Disila-Phantolide and Derivatives: Synthesis and ... - ACS Publications

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Organometallics 2009, 28, 4700–4712 DOI: 10.1021/om9003219

Disila-Phantolide and Derivatives: Synthesis and Olfactory Characterization of Silicon-Containing Derivatives of the Musk Odorant Phantolide§ Stefan Metz,† Jennifer B. N€ atscher,† Christian Burschka,† Kathrin G€ otz,† Martin Kaupp,† ‡ ,† Philip Kraft, and Reinhold Tacke* †

Universit€ at W€ urzburg, Institut f€ ur Anorganische Chemie, Am Hubland, D-97074 W€ urzburg, Germany, and ‡ € Givaudan Schweiz AG, Fragrance Research, Uberlandstrasse 138, CH-8600 D€ ubendorf, Switzerland Received April 27, 2009

1-(1,1,2,3,3,6-Hexamethyl-1,3-disilaindan-5-yl)ethanone (disila-phantolide, 4), a disila-analogue of the musk odorant phantolide (3), and its silicon-containing derivatives 5-13 were prepared in multistep syntheses and studied for their olfactory properties. In addition, 7 and 11 were structurally characterized by single-crystal X-ray diffraction, and compounds 4-13 were studied computationally (calculations of minimum-energy conformers and the electrostatic potentials). Compounds 4-13 differ in their Si-X-Si moiety (X = CHMe, CdCH2, CH2, O, cyclopropane-1,1-diyl) and in an optional C-6 methyl substituent on the 1,3-disilaindane skeleton. Disila-phantolide (4, X=CHMe), the methylene derivatives 6 and 7 (X=CdCH2), and the cyclopropane-1,1-diyl derivatives 12 and 13 (X = cyclopropane-1,1-diyl) are new musk odorants, with 6 and 7 being the most interesting and powerful ones. In contrast, compounds 8 and 9 (X=CH2) as well as 10 and 11 (X = O) were found to be very weak to odorless and devoid of any musk character. Introduction To study structure-odor correlations and the biodegradability in the family of polycyclic musks (PCMs), siliconcontaining derivatives of the musk odorant versalide (1), such as disila-versalide (2), have recently been synthesized and evaluated.1 Before being withdrawn from the market for toxicological reasons in 1978, versalide (1; odor threshold 1.4 ng L-1 air) has been considered the benchmark musk of the PCM family, the first representative of which was phantolide (3; odor threshold, 6.7 ng L-1 air), discovered in 1951.2 While the disila-substitution of versalide (1) and its derivatives did not improve the biodegradability, it led indeed to a shift in the odor character and the odor intensity, albeit not in the desired direction.1 Disila-versalide (2) was found to be much less musky and less intense than the parent carbon compound versalide (1), with its main odor note being floralgreen with woody facets. In continuation of these studies, we have been interested in the olfactory properties of disilaphantolide (4) and its silicon-containing derivatives 5-13. Disila-phantolide (4) seemed to be a more promising target molecule than disila-versalide (2), with respect to the latitu§ Dedicated with best wishes to Dr. Horst Surburg on the occasion of his 60th birthday. *To whom correspondence should be addressed. Phone: +49-931-8885250. Fax: +49-931-888-4609. E-mail: [email protected]. (1) B€ uttner, M. W.; Penka, M.; Doszczak, L.; Kraft, P.; Tacke, R. Organometallics 2007, 26, 1295–1298. (2) For recent reviews dealing with musk odorants, see: (a) Kraft, P. In Perspectives in Flavor and Fragrance Research; Kraft, P., Swift, K. A. D., Eds.; Verlag Helvetica Chimica Acta: Z€urich, Switzerland, 2005, and WileyVCH: Weinheim, Germany, 2005; pp 127-144. (b) Kraft, P. In Chemistry and Technology of Flavors and Fragrances; Rowe, D. J., Ed.; CRC Press: Boca Raton, FL, 2005, and Blackwell: Oxford, U.K., 2005; pp 143-168.

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dinal dimension of its hydrophobic bulk region,1 but most importantly with respect to the vapor pressure3 since disila-substitution increases the molecular mass and thereby reduces the volatility. Phantolide (3) possesses a clean, sweet-powdery musk note with slightly animalic and sour-sweaty nuances and is synthesized by acid-catalyzed Friedel-Crafts alkylation of 1-isopropyl-4-methylbenzene with 2-methylbutan-2-ol and subsequent Friedel-Crafts acylation with acetyl chloride in the presence of aluminum trichloride.2a Thus, the 1,1,2,3,3pentamethylindane skeleton can be easily built up, but related compounds with molecular features that are incompatible with the formation of carbenium ions cannot be synthesized on that route. For this reason, there are some limitations with respect to an easy access to certain compounds of the phantolide type. Nevertheless, there is some information about structure-odor correlations of phantolide derivatives in the literature. For example, it is known that the gem-dimethyl groups of 3 are essential for the musk odor, especially that on the carbon atom C-3, since the 1,1,2,3,6-pentamethylindane derivative of 3 is odorless.4 The 2-demethyl derivative of 3 was found to be weaker than the parent compound, but possessed a musky, woody odor. A 2-oxa substituent, however, has been demonstrated to be detrimental for the musk character, and none of the 2-oxa derivatives of 3 exhibited a typical musk odor.5 Accordingly, (3) B€ uttner, M. W.; Metz, S.; Kraft, P.; Tacke, R. Organometallics 2007, 26, 3925–3929. (4) Weber, S. H.; Spoelstra, D. B.; Polak, E. H. Recl. Trav. Chim. Pays-Bas 1955, 74, 1179–1196. (5) Shi, G.-q.; Cottens, S.; Shiba, S. A.; Schlosser, M. Tetrahedron 1992, 48, 10569–10574. r 2009 American Chemical Society

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the moiety that bridges the two quaternary carbon atoms of phantolide (3) and its derivatives is very important for the musk character of these compounds. Therefore, the synthesis and olfactory characterization of disila-phantolide derivatives with different Si-X-Si moieties, compounds 6 (X=CdCH2), 8 (X= CH2), 10 (X=O), and 12 (X=cyclopropane-1,1-diyl), was very challenging (Chart 1). The same holds true for the corresponding demethyl derivatives 5, 7, 9, 11, and 13 (Chart 1). We report here on the synthesis and olfactory evaluation of disila-phantolide (4) and its derivatives 5-13 and the crystal structure analyses of 7 and 11. These experimental studies were complemented by computational investigations of 4-13 (calculations of minimum-energy conformers and electrostatic potentials). Preliminary results of the studies described here have already been reported elsewhere.6

