Synthesis and optical resolution of the floral odorant (±)-2,3- dihydro-2,5-dimethyl-1H-indene-2-methanol, and preparation of analogues

Article abstract of DOI:10.1002/hlca.200590250

The title compound (±)-1, a recently discovered, valuable, floral-type odorant, has been synthesized by a straightforward procedure (Scheme 1), To determine the properties of the enantiomers of 1, their separation by preparative HPLC and the determination of their absolute configuration by X-ray crystallography were carried out (Figure). Furthermore, the analogues 2-6 were synthesized, either from differently methylated 2-methylin-dan-1-ones (Schemes 2 and 3) or, in the case of the 2,4,6-trimethylated homologue 6, by a completely different synthetic approach (Scheme 4). An evaluation of (+)-(S)-1, (-)-(R)-1, and (±)-1 showed only minor differences in terms of odor (Table).

Full text of DOI:10.1002/hlca.200590250

Helvetica Chimica Acta – Vol. 88 (2005)
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Synthesis and Optical Resolution of the Floral Odorant (ꢀ)-2,3-Dihydro-2,5-
dimethyl-1H-indene-2-methanol, and Preparation of Analogues
by Christian Viala), Gérald Bernardinellib), Philippe Schneidera), Michael Aizenberga), and Béat Winter*a)
a) Firmenich SA, Corporate R&D Division, P. O. Box 239, CH-1211 Geneva 8
(phone: +41-22-7803612; fax: +41-22-780 3334; e-mail: beat.winter@firmenich.com)
b) Université de Genève, Laboratoire de cristallographie, 24 quai Ernest-Ansermet, CH-1211 Geneva 4
(phone: +41223796202; fax: +41223796108; e-mail: gerald.bernardinelli@cryst.unige.ch)
Dedicated to Dr. Ferdinand Näf on the occasion of his 65th birthday
The title compound (ꢀ)-1, a recently discovered, valuable, floral-type odorant, has been synthesized by a
straightforward procedure (Scheme 1). To determine the properties of the enantiomers of 1, their separation by
preparative HPLC and the determination of their absolute configuration by X-ray crystallography were carried
out (Figure). Furthermore, the analogues 2–6 were synthesized, either from differently methylated 2-methylin-
dan-1-ones (Schemes 2 and 3) or, in the case of the 2,4,6-trimethylated homologue 6, by a completely different
synthetic approach (Scheme 4). An evaluation of (+)-(S)-1, (ꢁ)-(R)-1, and (ꢀ)-1 showed only minor differences
in terms of odor (Table).
1. Introduction. – Racemic 2,3-dihydro-2,5-dimethyl-1H-indene-2-methanol ((ꢀ)-
1)1) [1], discovered during work on analogues of known floral-type odorants, was
found to possess very valuable odoriferous properties [2], but required a cost-effective
synthesis in view of commercialization. Furthermore, it became of interest to know the
properties of the two enantiomers of 1, as well as of the 2,4-isomer (ꢀ)-2 and the homo-
logues 3–6 with two Me groups on the aromatic ring.
In this work, we report a straightforward synthesis of alcohol (ꢀ)-1, which was
applied to the preparation of the isomer (ꢀ)-2 and the homologues 3–5, 6 being pre-
pared by an alternative route. Moreover, we report the preparative-HPLC separation
of the antipodes of 1, as well as the determination of the absolute configurations of (+)-1
by X-ray crystallographic analysis of the camphanic acid derivative (+)-7.
2. Results. – 2.1. Synthesis. As shown in Scheme 1, alcohol (ꢀ)-1 was easily synthe-
sized from the known indanones (ꢀ)-8 [3] or (ꢀ)-9 [4] by a sequence of aldol reactions
with formaldehyde, followed by hydrogenolysis of the resulting adducts 10 and 11,
1
)
This compound has also been named ‘2,5-dimethyl-2-indanemethanol’.
© 2005 Verlag Helvetica Chimica Acta AG, Zürich

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Scheme 1
a) Formcel (55% CH2O in MeOH; Hoechst), K2CO3, toluene, 508, 2–3 h. b) H2 (1 bar), 10% Pd/C, AcOH,
r.t., 72 h. c) H2 (3 bar), 5% Pd/C, MeSO3H, i-PrOH, 808, 7.5 h.
Scheme 2
a) Hexamethylenetetramine, Ac2O, 808, 6.5 h. b) H2SO4 (conc.), r.t. ! 588, 1.5 h. c) Formcel® (55% CH2O
in MeOH; Hoechst), K2CO3, toluene, 508, 4.5 h. d) H2 (1 bar), 10% Pd/C, AcOH, r.t., 125 h.
respectively. For the synthesis of the isomeric alcohol (ꢀ)-2, we chose the route shown
in Scheme 2.
Starting from the known ketone 12 [5], we selectively prepared, via 13, the indan-
one (ꢀ)-14 [4d] by a procedure [6] similar to the one used for the synthesis of (ꢀ)-8 [3].
Compound 14 was then converted via 15 to 2 by the same methodology as above.
For the syntheses of the homologues 3–5, the known indanones (ꢀ)-16 [7], (ꢀ)-17
[4b], and (ꢀ)-18 [3][4b] [8] were subjected to aldol condensation to afford 19–21,
respectively, from which the target homologues were readily obtained (Scheme 3).
However, in the case of the homologue 6, we were confronted with the fact that
there is no reported selective synthesis of 2,5,6-trimethylindan-1-one [4d]. Conse-
quently, we explored another approach to 6, starting from the known dichloride 22
[9], as shown in Scheme 4.
