25.03; 25.15; 26.75; 30.13; 33.56; 37.24; 46.75; 60.73;
102.91. EI-MS (70 eV): 244 ( < 1, M þ ), 199 (7), 103 (100), 97 (15), 75 (22), 57 (10), 47 (16), 43 (9). Odor
description: peach, apricot (juice).
2-(5,7-Dimethyloctyl)[1,3]dioxolane (14’c). Obtained in quant. yield from 14c as described for 10’.
B.p. 678/0.7 Torr. 1H-NMR (CDCl3 ): 0.80 (d, J ¼ 6.7, 3 H); 0.81 (d, J ¼ 6.5, 3 H); 0.83 (d, J ¼ 7.0, 3 H);
0.87 – 1.17 (m, 4 H); 1.17 – 1.50 (m, 5 H); 1.50 – 1.72 (m, 3 H); 3.75 – 3.87 (m, 2 H); 3.87 – 3.97 (m, 2 H);
4.82 (t, J ¼ 4.8, 1 H). 13C-NMR (CDCl3 ): 19.69; 22.24; 23.36; 24.35; 25.15; 26.83; 30.10; 33.89; 37.21;
46.75; 64.75; 104.64. EI-MS (70 eV): 214 ( < 1, M þ ), 73 (100), 45 (6), 43 (5).
Methyl 4-Formylnonanoate (17b). A soln. of morpholine (418.0 g, 4.80 mol) in cyclohexane (344.0 g)
was heated to 65 – 708, and heptanal (444.2 g, 3.89 mol) added over a period of 5 h with removal of the
formed H2O in a trap. After completion of the reaction, the mixture was allowed to cool, and the
cyclohexane as well as the excess morpholine were distilled off under reduced pressure (808/30 Torr). A
soln. of KOH (4.0 g, 0.10 mol) in MeOH (40 ml) was then added, and the mixture was heated to 608.
Then, methyl acrylate (237.5 g, 2.76 mol) was added to the mixture over a period of 4 h, stirring continued
for further 12 h at 608, and methyl acrylate (165.3 g, 1.92 mol) was again added after 2 h 30 min. The
mixture was then stirred at 808 for further 12 h, prior to the addition of a pH 4 buffer soln. within 2 h. The
reaction was quenched, and the mixture was stirred for further 4 h, the aq. layer extracted twice with
cyclohexane (200 ml), and the combined org. layers washed with H2O (100 ml), sat. aq. NaHCO3
(100 ml), and brine (100 ml). After drying (MgSO4 ), the solvents were evaporated. The resulting crude
product was purified by short-path distillation to afford 17b in 83% purity (663 g, 2.74 mol, 70%).
3,4,5,6-Tetrahydro-5-pentyl-2H-pyran-2-one (VerbenolideH ; 15b). At 58, 17b was added slowly to a
suspension of NaBH4 (41.6 g, 1.1 mol) in EtOH (1500 ml), and the mixture was stirred at 58 overnight. A
10% aq. NaOH soln. (1900 ml) was then added dropwise at 108 within 2 h. Stirring was continued until
the colorless precipitate disappeared (2 h). Most of the EtOH was then evaporated, and the aq. layer was
washed twice with toluene/hexane 1 : 1 (200 ml). After cooling the mixture to 08, the aq. layer was further
acidified by adding a 10% aq. HCl soln. (1900 ml) dropwise at 108 over a period of 3 h. Stirring was
CHEMISTRY & BIODIVERSITY – Vol. 5 (2008) 1097
continued for further 4 h at r.t., the org. layer was then separated, and the aq. one was extracted twice
with toluene (200 ml). The combined org. layers were washed twice with H2O (100 ml) and brine
(200 ml), and dried (MgSO4 ). The solvents were evaporated under reduced pressure, and the crude
material purified by distillation to provide 15b (289 g, 1.7 mol, 61% yield). B.p. 90 – 928/27 Pa. IR (neat):
1055m, 1097w, 1183m, 1245w, 1342w, 1402w, 1460w, 1739s, 2858m, 2928s, 2957s. 1H-NMR (CDCl3 ): 0.88 (t,
J ¼ 4, 3 H); 1.2 – 1.4 (m, 8 H); 1.4 – 1.6 (m, 1 H); 1.8 – 1.95 (m, 1 H); 1.95 – 2.05 (m, 1 H); 2.48 (ddd, J ¼ 7.18,
9.4, 17.8, 1 H); 2.61 (ddd, J ¼ 4.7, 7.0, 17.8, 1 H); 3.94 (dd, J ¼ 9.7, 11.1, 1 H); 4.32 (ddd, J ¼ 1.9, 4.5, 11.1,
1 H). 13C-NMR (CDCl3 ): 14.01; 22.51; 25.53; 26.46; 29.11; 31.52; 31.82; 32.84; 73.73; 171.63. EI-MS
(70 eV): 170 (2, M þ ), 128 (32), 112 (60), 111 (25), 97 (22), 94 (22), 84 (69), 83 (32), 70 (80), 69 (69), 68
(60), 56 (97), 55 (100), 43 (65), 42 (49), 41 (92), 39 (32). Odor description: lemon, nitrile, green, lactonic.