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Scheme 1

Chart 1

Scheme 2

Results and Discussion Syntheses. The title compounds 4-13 were synthesized according to Scheme 1. The key step in these syntheses is the formation of the 1,3-disilaindane (2-oxa-1,3-disilaindane) skeleton using a cobalt-catalyzed [2+2+2] cycloaddition, with a catalytic system consisting of cobalt(II) iodide and zinc powder in acetonitrile.7 Thus, the silicon-containing diynes 14, 15, 28, and 29 were treated with the monoynes 30, 31, and 32, respectively, to give the corresponding cycloaddition products 20-27 (27-51% yield), which upon oxidation with manganese dioxide afforded 4-11 (77-97% yield). Treatment of the 2-methylene-1,3-disilaindane derivatives 6 and 7 with indium powder and diiodomethane in acetonitrile (in this context, see ref 8) furnished the 10 ,30 disilaspiro[cyclopropane-1,20 -indane] derivatives 12 and 13, respectively (yields: 12, 30%; 13, 28%). The hitherto unknown starting materials 1,1-bis(ethynyldimethylsilyl)ethane (14) and 1,1-bis(ethynyldimethylsilyl)ethene (15) were synthesized according to Scheme 2. (6) N€ atscher, J.; Metz, S.; Burschka, C.; Kraft, P.; Tacke, R. The 15th International Symposium on Organosilicon Chemistry, Jeju, Korea, June 1-6, 2008, Book of Abstracts, p 160. (7) (a) Doszczak, L.; Fey, P.; Tacke, R. Synlett 2007, 753–756. (b) B€ uttner, M. W.; N€atscher, J. B.; Burschka, C.; Tacke, R. Organometallics 2007, 26, 4835–4838. (c) Doszczak, L.; Tacke, R. Organometallics 2007, 26, 5722–5723. (8) Jain, S. L.; Sain, B. Tetrahedron Lett. 2005, 46, 37–38.

Compound 14 was prepared in a three-step synthesis, starting from 1,4-dioxa-5,5,7,7-tetramethyl-6-methylene-5,7-disilacycloheptane (16). Thus, hydrogenation of 16, in the presence of palladium on charcoal, gave 1,4-dioxa-5,5,6,7,7pentamethyl-5,7-disilacycloheptane (17) (81% yield), which upon treatment with oxalyl chloride, in the presence of catalytic amounts of aluminum trichloride, afforded 1,1bis(chlorodimethylsilyl)ethane (18) (50% yield). Reaction of 18 with ethynylmagnesium bromide finally furnished the diyne 14 (90% yield). Compound 15 was synthesized by treatment of 16 with oxalyl chloride, in the presence of catalytic amounts of aluminum trichloride, to afford 1,1-bis(chlorodimethylsilyl)ethene (19) (33% yield), which upon reaction with ethynylmagnesium bromide gave 15 (87% yield). As the silicon compounds 6 and 7 were found to be strong musk odorants (see Olfactory Studies), attempts were made to synthesize the corresponding carbon analogue 1-(1,1,3,3tetramethyl-2-methyleneindan-5-yl)ethanone (33), starting from 1,1,2,3,3-pentamethylindan-2-ol (34) and 1,1,3,3-tetramethyl-2-methyleneindane (35), respectively (Scheme 3). However, treatment of 34 with acetyl chloride/aluminum trichloride afforded 2,2,3,3-tetramethyl-1-methyleneindane (36). Treatment of 35 with aluminum trichloride also provided only compound 36. Addition of acetyl chloride even accelerated the migration of the methyl group and resulted (after a few minutes at 0 °C) in a complex product mixture.

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Scheme 3

Table 1. Crystal Data and Experimental Parameters for the Crystal Structure Analyses of 7 and 11 7

11

C12H18O2Si2 C14H20OSi2 260.48 250.44 100(2) 193(2) 0.71073 0.71073 triclinic monoclinic P21/c (14) P1 (2) 8.4020(3) 14.234(3) 12.1888(5) 8.4211(17) 15.7181(7) 12.165(2) 72.813(2) 90 82.680(2) 94.99(3) 89.953(2) 90 1524.13(11) 1452.7(5) 4 4 1.135 1.145 0.217 0.230 560 536 0.19 0.16 0.05 0.5 0.4 0.3 2.74-66.26 5.62-57.96 -12 e h e 12, -19 e h e 19, -18 e k e 18, -11 e k e 11, -24 e l e 24 -16 e l e 16 no. of collected reflns 62 199 19 782 no. of indep reflns 11 555 3782 0.0457 0.0534 Rint no. of reflns used 11 555 3782 no. of params 317 150 a 1.044 1.084 S b 0.0483/0.3811 0.0765/0.5121 weight params a/b 0.0321 0.0487 R1c[I > 2σ(I)] 0.0958 0.1384 wR2d (all data) +0.349/-0.352 max./min. residual electron +0.534/-0.231 -3 density, e A˚ P a S={ [w(Fo2 - Fc2)2]/(n-p)}0.5; n=no. of reflections; p=no. of b -1 2 2 w =P σ2(Fo2) + (aP)2+bP, parameters. P P with P=[max(F Po ,0) + 2Fc ]/3. c R1 = ||Fo|-|Fc||/ |Fo|. d wR2={ [w(Fo2 - Fc2)2]/ [w(Fo2)2]}0.5. empirical formula formula mass, g mol-1 collection T, K λ(Mo KR), A˚ cryst syst space group (no.) a, A˚ b, A˚ c, A˚ R, deg β, deg γ, deg V, A˚3 Z D(calcd), g cm-3 μ, mm-1 F(000) cryst dimens, mm 2θ range, deg index ranges

Reaction of 35 with lithium perchlorate/acetic acid anhydride (in this context, see ref 9) at 100 °C also resulted in the formation of 36, accompanied by small amounts of 1-(2,2,3,3-tetramethylindan-1-ylidene)acetone (37). Treatment of 35 with graphite/acetyl bromide/sodium carbonate in refluxing benzene (in this context, see ref 10) afforded after 3 days small amounts of 36, but again no acylation product. (9) Bartoli, G.; Bosco, M.; Marcantoni, E.; Massaccesi, M.; Rinaldi, S.; Sambri, L. Tetrahedron Lett. 2002, 43, 6331–6633. (10) Kodomari, M.; Suzuki, Y.; Yoshida, K. Chem. Commun. 1997, 1567–1568.

Figure 1. Molecular structures of the two crystallographically independent molecules in the crystal of 7 (probability level of displacement ellipsoids 50%). Selected bond lengths [A˚], bond angles [deg], and torsion angles [deg]: Molecule 1: Si1-C3 1.8736(8), Si2-C3 1.8705(9), Si1-C8 1.8831(8), Si2-C7 1.8806(9), C7-C8 1.4169(11); Si1-C3-Si2 109.93(4), Si1-C8C7 116.03(6), Si2-C7-C8 115.93(6), C3-Si1-C8 98.80(4), C3Si2-C7 98.97(4); C7-C8-Si1-C3 2.93(7), C8-Si1-C3-Si2 -5.36(5), Si1-C3-Si2-C7 5.69(5), C3-Si2-C7-C8 -4.12(7), Si2-C7-C8-Si1 0.79(8). Molecule 2: Si3-C23 1.8744(9), Si4C23 1.8711(8), Si3-C28 1.8827(8), Si4-C27 1.8806(8), C27-C28 1.4183(11); Si3-C23-Si4 110.10(4), Si3-C28-C27 115.81(6), Si4-C27-C28 116.26(6), C23-Si3-C28 98.92(4), C23-Si4C27 98.86(4), C27-C28-Si3-C23 -1.05(7), C28-Si3-C23Si4 2.00(5), Si3-C23-Si4-C27 -2.15(5), C23-Si4-C27-C28 1.60(7), Si4-C27-C28-Si3 -0.37(8).