Alkylation of diethyl malonate with the dichloride 22 afforded the diester 23, which
was reduced to the diol 24 with LiAlH4. Compound 24 was then converted according to

Helvetica Chimica Acta – Vol. 88 (2005)
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Scheme 3
a) Formcel® (55% CH2O in MeOH; Hoechst), K2CO3, toluene, 508, 2–3 h. b) H2 (1 bar), 10% Pd/C, AcOH,
r.t., 36 h. c) H2 (3 bar), 5% Pd/C, MeSO3H, i-PrOH, 808, 7.5 h.
Scheme 4
a) CH2(COOEt)2, EtONa, EtOH, reflux, 2 h. b) LiAlH4, Et2O, r.t., 1 h. c) 1. BuLi, TsCl (=4-methylbenze-
nesulfonyl chloride), THF, ꢁ238, 4 h; 2. BuLi, THF, r.t., 2.5 d. d) LiAlH4, THF, reflux, 22 h.
the method of Picard et al. [10] to the spiro-oxetane 25, which was reductively ring-
opened with LiAlH4 to afford the desired alcohol 6.
2.2. Enantiomer Separation. Initial attempts to obtain the pure enantiomers of 1 by
enzymatic resolution of its acetate or chloroacetate with the aid of a variety of lipases
failed [11]. Thus, we turned our attention to chiral HPLC. After screening the chiral
columns found in the Daicel catalogue, the analytical resolution of (ꢀ)-1 was found
to be possible on a 10-mm Chiralpack AD column (Daicel), eluting with a 95 :5 mixture
of hexane/i-PrOH. The preparative separation2) was performed with a 25×11 cm col-
umn packed with Chiralpack AD (20 mm), eluting with isohexane/EtOH 95 :5. As
the crude antipodes of 1 were contaminated by solvent, they were purified by flash
chromatography and bulb-to-bulb distillation, which afforded analytically pure (+)-1
and (ꢁ)-1 (>98% ee by chiral HPLC). Both compounds presented good olfactory
properties (see Sect. 2.4).
2.3. Absolute Configuration of (+)-1. (ꢁ)-Camphanoyl chloride is an excellent chi-
ral derivatizing agent often used for the determination of absolute configurations by X-
ray crystallography [12]. Indeed, the condensation between (+)-1 and (ꢁ)-camphanoyl
2
)
These experiments were performed at Chiral Technologies Europe SAS, Parc d’Innovation, Bd Gonthier
d’Andernach, BP 80140, 67404 Illkirch, France.

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Figure. a) Perspective view of the crystal structure of (+)-7, and b) absolute configurations of the antipodes of
1. Ellipsoids are represented at the 40% probability level.
chloride furnished the crystalline ester (+)-7 in nearly quantitative yield. Suitable crys-
tals for X-ray diffraction were obtained from hexane/AcOEt 2 :1 at 08. A representa-
tion of (+)-7 is shown in the Figure. It turned out that the (+)-antipode of 1 corre-
sponds to the absolute (S)-configuration, while (ꢁ)-1 corresponds to the (R)-enan-
tiomer.
2.4. Olfactory Evaluation. The results of the olfactory evaluation of the alcohols
prepared in this work are presented in the Table. In conclusion, none of the analogues
of 2,3-dihydro-2,5-dimethyl-1H-indene-2-methanol ((ꢀ)-1) exhibited better olfactory
properties than the parent compound. Also, neither of the two enantiomers of 1 was
very different from the other, nor from the racemate, although (+)-1 was found to
be a slightly more-powerful odorant.
Table. Olfactory Properties of Compounds 1–6
Compound Odor description
(ꢀ)-1
(+)-1
Lilial®, hydroxycitronellal, aldehydic, muguet
Muguet, floral, Lilial®, hydroxycitronellal, stronger and more powerful, less hydroxycitronellal
than enantiomer, base more Lilial®
(ꢁ)-1
Floral, muguet, hydroxycitronellal, slightly plastic, similar to enantiomer, more plastic, base more
hydroxycitronellal
(ꢀ)-2
(ꢀ)-3
(ꢀ)-4
5
Floral, muguet, weaker, less character, less clear than (ꢀ)-1
Muguet, Lilial®, very weak, without character
Floral, Lilial®, Lyral®, similar to (ꢀ)-1, but weaker, more classical
Wet leather, old shoes
6
Muguet, hydroxycitronellal, Lilial®, base weaker and more Lilial® than (ꢀ)-1

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We gratefully acknowledge the technical assistance of Sandrine Gallo-Flückiger, Marina Etter, Amanda Vil-
loresi, and Luis Nicolas. We are also grateful to Walter Thommen and Robert Brauchli for the NMR analysis, as
well as to Dr. Pierre-Alain Blanc for the organoleptic evaluations and to Dr. Roger Snowden for stimulating dis-
cussions.
Experimental Part
1. General. All reactions were performed under N2. GLC: Hewlett-Packard 5890 instrument equipped with
a flame-ionization detector coupled to a Hewlett-Packard 3395 or 3396A integrator; with Chrompack CP-Wax-
52 CB (10 m, 0.25 mm i.d.) and CP-Sil-5 CB (10 m, 0.25 mm i.d.) capillary columns. TLC: silica gel 60 F254 plates
(0.25 mm; Merck). Flash column chromatography (FC): silica gel 60 (0.063–0.2 mm, 70–270 mesh, Merck).