3,4,5,6-Tetrahydro-5-propyl-2H-pyran-2-one (FigolideH ; 15a). Obtained from valeraldehyde as
described for 15b. Bp 808/0.8 Torr. 1H-NMR (CDCl3 ): 0.93 (t, J ¼ 6.7, 3 H); 1.2 – 1.43 (m, 4 H); 1.43 –
1.65 (m, 1 H); 1.92 – 2.10 (m, 2 H); 2.38 – 2.72 (m, 2 H); 3.96 (dd, J ¼ 9.6, 11.1, 1 H); 4.34 (ddd, J ¼ 2.0, 4.4,
11.1, 1 H). 13C-NMR (CDCl3 ): 13.58; 19.43; 24.91; 28.55; 32.01; 33.19; 73.10; 171.11. EI-MS (70 eV): 142
(5, M þ ), 112 (9), 94 (10), 84 (93), 70 (32), 69 (30), 56 (69), 55 (100), 42 (55), 41 (45), 39 (24). Odor
description: Lactonic, coconut, fig leaves.
3,4,5,6-Tetrahydro-3-heptyl-2H-pyran (CilandraneH ; 16c). To a suspension of NaBH4 (22.4 g,
0.59 mol) in iPrOH (400 ml) was added dropwise with stirring over a period of 1 h the formyl-ester
17c (0.59 mol, obtained from nonanal as described for 17b). The mixture was stirred at r.t. overnight.
After cooling to 108, acetone (8.6 g, 0.15 mol) was added at 108 and then over 1 h concentrated HCl
(240 g). H2O was added (250 ml), and the aq. layer was extracted twice with toluene (200 ml). The
combined org. layers were washed with H2O (100 ml) and with brine (100 ml), and then dried (MgSO4 ).
The solvents were evaporated, and the crude diol (118 g, 0.42 mol) was treated with 85% H3PO4 (52.6 g).
The mixture was then stirred at 1208 for 4 h. After cooling to r.t., H2O (150 ml) was added. The aq. layer
was extracted with t-BuOMe (100 ml), and the combined org. layers were washed twice with sat. aq.
NaHCO3 (50 ml) and once with brine (50 ml), dried (MgSO4 ), and concentrated under reduced
pressure. The crude product was purified by distillation to provide 16c (28 g, 0.18 mol, 73%). B.p. 1008/
7 Torr. 1H-NMR (CDCl3 ): 0.8 – 0.95 (m, 3 H); 0.95 – 1.17 (m, 3 H); 1.17 – 1.4 (m, 10 H); 1.42 – 1.70 (m,
3 H); 1.85 (dtdd, J ¼ 1.6, 3.5, 5.3, 12.8, 1 H); 3.02 (dd, J ¼ 10.2, 11.0, 1 H); 3.25 – 3.42 (m, 1 H); 3.80 – 3.94
(m, 2 H). 13C-NMR (CDCl3 ): 14.08; 22.65; 25.99; 26.61; 29.24; 29.82; 30.07; 31.85; 32.53; 36.02; 68.49;
73.64. EI-MS (70 eV): 184 (1, M þ ), 166 (4), 123 (17), 109 (29), 95 (18), 81 (48), 71 (74), 68 (71), 55 (67),
43 (52), 41 (100), 39 (24). Odor description: lactonic, green, aldehydic (mandarin), coriander leaves.
3-Benzyltetrahydro-2H-pyran (BetahydraneH ; 16d). Obtained from 3-phenylpropanal as described
for the preparation of 16c. B.p. 748/0.4 Torr. 1H-NMR (CDCl3 ): 1.15 – 1.30 (m, 1 H); 1.51 – 1.67 (m, 2 H);
1.77 – 1.99 (m, 2 H); 2.44 (dd, J ¼ 7.6, 13.6, 1 H); 2.56 (dd, J ¼ 7.2, 13.6, 1 H); 3.16 (dd, J ¼ 9.6, 11.1, 1 H);
3.36 – 3.46 (m, 1 H); 3.82 – 3.93 (m, 2 H). 13C-NMR (CDCl3 ): 25.67; 29.61; 37.80; 38.99; 68.42; 73.09;
125.90; 128.22; 128.92; 139.86. EI-MS (70 eV): 176 (21, M þ ), 143 (5), 130 (8), 117 (16), 104 (10), 98 (19),
92 (100), 91 (54), 84 (28), 71 (10), 65 (16), 57 (10), 41 (15). Odor description: rosy (geranium), metallic,
nitrile, rhubarb.
I would like to thank Piotr Jaunky and Martin Schrçder for their contributions to this paper by the
results of their research projects. I also would like to thank Yvan Klimkowicz for his helpful laboratory
work in connection with my own projects. The analytical team is also acknowledged, in particular
Christian Ozog for the mass spectra, as are the perfumers who have evaluated the different compounds,
especially Rolph Gasparian, Jean-Paul Pons, and Fabrice Pellegrin. Finally, I would like to thank Jean-
Jacques Chanot and Jean Mane for giving me the opportunity to present this overview of the chemistry
research at Mane during the F&F conference in London, last September.
REFERENCES
[1] P. Kraft, J. A. Bajgrowicz, C. Denis, G. Fráter, Angew. Chem., Int. Ed. 2000, 39, 2980.
[2] F. Ponge, J. Mane, to V. Mane & Fils, FR 2831165 (Chem. Abstr. 2003, 138, 343503); A. Muratore,
PhD thesis, University of Nice – Sophia-Antipolis, 2007; results to be published.
1098 CHEMISTRY & BIODIVERSITY – Vol. 5 (2008)