Figure 2. Molecular structure of 11 in the crystal (probability level of displacement ellipsoids 50%). Selected bond lengths [A˚], bond angles [deg], and torsion angles [deg]: Si1-O1 1.6575(14), Si2-O1 1.6538(14), Si1-C8 1.8817(17), Si2-C7 1.8863(18), C7-C8 1.416(2); Si1-O1-Si2 118.09(8), Si1-C8-C7 112.10(12), Si2-C7-C8 112.31(12), O1-Si1-C8 98.84(7), O1 -Si2-C7 98.64(7); C7-C8-Si1-O1 -0.88(14), C8-Si1-O1Si2 1.25(12), Si1-O1-Si2-C7 -1.11(12), O1-Si2-C7-C8 0.43(14), Si2-C7-C8-Si1 0.29(16).

Similarly, treatment with graphite/acetyl bromide in refluxing 1,2-dichloroethane furnished only small amounts of 36 and 37. As 37 turned out to be an odorant as well (albeit not musky), an alternative synthesis was developed starting from 36 (Scheme 3). Thus, by treatment of 36 with graphite/acetyl bromide in refluxing 1,2-dichloroethane, compound 37 was obtained in 34% yield as a mixture of the Z/E

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Figure 3. Calculated electrostatic potentials (-0.118, +0.112 au) of 4, 6, 8, 10, and 12 (view of the bicyclic ring systems from above).

isomers (96:4). In conclusion, no Friedel-Crafts acylation products of 34 and 35 were observed under the abovementioned reaction conditions. Thus, in our hands, neither 33 nor the respective acyl derivative of 36 could be synthesized from 34 or 35. Crystal Structure Analyses. Two representative compounds, 7 (strong musky) and 11 (not musky), were structurally characterized by single-crystal X-ray diffraction. The crystal data and the experimental parameters used for the crystal structure analyses are given in Table 1. The molecular structures of 7 and 11 are shown in Figures 1 and 2; selected bond distances, bond angles, and torsion angles are given in the respective figure legends. As can be seen from Figures 1 and 2, the overall structures of 7 (strong musky) and 11 (not musky) are rather

similar, with an almost planar 1,3-disilaindane and 2-oxa1,3-disilaindane skeleton, respectively. Very similar structural parameters were obtained by computational studies of 7 and 11 (structure optimizations; see Computational Studies). The only significant differences are the steric and electronic properties of the respective moieties in the 2-position of 7 and 11. In compound 7, the CdCH2 group is constrained in the 1,3-disilaindane plane, extending the longitudinal dimension of the molecule. Obviously, the CdCH2 moiety of 7 ideally addresses a hydrophobic binding site of the corresponding receptor that does not accept the disiloxane oxygen atom of 11 (for a detailed discussion of the olfactory properties, see Olfactory Studies). Computational Studies. The minimum-energy conformers and electrostatic potentials of compounds 4-13 were

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Table 2. Olfactory Profiles of Compounds 3-13 compound 3 4 5 6 7 8 9 10 11 12 13

threshold value [ng L-1]

olfactory properties clean sweet-powdery musk odor, with slightly animalic aspects and sour-sweaty nuances weaker than 3 but stronger and more pronounced than 5, with the musk note more round and refined, and the comforting character of polycyclic musks weak musk note of dry connotation, with slightly ambergris-like accents and a latex connotation soft but distinct musk note, with floral facets in the direction of neroli oil, and slightly green-fruity accents less pronounced and weaker than 6, with the musk note accompanied by a dry tonality with slightly animalic facets very weak, only slightly fruity odor impression very weak to odorless, with a slightly mossy, watery, somewhat musty-earthy connotation weak metallic-oily odor, with some dirty seaweed connotation very weak, slightly metallic, with green nuances green, musky odor, with ambrette seed facets; upon dry-down, the green note becomes more fruity, and also woody aspects become more apparentb on the blotter slightly weaker than 12 but more distinct in its musk character, accompanied by fruityfloral facets in the direction of rose

6.7 18 41 0.79 0.94 >200a >200a >200a >200a 5.3 6.7

a Owing to their weak odor intensities and the lack of a musk character, no GC-odor thresholds were determined; however, by judging their strengths on the blotter, they are estimated to be significantly above 200 ng L-1. b Compound 12 was contaminated with a byproduct (ca. 1%) that could not be removed; an influence of this impurity on the olfactory profile cannot be ruled out completely.

calculated. All energy minimizations and frequency calculations were preformed at the BP8611,12/6-311G**13 level with the Gaussian98 program package.14 The electrostatic potentials were calculated and displayed with the Molekel software.15 The parameters of the calculated structures of 7 and 11 correspond well with the results obtained in the crystal structure analyses (e.g., 7, Si-C-Si, 109.93(4)° (expt) and 109.61° (calcd); 11, Si-O-Si, 118.09(8)° (expt) and 117.14° (calcd)), indicating theory and experiment to be in good accordance (for details of the calculated structures of 4-13, see the Supporting Information). The electrostatic potentials of the 1,3-disilaindane skeletons and the acyl moieties of 4-13 (-0.118, +0.112 au) are very similar, except for the 2-position, where the different X groups of the Si-X-Si moieties significantly modify the electrostatic potentials (Figure 3). Obviously, the different substitution types of the 1,3-disilaindane skeleton in the 2-position affect the olfactory properties more than the optional methyl substituent on the carbon atom C-6. In accordance with the olfactory profiles of 4-13, compounds 6/7 (Si-C(dCH2)Si group) and 12/13 (Si-X-Si, X=cyclopropane-1,1-diyl) also have the most similar electrostatic potentials. These results indicate that both the shape and the electrostatic (11) Becke, A. D. Phys. Rev. A 1988, 38, 3098–3100. (12) Perdew, J. P. Phys. Rev. B 1986, 33, 8822–8824. (13) Krishnan, R.; Binkley, J. S.; Seeger, R.; Pople, J. A. J. Chem. Phys. 1980, 72, 650–654. (14) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. A. Gaussian98, 7th ed.; Gaussian Inc.: Pittsburgh, PA, 1998. (15) Fl€ ukiger, P.; L€ uthi, H. P.; Portmann, S.; Weber, J. MOLEKEL 4.0; Swiss National Supercomputing Centre CSCS: Manno, Switzerland, 2000.