Anal. chiral HPLC: 10-mm Chiralpack® ADTM column (‘amylose tris(3,5-dimethylphenyl) carbamate’; Daicel),
with Varian Star 9012 pump and a Waters M-490 UV detector (270 nm). Prep. chiral HPLC: Chiralpack® ADTM
column (25×11 cm; 20 mm). Bulb-to-bulb distillation: Büchi GKR-50 or GRK-51 oven; b.p. corresponded to the
air temp. Optical rotation: Perkin-Elmer 241 polarimeter; cell thermostated at 208, path length 0.1 cm. IR Spec-
1
tra (liquid film): Perkin-Elmer 297 or 1600 FT-IR spectrometers; in cmꢁ1. H- and 13C-NMR Spectra (CDCl3):
Bruker AMX-360, DPX-400, or AV-500 spectrometers; d in ppm rel. to Me4Si, J in Hz. MS: HP 5972 or 5973
MSD (70 Ev); in m/z (rel. intensity in %).
2. General Procedure (GP 1) for the Aldol Reaction of 2-Methylindan-1-ones with Formaldehyde. To a stir-
red mixture of the given ketone (1.0 equiv.) and K2CO3 (0.5 equiv.) in toluene at 508 was added dropwise a 55%
soln. of formaldehyde in MeOH (Formcel® (Hoechst); 2.0 equiv.), and the mixture was stirred at 508 during 2–3
h. As the product partially decomposes by a retro-aldol reaction upon GC analysis, all reactions were monitored
by TLC. After completion of the reaction, the mixture was diluted with Et2O, washed with H2O (2×) and brine,
dried (Na2SO4), and concentrated.
3. General Procedure (GP 2) for the Hydrogenation of Hydroxy Ketones. To a 10% (w/w) soln. of a given
hydroxy ketone (1.0 equiv.) in AcOH was added 10% Pd/C (0.03–0.05 equiv.), and the mixture was agitated
under H2 (1 bar) at r.t. during 18–125 h. The catalyst was filtered off, and the filtrate was concentrated. The
crude alcohol contained variable amounts of the corresponding acetate, and the mixture was saponified with
2.5
N
NaOH in EtOH/H2O 1:1 at reflux for 1 h.
4. Synthesis of Compound 1. 4.1. (ꢀ)-2-(Hydroxymethyl)-2,5-dimethylindan-1-one (10). Prepared according
to GP 1 from 8 (500 g, 3.13 mol), and purified by distillation in vacuo. Yield: 567 g (93%; purity 98%). Colorless,
viscous oil that solidified upon standing. M.p. 46–478. B.p. 120–1238/0.1 mbar. IR (neat): 3425 (br.), 2920, 1690,
1600, 1450, 1325, 1045, 825. 1H-NMR: 7.60 (d, J=8, 1 H); 7.26 (br. s, 1 H); 7.16 (br. d, J=8, 1 H); 3.80 (d, J=11,
1 H); 3.60 (d, J=11, 1 H), 3.20 (d, J=16, 1 H); 2.82 (d, J=16, 1 H); 2.62 (br. s, OH); 2.43 (s, 3 H); 1.21 (s, 3 H).
13C-NMR: 210.8 (s); 153.9 (s); 146.5 (s); 133.5 (s); 128.8 (d); 127.0 (d); 124.1 (d); 67.7 (t); 51.0 (s); 37.8 (t); 22.1
(q); 20.7 (q). MS: 190 (62, M+), 175 (100), 159 (82), 145 (70), 129 (61), 115 (60), 91 (42), 77 (31), 63 (20), 51 (19),
39 (21), 31 (22).
4.2. (ꢀ)-2-(Hydroxymethyl)-2,6-dimethylindan-1-one (11). Prepared according to GP 1 from 9 (350 g, 2.18
mol), and purified by distillation in vacuo. Yield: 405 g (97%; purity 99%). Colorless, viscous oil that solidified
upon standing. M.p. 49–508. B.p. 119–1228/0.1 mbar. IR (CHCl3): 3430, 2910, 1685, 1600, 1485, 1380, 1035, 810.
1H-NMR: 7.48 (br. s, 1 H); 7.40 (br. d, J=8, 1 H); 7.33 (d, J=8, 1 H); 3.60 (d, J=11, 1 H); 3.22 (d, J=16, 1 H);
2.82 (d, J=16, 1 H); 2.78 (br., OH); 2.36 (s, 3 H); 1.20 (s, 3 H). 13C-NMR: 211.4 (s); 150.8 (s); 137.4 (s); 136.5 (d);
136.0 (s); 126.3 (d); 124.1 (d); 67.6 (t); 51.3 (s); 37.6 (t); 21.0 (q); 20.7 (q). MS: 190 (56, M+), 175 (65), 172 (78),
159 (100), 145 (72), 129 (73), 115 (62), 104 (27), 91 (44), 77 (33), 63 (18), 51 (20), 39 (19), 31 (21).
4.3. (ꢀ)-2,3-Dihydro-2,5-dimethyl-1H-indene-2-methanol (1). 4.3.1. Synthesis from 10. Prepared according
to GP 2 from 10 (62.7 g, 0.33 mol), and purified by distillation in vacuo. Yield: 32.1 g (55%). Colorless, viscous
oil. B.p. 83–918/0.1 mbar. IR (neat): 3330 (br.), 2910, 1485, 1035, 810. 1H-NMR: 7.04 (d, J=8, 1 H); 6.98 (s, 1 H);
6.93 (d, J=8, 1 H); 3.49 (s, 2 H); 2.87 (d, J=16, 1 H); 2.85 (d, J=16, 1 H); 2.60 (d, J=16, 2 H); 2.30 (s, 3 H); 1.80
(s, OH); 1.16 (s, 3 H). 13C-NMR: 142.6 (s); 139.4 (s); 135.8 (s); 127.0 (d); 125.5 (d); 124.5 (d); 70.5 (t); 45.0 (s);
42.7 (t); 42.4 (t); 24.0 (q); 21.2 (q). MS: 176 (33, M+), 158 (11), 143 (100), 128 (35), 115 (21), 105 (11), 91 (11), 77
(8), 51 (6), 39 (7), 31 (15).