potential of the Si-X-Si moiety are crucial parameters for the odor of the compounds studied. Olfactory Studies. The silicon compounds 4-13 were characterized for their olfactory properties. The parent carbon compound phantolide (3) was included in these studies. As can be seen from Table 2, the different substitution types of the 1,3-disilaindane skeleton in the 2-position have a more decisive influence on the olfactory profiles than the optional methyl substituent on the carbon atom C-6. Although the parent silicon compound disila-phantolide (4) clearly is a musk odorant and possesses the typical cozy, comforting character conveyed by polycyclic musks (for instance in laundry applications), it is weaker (odor threshold 18 ng L-1 air) than the carbon analogue phantolide (3, 6.7 ng L-1 air), with its clean, sweet-powdery musk odor accompanied by slightly animalic aspects and sour-sweaty nuances. As we already observed for versalide (1) and disilaversalide (2),1 replacement of the 6-methyl group by a hydrogen atom decreases the muskiness and the overall odor intensity: The demethyl-disila-phantolide derivative 5 possesses an odor threshold value of 41 ng L-1 air, and besides the weak musky note, ambergris-like accents and a latex connotation are discernible. However, the two 2-methylene derivatives 6 and 7, with odor threshold values below 1 ng L-1 air, are more potent than phantolide (3, 6.7 ng L-1 air) and disila-phantolide (4, 18 ng L-1 air), with the demethyl derivative 7 (0.94 ng L-1 air) a bit less powerful than 6 (0.79 ng L-1 air), slightly less musky, drier in tonality, and a touch animalic. The 2methylene-6-methyl derivative 6 in fact turned out to be the best musk odorant of this series of silicon compounds investigated, with a soft and distinct musk character, accompanied by a floral-spicy, orange-blossom note in the direction of neroli oil, and slightly green-fruity accents. As was the case for the corresponding carbon analogues with a C-O-C moiety,5 none of the disiloxanes 10 and 11 (Si-O-Si unit) exhibited a typical musk odor nor much of an odor at all. In contrast to the 2-demethyl derivative of phantolide (3), which is musky (albeit weaker than 3), the disila-analogue 8 and its 6-demethyl derivative 9 lack any musk character. Compounds 8-11 were all very weak, with odor threshold values estimated above 200 ng L-1 air: 8, slightly fruity; 9, slightly mossy, watery, somewhat

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Figure 4. Calculated electrostatic potentials (-0.118, +0.090 au) of 5, 7, 9, 11, and 13 (view of the bicyclic ring systems from above).

musty-earthy; 10 and 11, slightly metallic, with a dirty, oily, seaweed connotation, and green nuances. The cyclopropane-1,1-diyl derivatives 12 and 13 were again musky, however, with odor threshold values of 5.3 and 6.7 ng L-1 air, respectively, less potent than their 2methylene counterparts 6 and 7, and like these they did not differ much in strength. The 6-methyl derivative 12 was slightly more powerful also on the blotter, with its musk note accompanied by ambrette seed facets, but it was getting more woody and fruity upon dry-down. Perhaps this shift toward a woody-fruity note was due to a byproduct (ca. 1%) that could not be removed completely. The 6-demethyl analogue 13 was more distinct in its musk character, albeit slightly weaker, and only slightly fruity-floral facets in the direction of rose accompanied its musk profile. Concerning their odor thresholds, 12 and 13 equal the parent carbon compound phantolide (3); however, the 2-methylene derivatives 6 and 7 are more potent than 3 in terms of odor threshold.

Conclusions Using a cobalt-catalyzed [2+2+2] cycloaddition of a silicon-containing diyne and a monoyne as the synthetic key step for the construction of the 1,3-disilaindane skeleton, disila-phantolide (4), a silicon analogue of the musk odorant phantolide (3), was synthesized. In addition, the related silicon compounds 5-13 were prepared following an analogous synthetic strategy. Disila-phantolide (4) and its derivatives 5-13 differ in their Si-X-Si moiety (X = CHMe, CdCH2, CH2, O, cyclopopane-1,1-diyl) and an optional C-6 methyl substituent on the 1,3-disilaindane skeleton. The SiX-Si group of 4-13 has a strong influence on the muskiness and the odor intensities (odor threshold values) of these compounds. The X-depending rank order of muskiness and odor threshold is CdCH2>cyclopropane-1,1-diyl > CHMe . CH2 ≈ O, with compound 6 (X = CdCH2) being the most intense musk odorant. In general, the Me/H substitution on

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Figure 5. Biflexible superposition of the best musk odorant of this study, compound 6 (odor threshold, 0.79 ng L-1 air), on the high-impact macrocyclic musk (R,Z)-nirvanolide (depicted in black; odor threshold, 0.05 ng L-1 air]19 employing the MOE 2008.10 software package.21

the carbon atom C-6 (4 f 5, 6 f 7, 8 f 9, 10 f 11, 12 f 13) leads to a decrease in both odor intensity and muskiness, which is most significant for the pair 4/5, as has also been reported for related carbon-based musk odorants. Disilasubstitution of phantolide (3) (f4) results in a decreased odor intensity, whereas the disila-phantolide derivatives 12 and 13 have similar odor thresholds to the parent carbon compound 3, and compounds 6 and 7 have even lower ones than phantolide (3). In the domain of macrocyclic musks, it is known that a double bond can have a distinct influence on the musk odor not only because it somewhat constrains the conformational freedom of a molecule16 but also since its electrostatic potential is a binding feature in itself, as was demonstrated by related thia analogues.2b,17 In fact, (R,Z)-nirvanolide18 (38) and (R,5Z)-muscenone19 (39) are among the most powerful musk odorants know to date,2b and the methylene macrolide 40 possesses a very intense musk odor as well.2b The 2-methylene substituent on the 1,3-disilaindane skeleton of 6 and 7 is an unprecedented motif in the family of polycyclic musks, and the amplification of the musk intensity by this particular substituent calls for a superposition analysis with unsaturated macrocyclic musks. The biflexible overlay of 6 (odor threshold, 0.79 ng L-1 air) on (R,Z)nirvanolide (38) (odor threshold, 0.05 ng L-1 air)20 with the MOE 2008.10 software package20 is shown in Figure 5. Evidently, the gauche-corners of 38 as defined by the carbonyloxy function and the methyl group span the same distance as one of the two C-3 methyl groups and the carbonyl (16) Kraft, P.; Berthold, C. Synthesis 2008, 543–550. (17) Kraft, P.; Cadalbert, R. Synlett 1997, 600–602. (18) Kraft, P.; Fr ater, G. Chirality 2001, 13, 388–394. (19) Fehr, C.; Galindo, J.; Etter, O. Eur. J. Org. Chem. 2004, 1953– 1957. (20) Chemical Computing Group Inc. Molecular Operating Environment MOE 2008.10 software package, Montreal, Quebec, Canada H3A 2R7, 2008. For further information, see http://www.chemcomp.com.

function of 6, which is in fact always oriented toward the C-6 substituent. This substituent itself intensifies the musk odor sensation if it is a methyl group. In this alignment, the double bonds of (R,Z)-nirvanolide (38) and 6 come to lie right-angled on top of one another (Figure 5). It has been speculated21 that macrocyclic and polycyclic musk odorants address the same receptor(s), but as this is far from proven one has to be cautious with extrapolations based on such a superposition analysis as described here. In light of the structure-odor relationships found in this study, the carbon-based derivative of the most powerful silicon-containing musk odorant 6 would have been a challenging target structure, but all attempts to synthesize compound 33 failed. Indeed, there are many classes of silicon compounds, the carbon analogues of which are difficult to synthesize or cannot be synthesized at all for principle reasons. In addition to the already established carbon/silicon switch strategy,22 the synthesis of completely new siliconbased classes of compounds (the carbon analogues of which do not exist or are difficult to synthesize) represents a further challenging approach for odorant design.