4.3.2. Synthesis from 11. To a soln. of 11 (200 g, 1.04 mol) in i-PrOH (3 kg) was added 5% Pd/C (20 g) and
methanesulfonic acid (2.0 g, 21.0 mmol), and the mixture was stirred under H2 (3 bar) at 808 during 7.5 h. The

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mixture was diluted with toluene (200 g), washed with 5% aq. H2SO4, H2O, sat. aq. NaHCO3 soln., and H2O, and
concentrated. Distillation in vacuo (0.08 mbar) afforded 1 (161.2 g, 83%; purity 95%). Colorless viscous liquid
that solidified on standing. M.p. 42–448.
5. Synthesis of Compound 2. 5.1. (ꢀ)-2,7-Dimethylindan-1-one (14). A stirred mixture of ketone 7 (5.9 g,
39.0 mmol; purity 98%), hexamethylenetetramine (7.89 g, 55.0 mmol), and Ac2O (7.2 g, 71.0 mmol) was heated
to 808 (bath temp.) for 7 h. The mixture was cooled, and then poured onto a mixture of 2.5
N aq. NaOH soln. and
CH2Cl2. The org. phase was washed with brine, 1.5 aq. HCl, dried (Na2SO4), and concentrated on a rotary evap-
N
orator to an orange oil. GC Analysis indicated the presence of 12% of 7 (starting material) and 87% of the inter-
mediate 13. The oil was added dropwise to conc. H2SO4 (23 ml), and the mixture was kept at ca. 158 with a water
bath. The mixture was then heated to 588 (bath temp.) during 1.5 h. The cooled mixture was poured into a mix-
ture of iced H2O and Et2O. The org. phase was washed with H2O, sat. aq. NaHCO3 soln., dried (Na2SO4), and
concentrated to a yellow liquid (4.06 g), which was purified by FC (200 g SiO2; CH2Cl2) followed by bulb-to-bulb
distillation (oven temp. 50 ! 858 at 0.3 mbar). Yield of 14: 2.85 g (45%; purity 98%). Colorless oil. IR (neat):
2980, 2950, 1715, 1605, 1485, 1340, 1240, 1210, 875, 790. 1H-NMR: 7.41 (t, J=8, 1 H); 7.24 (d, J=8, 1 H); 7.08 (d,
J=8, 1 H); 3.33 (br. q, J=8, 1 H); 2.70–2.64 (m, 2 H); 2.63 (s, 3 H); 1.28 (s, 3 H). 13C-NMR: 210.3 (s); 154.1 (s);
139.0 (s); 133.9 (d); 133.8 (s); 129.1 (d); 123.8 (d); 43.3 (d); 34.6 (t); 18.3 (q); 16.4 (q). MS: 160 (60, M+), 145
(100), 115 (28), 91 (14), 77 (9), 63 (9), 51 (11), 39 (8), 27 (4).
5.2. (ꢀ)-2-(Hydroxymethyl)-2,7-dimethylindan-1-one (15). Prepared according to GP 1 from 14 (1.17 g, 7.3
mmol), and purified by crystallization from Et2O/pentane at ꢁ308. Yield: 1.29 g (92%). Colorless crystals. M.p.
93.5–948. IR (neat): 3482, 2963, 2915, 2867, 1687, 1592, 1473, 1376, 1199, 1055, 928, 800, 784. 1H-NMR: 7.44 (t,
J=7, 1 H); 7.27 (d, J=7, 1 H); 7.10 (d, J=7, 1 H); 3.79 (dd, J=10, 6, 1 H); 3.60 (dd, J=10, 4, 1 H), 3.18 (d,
J=16, 1 H); 2.83 (d, J=16, 1 H); 2.61 (s, 3 H), 2.61–2.53 (br. m, OH); 1.22 (s, 3 H). 13C-NMR: 212.1 (s);
153.9 (s); 139.4 (s); 134.4 (d); 133.2 (s); 129.3 (d); 124.0 (d); 67.9 (t); 50.7 (s); 37.5 (t); 20.9 (q); 18.3 (q). MS:
190 (86, M+), 175 (32), 172 (43), 159 (100), 145 (54), 129 (40), 115 (37), 91 (23), 77 (13), 63 (6), 51 (5), 39 (5).
5.3. (ꢀ)-2,3-Dihydro-2,4-dimethyl-1H-indene-2-methanol (2). Prepared according to GP 2 from 15 (0.67 g,
3.5 mmol), and purified by bulb-to-bulb distillation (oven temp. 75 ! 1358 at 0.2 mbar). Yield: 0.51 g (83%).