Experimental Section General Procedures. All syntheses were carried out under dry nitrogen or argon. The organic solvents used were dried and purified according to standard procedures and stored under dry nitrogen. Compounds 4, 5, 22-27, and 30-32 were obtained as racemic mixtures, whereas 20 and 21 were isolated as mixtures of diastereomers (molar ratio (R,R)/(S,S):(R,S)/(S,R), ca. 1:1). A B€ uchi GKR 50 apparatus was used for the bulb-to-bulb distillations. The 1H, 13C, and 29Si NMR spectra were recorded at 23 °C on a Bruker Avance 500 (1H, 500.1 MHz; 13C, 125.8 MHz; 29 Si, 99.4 MHz) or a Bruker DRX-300 NMR spectrometer (1H, 300.1 MHz; 13C, 75.5 MHz; 29Si, 59.6 MHz) using C6D6 or CD2Cl2 as the solvent. Chemical shifts (ppm) were determined relative to internal C6HD5 (1H, δ 7.28; C6D6), C6D6 (13C, δ 128.0; C6D6), CHDCl2 (1H, δ 5.32; CD2Cl2), CD2Cl2 (13C, δ 53.8; CD2Cl2), or external TMS (29Si, δ 0; C6D6, CD2Cl2). Assignment of the 1H NMR data was supported by 1H,1H gradient-selected COSY, 13C,1H gradient-selected HMQC and gradient-selected HMBC, and 29Si,1H gradient-selected HMQC experiments (optimized for 2JSi,H = 7 Hz). Assignment of the 13 C NMR data was supported by DEPT135 and the aforementioned 13C,1H correlation experiments. Olfactory evaluations of the samples as 10% solution in dipropylene glycol (DPG) on smelling blotters were performed by expert perfumers. The odor threshold values were determined by GC-olfactometry. Different dilutions of the sample substances were injected into a gas chromatograph in descending order until the panelists evaluating in blind failed to detect the odor impression at the correct retention time. The reported threshold values are geometrical means of the different values of the individual panelists. (21) Kraft, P.; Cadalbert, R. Chem. Eur. J. 2001, 7, 3254–3262. (22) For a review dealing with silicon-based odorants, see: Tacke, R.; Metz, S. Chem. Biodiversity 2008, 5, 920–941.

Article Preparation of 1-(1,1,2,3,3,6-Hexamethyl-1,3-disilaindan-5yl)ethanone (Disila-phantolide, 4). A stirred mixture of 20 (600 mg, 2.15 mmol), manganese dioxide (936 mg, 10.8 mmol), and dichloromethane (15 mL) was heated under reflux for 36 h. After cooling to 20 °C, the reaction mixture was filtered through a pad of silica gel (35-70 μm, 50 g), followed by elution with nhexane/ethyl acetate (9:1 (v/v), 100 mL). The solvent of the filtrate (including the eluate) was removed under reduced pressure, and the residue was purified by column chromatography (silica gel (35-70 μm); eluent, n-hexane/ethyl acetate (96:4 (v/v))). The relevant fractions (GC control) were combined, the solvent was removed under reduced pressure, and the residue was purified by bulb-to-bulb distillation (120-140 °C/0.04 mbar) to afford compound 4 in 83% yield as a colorless solid (494 mg, 1.79 mmol); mp 26-27 °C. 1H NMR (500.1 MHz, C6D6): δ 0.27 (q, 3JH,H = 7.7 Hz, 1 H, CHCH3), 0.31 (s, 3 H, SiCH3), 0.33 (s, 3 H, SiCH3), 0.37 (s, 3 H, SiCH3), 0.38 (s, 3 H, SiCH3), 1.22 (d, 3JH,H = 7.7 Hz, 3 H, CHCH3), 2.31 (s, 3 H, C(O)CH3), 2.69-2.70 (m, 3 H, CCH3), 7.47-7.48 (m, 1 H, H-7), 7.85 (s, 1 H, H-4). 13C NMR (125.8 MHz, C6D6): δ -3.1 (SiCH3), -2.9 (SiCH3), -0.8 (SiCH3), -0.6 (SiCH3), 4.0 (CHCH3), 8.5 (CHCH3), 21.7 (CCH3), 29.2 (C(O)CH3), 132.2 (C-4), 135.8 (C-7), 138.2 (C-6), 139.4 (C-5), 146.7 (C-3a or C-7a), 153.8 (C-3a or C-7a), 201.1 (C(O)CH3). 29Si NMR (99.4 MHz, C6D6): δ 9.85, 9.87. Anal. Calcd for C15H24OSi2: C, 65.15; H, 8.75. Found: C, 65.0; H, 8.6. Odor description: Stronger and more pronounced than 5, with the musk note more round and refined and the comforting character of polycyclic musks. Odor threshold: 18 ng L-1 air. Preparation of 1-(1,1,2,3,3-Pentamethyl-1,3-disilaindan-5yl)ethanone (5). A mixture of 21 (1.00 g, 3.78 mmol), manganese dioxide (1.64 g, 18.9 mmol), and dichloromethane (30 mL) was stirred at 20 °C for 48 h. The reaction mixture was then filtered through a pad of silica gel (35-70 μm, 50 g), followed by elution with n-hexane/ethyl acetate (9:1 (v/v), 100 mL). The solvent of the filtrate (including the eluate) was removed under reduced pressure, and the residue was purified by column chromatography (silica gel (35-70 μm); eluent, n-hexane/ethyl acetate (96:4 (v/v))). The relevant fractions (GC control) were combined, the solvent was removed under reduced pressure, and the residue was purified by bulb-to-bulb distillation (110-125 °C/0.02 mbar) to afford compound 5 in 89% yield as a colorless oily liquid (885 mg, 3.37 mmol). 1H NMR (500.1 MHz, C6D6): δ 0.24 (q, 3JH,H=7.7 Hz, 1 H, CHCH3), 0.27 (s, 3 H, SiCH3), 0.29 (s, 3 H, SiCH3), 0.33 (s, 3 H, SiCH3), 0.34 (s, 3 H, SiCH3), 1.17 (d, 3 JH,H=7.7 Hz, 3 H, CHCH3), 2.31 (s, 3 H, C(O)CH3), 7.56 (dd, 3 JH,H=7.6 Hz, 5JH,H = 0.8 Hz, 1 H, H-7), 7.96 (dd, 3JH,H=7.6 Hz, 4JH,H=1.7 Hz, 1 H, H-6), 8.38 (dd, 4JH,H=1.7 Hz, 5JH,H= 0.8 Hz, 1 H, H-4). 13C NMR (125.8 MHz, C6D6): δ -3.2 (SiCH3), -3.1 (SiCH3), -0.9 (SiCH3), -0.8 (SiCH3), 3.9 (CHCH3), 8.4 (CHCH3), 26.3 (C(O)CH3), 128.7 (C-6), 131.5 (C-4), 132.4 (C-7), 137.8 (C-5), 150.3 (C-3a or C-7a), 155.7 (C-3a or C-7a), 197.3 (C(O)CH3). 29Si NMR (99.4 MHz, C6D6): δ 10.0, 10.2. Anal. Calcd for C14H22OSi2: C, 64.06; H, 8.45. Found: C, 63.7; H, 8.5. Odor description: Weak musk note of dry connotation, with slightly ambery accents and a latex connotation. Odor threshold: 41 ng L-1 air. Preparation of 1-(1,1,3,3,6-Pentamethyl-2-methylene-1,3-disilaindan-5-yl)ethanone (6). A stirred mixture of 22 (750 mg, 2.71 mmol), manganese dioxide (1.18 g, 13.6 mmol), and dichloromethane (20 mL) was heated under reflux for 24 h. After cooling to 20 °C, the reaction mixture was filtered through a pad of silica gel (35-70 μm, 50 g), followed by elution with n-hexane/ethyl acetate (9:1 (v/v), 100 mL). The solvent of the filtrate (including the eluate) was removed under reduced pressure, and the residue was purified by bulb-to-bulb distillation (90-110 °C/0.02 mbar) to afford compound 6 in 93% yield as a colorless solid (692 mg, 2.52 mmol); mp 68-69 °C. 1H NMR (500.1 MHz, C6D6): δ 0.41 (s, 6 H, SiCH3), 0.42 (s, 6 H, SiCH3), 2.31 (s, 3 H, C(O)CH3), 2.70 (d, 4JH,H = 0.4 Hz, 3 H, CCH3),