Colorless oil. IR (neat): 3320 (br.), 2900, 1585, 1455, 1370, 1030, 760. 1H-NMR: 7.04 (t, J=7, 1 H); 6.99 (d,
J=7, 1 H); 6.94 (d, J=7, 1 H); 3.50 (s, 2 H); 2.91 (d, J=16, 1 H); 2.83 (d, J=16, 1 H); 2.67 (d, J=16, 1 H);
2.58 (d, J=16, 1 H); 2.21 (s, 3 H); 1.84 (br. s, OH); 1.18 (s, 3 H). 13C-NMR: 142.2 (s); 141.3 (s); 134.1 (s);
127.0 (d); 126.4 (d); 122.1 (d); 70.8 (t); 44.2 (s); 43.0 (t); 41.5 (t); 24.3 (q); 19.0 (q). MS: 176 (32, M+), 158
(15), 143 (100), 128 (32), 115 (19), 105 (11), 91 (10), 77 (8), 63 (4), 51 (6), 39 (7), 31 (6).
6. Synthesis of Compound 3. 6.1. (ꢀ)-2-(Hydroxymethyl)-2,4,5-trimethylindan-1-one (19). Prepared accord-
ing to GP 1. from 16 (1.27 g, 7.3 mmol), and purified by crystallization from CH2Cl2/Et2O at ꢁ308. Yield: 1.08 g
(72%). Colorless crystals. M.p. 110–1118. IR (neat): 3402, 2963, 2927, 2861, 1675, 1592, 1454, 1300, 1277, 1243,
1055, 830. 1H-NMR: 7.47 (d, J=8, 1 H); 7.16 (d, J=8, 1 H); 3.82 (d, J=10, 1 H); 3.61 (d, J=10, 1 H); 3.14 (d,
J=16, 1 H); 2.78 (d, J=16, 1 H); 2.66 (br. s, OH); 2.36 (s, 3 H); 2.24 (s, 3 H); 1.22 (s, 3 H). 13C-NMR: 211.3 (s);
152.5 (s); 144.5 (s); 134.0 (s); 133.7 (s); 129.7 (d); 121.4 (d); 67.9 (t); 51.1 (s); 37.3 (t); 20.8 (q); 20.3 (q); 14.6 (q).
MS: 204 (68, M+), 189 (22), 186 (40), 173 (100), 159 (72), 143 (21), 128 (26), 115 (24), 105 (9), 91 (14), 77 (9), 51
(4), 39 (4).
6.2. (ꢀ)-2,3-Dihydro-2,4,5-trimethyl-1H-indene-2-methanol (3). Prepared according to GP 2 from 19 (1.03
g, 5.0 mmol), and purified by bulb-to-bulb distillation (oven temp. 90 ! 2008 at 0.2 mbar). Yield: 0.82 g (84%;
purity 98%). Colorless oil. IR (neat): 3330, 2900, 2860, 1450, 1370, 1030, 880. 1H-NMR: 6.94 (d, J=8, 1 H); 3.50
(s, 2 H); 2.88 (d, J=16, 1 H); 2.84 (d, J=16, 1 H); 2.63 (d, J=16, 1 H); 2.59 (d, J=16, 1 H); 2.23 (s, 3 H); 2.13 (s,
3 H); 1.78 (br. s, OH); 1.18 (s, 3 H). 13C-NMR: 141.5 (s); 139.7 (s); 134.1 (s); 132.6 (s); 128.0 (d); 121.8 (d); 70.9
(t); 44.4 (s); 42.9 (t); 42.0 (t); 24.4 (q); 19.6 (q); 15.8 (q). MS: 190 (47, M+), 172 (16), 157 (100), 142 (19), 128 (19),
115 (11), 105 (4), 91 (5), 77 (4), 51 (2), 39 (2), 31 (2).
7. Synthesis of Compound 4. 7.1. (ꢀ)-2-(Hydroxymethyl)-2,4,6-trimethylindan-1-one (20). Prepared accord-
ing to GP 1 from 17 (0.53 g, 3.0 mmol), and purified by crystallization from Et2O at ꢁ308. Yield: 0.45 g (73%).
Colorless crystals. M.p. 1108. IR (neat): 3396, 2914, 2869, 1674, 1482, 1309, 1047, 993, 871. 1H-NMR: 7.35 (br. s, 1
H); 7.25 (br. s, 1 H); 3.82 (dd, J=10, 7, 1 H); 3.62 (dd, J=10, 4, 1 H); 3.08 (d, J=16, 1 H); 2.73 (d, J=16, 1 H);
2.56 (br. dd, J=7, 4, OH); 2.35 (s, 3 H); 2.31 (s, 3 H); 1.23 (s, 3 H). 13C-NMR: 211.6 (s); 149.8 (s); 137.6 (s); 137.0
(d); 135.7 (s); 135.5 (s); 121.5 (d); 68.0 (t); 51.1 (s); 36.6 (t); 21.0 (q); 20.8 (q); 17.7 (q). MS: 174 (50), 159 (100),
131 (21), 128 (8), 115 (12), 91 (8), 77 (4), 51 (3), 39 (2).
7.2. (ꢀ)-2,3-Dihydro-2,4,6-trimethyl-1H-indene-2-methanol (4). Prepared according to GP 2 from 20 (0.40
g, 1.96 mmol), and purified by bulb-to-bulb distillation (oven temp. 100 ! 1558 at 0.2 mbar). Yield: 0.30 g (78%;
purity 98%). Colorless oil. IR (neat): 3330 (br.), 2900, 1470, 1370, 1030, 840. 1H-NMR: 6.82 (br. s, 1 H); 6.78 (br.

Helvetica Chimica Acta – Vol. 88 (2005)
3115
s, 1 H); 3.50 (s, 2 H); 2.87 (d, J=16, 1 H); 2.78 (d, J=16, 1 H); 2.62 (d, J=16, 1 H); 2.53 (d, J=16, 1 H); 2.28 (s, 3
H); 2.18 (s, 3 H); 1.80 (s, OH); 1.18 (s, 3 H). 13C-NMR: 142.4 (s); 138.2 (s); 136.1 (s); 133.8 (s); 128.0 (d); 122.8
(d); 70.9 (t); 44.4 (s); 42.9 (t); 41.1 (t); 24.4 (q); 21.1 (q); 19.0 (q). MS: 190 (46, M+), 172 (14), 157 (100), 142 (18),
128 (19), 115 (10), 105 (4), 91 (5), 77 (3), 65 (2), 51 (2), 39 (2).
8. Synthesis of Compound 5. 8.1. (ꢀ)-2-(Hydroxymethyl)-2,4,7-trimethylindan-1-one (21). Prepared accord-
ing to GP 1 from 18 (30 g, 165.0 mmol; purity 95%), and purified by crystallization. Yield: 33.1 g (92%; purity
94%). Colorless crystals. M.p. 113–1148. IR (neat): 3437 (br.), 2965, 2922, 2865, 1682, 1585, 1499, 1250, 1055,
968, 848. 1H-NMR: 7.26 (d, J=7.2, 1 H); 7.03 (d, J=7.2, 1 H); 3.80 (d, J=10.7, 1 H); 3.62 (d, J=10.7, 1 H);
3.03 (d, J=17.4, 1 H); 2.73 (d, J=17.4, 1 H); 2.58 (s, 3 H); 2.34 (br. s, OH); 2.29 (s, 3 H); 1.24 (s, 3 H). 13C-
NMR: 212.5 (s); 152.7 (s); 136.5 (s); 135.0 (s); 132.9 (s); 132.8 (s); 129.5 (d); 67.9 (t); 50.3 (s); 36.6 (t); 21.0
(q); 18.0 (q); 17.5 (q). MS: 204 (55, M+), 189 (9), 186 (29), 174 (47), 173 (100), 171 (37), 159 (56), 145 (12),
143 (17), 130 (12), 129 (18), 128 (23), 117 (8), 116 (6), 115 (20), 105 (7), 91 (10), 77 (6), 65 (3), 51 (3), 39 (2).
8.2. 2,3-Dihydro-2,4,7-trimethyl-1H-indene-2-methanol (5). To a soln. of 21 (17.0 g, 78.0 mmol; purity 94%)
in i-PrOH (30 ml) was added 5% Pd·C (2 g) and methanesulfonic acid (0.2 g, 2.1 mmol), and the mixture was
stirred under H2 (3 bar) at 808 for 7.5 h. The mixture was diluted with toluene (20 ml), washed with 5% aq.
H2SO4, H2O, sat. aq. NaHCO3 soln., and H2O, and then concentrated. Bulb-to-bulb distillation (oven temp.
170 ! 1958 at 1.5 mbar) gave 5 (7.4 g, 48%; purity 96%). Colorless oil that solidified on standing. M.p. 40–
1
418. IR (neat): 3291 (br.), 2952, 2916, 2865, 1498, 1460, 1433, 1376, 1030, 803. H-NMR: 6.87 (s, 2 H); 3.50 (s,
2 H); 2.83 (d, J=15.8, 2 H); 2.58 (d, J=15.8, 2 H); 2.18 (s, 6 H); 1.94 (s, OH); 1.18 (s, 3 H). 13C-NMR: 140.9
(2s); 131.2 (2s); 127.3 (2d); 71.0 (t); 43.7 (s); 41.8 (2t); 24.7 (q); 18.7 (2q). MS: 190 (46, M+), 173 (9), 172
(17), 160 (10), 159 (72), 158 (20), 157 (100), 145 (7), 144 (20), 143 (24), 142 (22), 141 (15), 129 (20), 128 (23),
127 (6), 119 (5), 115 (12), 91 (5), 77 (4), 65 (2), 51 (2), 39 (1).
9. Synthesis of Compound 6. 9.1. Diethyl 1,3-Dihydro-5,6-dimethyl-2H-indene-2,2-dicarboxylate (23). Ele-
mental Na (0.31 g, 13.5 mmol) was dissolved in EtOH (10 ml), and a soln. of diethyl malonate (0.94 g, 5.9
mmol) in EtOH (3 ml) was added dropwise with stirring. After 5 min, a soln. of the dichloride 22 (1.1 g, 5.4
mmol) [9] in EtOH (12 ml) was added, and the mixture was heated at reflux for 3 h. The cooled mixture was
diluted with Et2O, washed with brine (2×), dried (Na2SO4), and concentrated. Bulb-to-bulb distillation (oven
temp. 100 ! 1508 at 0.3 mbar) afforded 23 (0.81 g, 46%; purity 88%). Colorless oil. IR (neat): 2970, 2920,
1730, 1440, 1360, 1275, 1230, 1180, 1155, 1075, 860. 1H-NMR: 6.97 (s, 2 H); 4.18 (q, J=7, 4 H); 3.52 (s, 4 H);
2.21 (s, 6 H); 1.24 (t, J=7, 6 H). 13C-NMR: 171.8 (2s); 137.5 (2s); 135.1 (2s); 125.3 (2d); 61.6 (2t); 60.6 (s);
40.2 (2t); 19.7 (2q); 14.0 (2q). MS: 290 (36, M+), 245 (5), 216 (100), 189 (18), 171 (12), 157 (13), 143 (42), 128
(21), 115 (6), 91 (2), 77 (1), 29 (4).