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6.63-6.64 (m, 2 H, CCH2), 7.51-7.52 (m, 1 H, H-7), 7.89 (s, 1 H, H-4). 13C NMR (125.8 MHz, C6D6): δ -1.2 (2 C, SiCH3), -0.9 (2 C, SiCH3), 21.7 (CCH3), 29.2 (C(O)CH3), 132.6 (C-4), 136.2 (C-7), 138.4 (C-5 or C-6), 139.4 (C-5 or C-6), 140.5 (CCH2), 146.5 (C-3a or C-7a), 153.1 (CCH2), 153.6 (C-3a or C-7a), 201.0 (C(O)CH3). 29Si NMR (99.4 MHz, C6D6): δ -4.22, -4.19. Anal. Calcd for C15H22OSi2: C, 65.63; H, 8.08. Found: C, 65.6; H, 7.9. Odor description: Soft but distinct musk note, with floral facets in the direction of neroli oil and slightly greenfruity accents. Odor threshold: 0.79 ng L-1 air. Preparation of 1-(1,1,3,3-Tetramethyl-2-methylene-1,3-disilaindan-5-yl)ethanone (7). A stirred mixture of 23 (540 mg, 2.06 mmol), manganese dioxide (894 mg, 10.3 mmol), and dichloromethane (15 mL) was heated under reflux for 8 h. After cooling to 20 °C, the reaction mixture was filtered through a pad of silica gel (35-70 μm, 50 g), followed by elution with n-hexane/ ethyl acetate (9:1 (v/v), 100 mL). The solvent of the filtrate (including the eluate) was removed under reduced pressure, and the residue was purified by bulb-to-bulb distillation (90-100 °C/ 0.02 mbar) to afford compound 7 in 77% yield as colorless crystals (414 mg, 1.59 mmol); mp 53-54 °C. 1H NMR (300.1 MHz, C6D6): δ 0.37 (s, 6 H, SiCH3), 0.39 (s, 6 H, SiCH3), 2.31 (s, 3 H, C(O)CH3), 6.60 (s, 2 H, CCH2), 7.58 (dd, 3JH,H = 7.6 Hz, 5 JH,H = 0.8 Hz, 1 H, H-7), 7.96 (dd, 3JH,H = 7.6 Hz, 4JH,H = 1.7 Hz, 1 H, H-6), 8.42 (dd, 4JH,H = 1.7 Hz, 5JH,H = 0.8 Hz, 1 H, H4). 13C NMR (75.5 MHz, C6D6): δ -1.25 (2 C, SiCH3), -1.17 (2 C, SiCH3), 26.2 (C(O)CH3), 128.7 (C-6), 131.9 (C-4), 132.9 (C-7), 137.9 (C-5), 140.7 (CCH2), 150.1 (C-3a or C-7a), 152.8 (CCH2), 155.4 (C-3a or C-7a), 197.2 (C(O)CH3). 29Si NMR (59.6 MHz, C6D6): δ -3.9, -3.6. Anal. Calcd for C14H20OSi2: C, 64.55; H, 7.74. Found: C, 64.6; H, 7.6. Odor description: Less pronounced and weaker than 6, with the musk note accompanied by a dry tonality with slightly animalic facets. Odor threshold: 0.94 ng L-1 air. Preparation of 1-(1,1,3,3,6-Pentamethyl-1,3-disilaindan-5yl)ethanone (8). A mixture of 24 (210 mg, 794 μmol), manganese dioxide (690 mg, 7.94 mmol), and acetonitrile (7 mL) was stirred at 20 °C for 2 days, followed by heating under reflux for 5 h. After cooling to 20 °C, the reaction mixture was filtered through a pad of silica gel (63-200 μm, 60 g), followed by elution with diethyl ether/n-hexane (4:1 (v/v), 150 mL). The solvent of the filtrate (including the eluate) was removed under reduced pressure, and the residue was purified by column chromatography (silica gel (32-63 μm); eluent, n-hexane/ethyl acetate (3.5:1 (v/v))). The relevant fractions (GC control) were combined, the solvent was removed under reduced pressure, and the residue was dried in vacuo (10 mbar, 50 °C, 1 h) and then recrystallized from n-hexane (3 mL; slow cooling of a hot solution to 20 °C) to afford compound 8 in 91% yield as a colorless solid (189 mg, 720 μmol); mp 82-87 °C. 1H NMR (500.1 MHz, C6D6): δ 0.05 (s, 2 H, SiCH2Si), 0.38 (s, 6 H, SiCH3), 0.40 (s, 6 H, SiCH3), 2.32 (s, 3 H, C(O)CH3), 2.69-2.71 (m, 3 H, CCH3), 7.48-7.50 (m, 1 H, H7), 7.86 (br s, 1 H, H-4). 13C NMR (125.8 MHz, C6D6): δ -2.3 (SiCH2Si), 0.3 (2 C, SiCH3), 0.6 (2 C, SiCH3), 21.7 (C(O)CH3), 29.3 (CCH3), 132.0 (C-4), 135.6 (C-7), 138.2 (C-6), 139.3 (C-5), 147.4 (C-3a), 154.5 (C-7a), 201.1 (C(O)CH3). 29Si NMR (99.4 MHz, C6D6): δ 8.7. Anal. Calcd for C14H22OSi2: C, 64.06; H, 8.45. Found: C, 64.3; H, 8.4. Odor description: Very weak, only a slightly fruity odor impression. Preparation of 1-(1,1,3,3-Tetramethyl-1,3-disilaindan-5-yl)ethanone (9). A mixture of 25 (643 mg, 2.57 mmol), manganese dioxide (2.23 g, 25.7 mmol), and acetonitrile (10 mL) was stirred at 20 °C for 19 h. The reaction mixture was then filtered through a pad of silica gel (63-200 μm, 70 g), followed by elution with diethyl ether/n-hexane (4:1 (v/v), 140 mL). The solvent of the filtrate (including the eluate) was removed under reduced pressure, and the residue was purified by column chromatography (silica gel (32-63 μm); eluent, n-hexane/ethyl acetate (3.5:1 (v/v))). The relevant fractions (GC control) were combined, the solvent was removed under reduced pressure, and the residue was purified by bulb-to-bulb distillation (100-110 °C/0.01 mbar). The solidified