9.2. 1,3-Dihydro-5,6-dimethyl-2H-indene-2,2-dimethanol (24). To a stirred suspension of LiAlH4 (0.17 g, 4.4
mmol) in Et2O (5 ml) was added dropwise a soln. of 23 (0.64 g, 2.1 mmol; purity 96%) in Et2O (10 ml), and the
mixture was stirred at r.t. for 15 h. The mixture was cooled to 4–58, 10% aq. NaOH soln. (0.9 ml) was added
cautiously, and the mixture was stirred at r.t. for 1 h, dried (Na2SO4), and filtered. The solids were rinsed
with Et2O, and the filtrate was concentrated to a solid (0.38 g), which was crystallized from AcOEt at 08 to afford
24 (0.31 g, 72%). Colorless needles. M.p. 168–168.58. IR (neat): 3287 (br.), 2923, 2873, 1429, 1377, 1219, 1081,
1044, 1023, 990, 884. 1H-NMR ((D6)acetone): 6.90 (s, 2 H); 3.59 (s, 4 H); 2.86 (br. s, 2 OH); 2.72 (s, 4 H); 2.18 (s, 6
H). 13C-NMR ((D6)acetone): 140.7 (2s); 134.7 (2s); 126.7 (2d); 67.2 (2t); 50.5 (s); 38.5 (2t); 19.7 (2q). MS: 206
(12, M+), 188 (2), 173 (6), 157 (100), 142 (20), 128 (12), 115 (8), 91 (4), 77 (3), 31 (2).
9.3. 1,3-Dihydro-5,6-dimethyl-spiro[indene-2,3’-oxetane] (25). To a stirred soln. of 24 (1.37 g, 6.6 mmol) in
THF (20 ml) at ꢁ238 was added dropwise BuLi (1.6
M soln. in hexane, 4.6 ml, 7.3 mmol). After 30 min at
ꢁ238, a soln. of TsCl (1.28 g, 6.6 mmol) in THF (13 ml) was added dropwise, and the mixture was stirred at
ꢁ238 for 4 h (TLC control: toluene/AcOEt 1:1). A second portion of BuLi (4.6 ml, 7.3 mmol) was added drop-
wise at ꢁ238, and the mixture was stirred at r.t. for 60 h. Then, the mixture was diluted with Et2O, washed with
sat. aq. NaHCO3 soln. and brine, dried (K2CO3), and concentrated to a solid, which was purified by FC (150 g
SiO2; toluene/AcOEt 4 :1) to afford 25 (0.95 g, 76%). An anal. sample was crystallized from pentane at ꢁ308 to
afford colorless crystals. M.p. 82–838. IR (neat): 2920, 2855, 1492, 1451, 1431, 1023, 992, 967, 859, 829. 1H-NMR:
6.98 (s, 2 H); 4.65 (s, 4 H); 3.17 (s, 4 H); 2.22 (s, 6 H). 13C-NMR: 139.0 (2s); 134.9 (2s); 125.7 (2d); 83.6 (2t); 47.0
(s); 43.8 (2t); 19.7 (2q). MS: 188 (55, M+), 158 (52), 143 (100), 128 (32), 115 (15), 91 (3), 77 (4), 51 (2), 32 (2).
9.4. 2,3-Dihydro-2,5,6-trimethyl-1H-indene-2-methanol (6). To a stirred suspension of LiAlH4 (0.16 g, 4.1
mmol) in THF (10 ml) was added dropwise a soln. of 25 (0.77 g, 4.1 mmol) in THF (5 ml), and the mixture
was heated to reflux for 22 h. To the cooled mixture was added 10% aq. NaOH soln. (1 ml), and the mixture
was stirred at r.t. for 1 h. Then, Na2SO4 was added, the solids were filtered off, and the filtrate was concentrated
to a solid, which was crystallized from Et2O/pentane at 08 to afford 6 (0.52 g, 67%). Colorless crystals. M.p.

3116
Helvetica Chimica Acta – Vol. 88 (2005)
68.5–698. IR (neat): 3264 (br.), 2919, 2865, 2840, 1490, 1450, 1433, 1358, 1095, 1042, 888, 859. 1H-NMR: 6.94 (s, 2
H); 3.50 (br. s, 2 H); 2.84 (d, J=16, 2 H); 2.58 (d, J=16, 2 H); 2.21 (s, 6 H); 1.16 (s, 3 H). 13C-NMR: 140.0 (2s);
134.4 (2s); 126.0 (2d); 70.8 (t); 45.0 (s); 42.5 (2t); 24.1 (q); 19.7 (2q). MS: 190 (45, M+), 172 (16), 157 (100), 142
(20), 128 (22), 115 (12), 105 (5), 91 (7), 77 (5), 51 (3), 39 (4), 31 (4).
10. Enantiomer Separation of (ꢀ)-1. Racemic 1 (14.4 g) was resolved in portions of 1 g on a prep. HPLC
column (Chiralpack AD; 25×11 cm, 20 mm), eluting with isohexane/EtOH 95 :5. After concentration to dryness,
(+)-(S)-1 (6.39 g) and (ꢁ)-(R)-1 (6.15 g) were obtained and further purified by FC and bulb-to-bulb distillation
(boiling at 1108 oven temp./0.01 mbar). The (S)- and (R)-isomers of 1 were >99% and >98% pure according to
anal. HPLC. [a]2D0 =+3.2 (c=1.5, CHCl3) for (+)-(S)-1; [a]D20 =ꢁ3.1 (c=1.5, CHCl3) for (ꢁ)-(R)-1. The IR,
NMR, and MS data were identical with those of the racemic compound (see above).
11. [(2S)-2,3-Dihydro-2,5-dimethyl-1H-inden-2-yl]methyl (1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo-
[2.2.1]heptane-1-carboxylate (7).
To a soln. of (+)-1 (2.0 g, 11.3 mmol; >99% pure) in anh. pyridine (20 g) at 08 was added (ꢁ)-camphanoyl
chloride (2.5 g, 11.5 mmol; Fluka), and the mixture was stirred overnight at r.t. After usual workup (extraction
with Et2O), the crude crystalline product (4.13 g, 100%) was recrystallized at 08 from hexane/AcOEt 2 :1 to
afford 2.45 g (61%) of pure (+)-7. The crystals were suitable for X-ray analysis. M.p. 85.5–86.68.
[a]2D0 =+3.28 (c=1.34, CHCl3). 1H-NMR: 0.97 (s, 3 H); 1.04 (s, 3 H); 1.12 (s, 3 H); 1.21 (s, 3 H); 1.64–1.72
(m, 1 H); 1.86–1.94 (m, 1 H); 1.98–2.06 (m, 1 H); 2.31 (s, 3 H); 2.33–2.41 (m, 1 H); 2.70 (d, J=15.8, 2 H);
2.89 (d, J=15.8, 2 H); 3.71 (d, J=10.7, 1 H); 3.76 (d, J=10.7, 1 H); 6.95 (d, J=7.5, 1 H); 6.98 (s, 1 H); 7.05
(d, J=7.5, 1 H). 13C-NMR: 9.7 (q); 16.8 (2q); 21.2 (q); 24.4 (q); 28.9 (t); 30.6 (t); 42.8 (t); 43.1 (s); 43.3 (t);
54.1 (s); 54.8 (s); 72.7 (t); 91.3 (s); 124.5 (d); 125.5 (d); 127.3 (d); 136.1 (s); 138.8 (s); 141.9 (s); 167.5 (s);
178.2 (s). MS: 365 (12, M+), 158 (100), 143 (92), 129 (13). X-Ray analysis: see the Figure and Sect. 12.
12. X-Ray Crystal-Structure Determination of 73). Crystal data: colorless prism, 0.10×0.17×0.40 mm; for-
mula, C22H28O4; Mr 356.5; m=0.082 mmꢁ1, Dx =1.211 g/cm3; crystal system, orthorhombic; space group,
P212121; lattice parameters: a=6.5599(3), b=12.1982(7), c=24.4410(12) Å, V=1955.7(2) Åꢁ3, Z=4. Cell
dimensions and intensities were measured at 200 K on a Stoe IPDS diffractometer with graphite-monochro-
mated MoKa radiation (0.71073 Å), 24426 measured reflections, 3799 unique reflections of which 2145 were
observables (|Fo|>4s(Fo)); Rint for 20627 equivalent reflections, 0.052. Data were corrected for Lorentz and
polarization effects, and for absorption (Tmin 0.9792, Tmax 0.9922). The structure was solved by direct methods
(SIR-97) [13], and all other calculations were performed with the XTAL system [14] and ORTEP [15] programs.
Full-matrix least-squares refinement based on
F using a
weight of 1/(s2(Fo)+0.00015(Fo2)) gave
R
final =wR=0.030, and S=1.46(2) for 235 variables and 2376 contributing reflections. The maximum shift/
error on the last cycle was 0.21×10ꢁ3. With the absolute configuration of the camphor moiety being known,
the Flack parameter was fixed at zero.
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[1] B. Winter, S. Gallo-Flückiger, Helv. Chim. Acta 2005, 88, 3118.
[2] B. Winter, P. Schneider, to Firmenich SA, Eur. Pat. Appl. E.P. 1022265, priority 22 Jan, 1999 (Chem. Abstr.
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[4] a) W. E. Bachmann, J. W. Cook, C. L. Hewett, J. Iball, J. Chem. Soc. 1936, 54; b) J. Colonge, G. Weinstein,
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[7] W. Herz, J. L. Rogers, J. Am. Chem. Soc. 1953, 75, 4498; B. B. Elsner, K. J. Parker, J. Chem. Soc. 1957, 592.
[8] R. T. Hart, R. F. Tebbe, J. Am. Chem. Soc. 1950, 72, 3286; W. Herz, J. Am. Chem. Soc. 1951, 73, 4923.
[9] I. Shahak, E. D. Bergmann, J. Chem. Soc. C 1966, 1005.
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[11] M. Lander, Firmenich SA, unpublished results.
3
)
The crystallographic data have been deposited with the Cambridge Crystallographic Data Centre as supple-
mentary publication number CCDC-282417. Copies of the data can be obtained, free of charge, via the
internet at http://www.ccdc.cam.ac.uk/data_request/cif.

Helvetica Chimica Acta – Vol. 88 (2005)
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[12] P. Kraft, S. Gallo, Synthesis 2004, 381; G. Helmchen, G. Staiger, Angew. Chem., Int. Ed. 1977, 16, 116.
[13] A. Altomare, M. C. Burla, M. Camalli, G. Cascarano, C. Giacovazzo, A. Guagliardi, A. G. G. Moliterni, G.
Polidori, R. Spagna, J. Appl. Crystallogr. 1999, 32, 115.
[14] XTAL3.2 (User’s Manual), Eds. S. R. Hall, H. D. Flack, J. M. Stewart, Universities of Western Australia
and Maryland, 1992.
[15] C. K. Johnson, ORTEP II, Report ORNL-5138, Oak Ridge National Laboratory, Oak Ridge, TN, 1976.
Received September 30, 2005