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product was recrystallized from n-hexane (8 mL; slow cooling of a hot solution to 20 °C) to afford compound 9 in 90% yield as a colorless solid (574 mg, 2.31 mmol); mp 42-43 °C. 1H NMR (500.1 MHz, C6D6): δ 0.02 (s, 2 H, SiCH2Si), 0.349 (s, 6 H, SiCH3), 0.354 (s, 6 H, SiCH3), 2.32 (s, 3 H, C(O)CH3), 7.56 (dd, 3JH,H=7.6 Hz, 5 JH,H = 0.8 Hz, 1 H, H-7), 7.97 (dd, 3JH,H=7.6 Hz, 4JH,H = 1.7 Hz, 1 H, H-6), 8.39 (dd, 4JH,H=1.7 Hz, 5JH,H = 0.8 Hz, 1 H, H-4). 13C NMR (125.8 MHz, C6D6): δ -2.4 (SiCH2Si), 0.3 (2 C, SiCH3), 0.4 (2 C, SiCH3), 26.3 (C(O)CH3), 128.6 (C-4), 131.3 (C-6), 132.2 (C-7), 137.8 (C-5), 150.9 (C-3a), 156.3 (C-7a), 197.3 (C(O)CH3). 29 Si NMR (99.4 MHz, C6D6): δ 8.8, 9.1. Anal. Calcd for C13H20OSi2: C, 62.84; H, 8.11. Found: C, 62.9; H, 8.1. Odor description: Very weak to odorless, with a slightly mossy, watery, somewhat musty-earthy connotation. Preparation of 1-(1,1,3,3,6-Pentamethyl-2-oxa-1,3-disilaindan-5-yl)ethanone (10). A stirred mixture of 26 (316 mg, 1.19 mmol), manganese dioxide (1.03 g, 11.8 mmol), and acetonitrile (10 mL) was heated under reflux for 8 h, followed by stirring at 20 °C for 17 h. The reaction mixture was then filtered through a pad of silica gel (63-200 μm, 50 g), followed by elution with diethyl ether/n-hexane (4:1 (v/v), 140 mL). The solvent of the filtrate (including the eluate) was removed under reduced pressure, and the residue was purified by column chromatography (silica gel (32-63 μm); eluent, n-hexane/ethyl acetate (3.5:1 (v/v))). The relevant fractions (GC control) were combined, the solvent was removed under reduced pressure, and the residue was dried in vacuo (10 mbar, 50 °C, 1 h) and then recrystallized from n-hexane (3 mL; slow cooling of a hot solution to 20 °C) to afford compound 10 in 97% yield as a colorless solid (304 mg, 1.15 mmol); mp 96-97 °C. 1H NMR (500.1 MHz, C6D6): δ 0.44 (s, 6 H, SiCH3), 0.45 (s, 6 H, SiCH3), 2.30 (s, 3 H, C(O)CH3), 2.68 (br s, 3 H, CCH3), 7.41 (br s, 1 H, H-7), 7.79 (br s, 1 H, H-4). 13C NMR (125.8 MHz, C6D6): δ 0.9 (2 C, SiCH3), 1.1 (2 C, SiCH3), 21.7 (CCH3), 29.3 (C(O)CH3) 131.0 (C-4), 134.7 (C-7), 138.5 (C-6), 139.6 (C-5), 145.6 (C-3a), 152.4 (C-7a), 201.1 (C(O)CH3). 29 Si NMR (99.4 MHz, C6D6): δ 14.4, 14.6. Anal. Calcd for C13H20O2Si2: C, 59.04; H, 7.62. Found: C, 59.2; H, 7.6. Odor description: Weak metallic-oily odor, with some dirty seaweed connotation. Preparation of 1-(1,1,3,3-Tetramethyl-2-oxa-1,3-disilaindan5-yl)ethanone (11). A stirred mixture of 27 (1.83 g, 7.25 mmol), manganese dioxide (6.31 g, 72.6 mmol), and acetonitrile (20 mL) was heated under reflux for 3 h. After cooling to 20 °C, the reaction mixture was filtered through a pad of silica gel (63200 μm, 70 g), followed by elution with diethyl ether/n-hexane (4:1 (v/v), 150 mL). The solvent of the filtrate (including the eluate) was removed under reduced pressure, and the residue was purified by column chromatography (silica gel (32-63 μm); eluent, n-hexane/ethyl acetate (3.5:1 (v/v))). The relevant fractions (GC control) were combined, the solvent was removed under reduced pressure, and the residue was dried in vacuo (10 mbar, 50 °C, 1 h) and then recrystallized from n-hexane (7 mL; slow cooling of a hot solution to 20 °C) to afford compound 11 in 84% yield as a colorless solid (1.53 g, 6.11 mmol); mp 86-87 °C. 1 H NMR (500.1 MHz, CD2Cl2): δ 0.36 (s, 6 H, SiCH3), 0.38 (s, 6 H, SiCH3), 2.60 (s, 3 H, C(O)CH3), 7.68 (dd, 3JH,H =7.6 Hz, 5 JH,H = 0.9 Hz, 1 H, H-7), 7.95 (dd, 3JH,H=7.6 Hz, 4JH,H = 1.6 Hz, 1 H, H-6), 8.13 (dd, 4JH,H =1.6 Hz, 5JH,H = 0.9 Hz, 1 H, H-4). 13C NMR (125.8 MHz, CD2Cl2): δ 0.8 (2 C, SiCH3), 1.0 (2 C, SiCH3), 27.0 (C(O)CH3), 128.8 (C-6), 130.6 (C-4), 131.5 (C-7), 137.6 (C-5), 149.2 (C-3a), 154.7 (C-7a), 198.9 (C(O)CH3). 29 Si NMR (99.4 MHz, CD2Cl2): δ 15.0, 15.2. Anal. Calcd for C12H18O2Si2: C, 57.55; H, 7.24. Found: C, 57.4; H, 7.3. Odor description: Very weak, slightly metallic with green nuances. Preparation of 1-(10 ,10 ,30 ,30 ,60 -Pentamethyl-10 ,30 -disilaspiro[cyclopropan-1,20 -indan]-50 -yl)ethanone (12). A mixture of 6 (1.08 g, 3.93 mmol), indium powder (1.36 g, 11.8 mmol), diiodomethane (3.16 g, 11.8 mmol), and acetonitrile (35 mL) was stirred at 60 °C for 3 days. The solvent was removed under reduced pressure, and the residue was filtered through a pad of

Metz et al. silica gel (35-70 μm, 70 g), followed by elution with n-hexane/ ethyl acetate (65:35 (v/v), 150 mL). The solvent of the filtrate (including the eluate) was removed under reduced pressure, and the residue was dissolved in acetonitrile (35 mL). Subsequently, indium powder (903 mg, 7.86 mmol) and diiodomethane (2.11 g, 7.88 mmol) were added, and the resulting mixture was stirred at 60 °C for 2 days. The latter step (treatment with indium powder and diiodomethane and stirring of the reaction mixture at 60 °C for 2 days) was repeated four times. Subsequently, the solvent was removed under reduced pressure, and the oily residue was applied to the top of a pad of silica gel (35-70 μm, 60 g), followed by elution with n-hexane/ethyl acetate (65:35 (v/v), 200 mL). The solvent of the filtrate (including the eluate) was removed under reduced pressure, and the residue was purified by column chromatography (silica gel (35-70 μm); eluent, nhexane/ethyl acetate (95:5 (v/v))). The relevant fractions (GC control) were combined, the solvent was removed under reduced pressure, and the solid residue was recrystallized from ethanol (700 μL; slow cooling of a hot solution to -20 °C) to afford compound 12 in 30% yield as colorless solid (335 mg, 1.16 mmol); mp 56-58 °C. 1H NMR (500.1 MHz, C6D6): δ 0.23 (s, 6 H, SiCH3), 0.24 (s, 6 H, SiCH3), 0.90-0.91 (m, 4 H, CCH2CH2), 2.32 (s, 3 H, C(O)CH3), 2.71 (d, 4JH,H = 0.3 Hz, 3 H, CCH3), 7.50-7.51 (m, 1 H, H-7), 7.87 (s, 1 H, H-4). 13C NMR (125.8 MHz, C6D6): δ -8.5 (CCH2CH2), -2.2 (2 C, SiCH3), -2.0 (2 C, SiCH3), 8.2 (CCH2CH2), 21.8 (CCH3), 29.2 (C(O)CH3), 132.2 (C-4), 135.8 (C-7), 138.1 (C-5 or C-6), 139.1 (C-5 or C-6), 147.2 (C-3a or C-7a), 154.3 (C-3a or C-7a), 201.1 (C(O)CH3). 29Si NMR (99.4 MHz, C6D6): δ 9.36, 9.39. Anal. Calcd for C16H24OSi2: C, 66.60; H, 8.38. Found: C, 66.3; H, 8.4. Odor description: Green, musky odor, with ambrette seed facets; upon dry-down, the green note becomes more fruity, and also woody aspects become more apparent. Odor threshold: 5.3 ng L-1 air. Preparation of 1-(10 ,10 ,30 ,30 -Tetramethyl-10 ,30 -disilaspiro[cyclopropan-1,20 -indan]-50 -yl)ethanone (13). A mixture of 7 (400 mg, 1.54 mmol), indium powder (529 mg, 4.61 mmol), diiodomethane (1.23 g, 4.59 mmol), and acetonitrile (12 mL) was stirred at 60 °C for 3 days. The solvent was removed under reduced pressure, and the residue was filtered through a pad of silica gel (35-70 μm, 50 g), followed by elution with n-hexane/ ethyl acetate (65:35 (v/v), 100 mL). The solvent of the filtrate (including the eluate) was removed under reduced pressure, and the residue was dissolved in acetonitrile (12 mL). Subsequently, indium powder (353 mg, 3.07 mmol) and diiodomethane (823 mg, 3.07 mmol) were added, and the resulting mixture was stirred at 60 °C for 2 days. The latter step (treatment with indium powder and diiodomethane and stirring of the reaction mixture at 60 °C for 2 days) was repeated four times. The solvent was removed under reduced pressure, and the oily residue was applied to the top of a pad of silica gel (35-70 μm, 50 g), followed by elution with n-hexane/ethyl acetate (65:35 (v/v), 150 mL). The solvent of the filtrate (including the eluate) was removed under reduced pressure, and the residue was purified by column chromatography (silica gel (35-70 μm); eluent, nhexane/ethyl acetate (95:5 (v/v))). The relevant fractions (GC control) were combined, the solvent was removed under reduced pressure, and the residue was purified by bulb-to-bulb distillation (100-130 °C/0.02 mbar) to afford compound 13 in 28% yield as a colorless oily liquid (118 mg, 430 μmol). 1H NMR (500.1 MHz, C6D6): δ 0.19 (s, 6 H, SiCH3), 0.21 (s, 6 H, SiCH3), 0.87 (s, 4 H, CCH2CH2), 2.32 (s, 3 H, C(O)CH3), 7.58 (dd, 3 JH,H =7.6 Hz, 5JH,H =0.8 Hz, 1 H, H-7), 7.97 (dd, 3JH,H =7.6 Hz, 4JH,H=1.7 Hz, 1 H, H-6), 8.41 (dd, 4JH,H = 1.7 Hz, 5JH,H = 0.8 Hz, 1 H, H-4). 13C NMR (125.8 MHz, C6D6): δ -8.6 (CCH2CH2), -2.3 (2 C, SiCH3), -2.2 (2 C, SiCH3), 8.2 (CCH2CH2), 26.3 (C(O)CH3), 128.5 (C-6), 131.4 (C-4), 132.4 (C-7), 137.6 (C-5), 150.8 (C-3a or C-7a), 156.1 (C-3a or C-7a), 197.4 (C(O)CH3). 29Si NMR (99.4 MHz, C6D6): δ 9.4, 9.7. Anal. Calcd for C15H22OSi2: C, 65.63; H, 8.08. Found: C, 65.7; H, 8.1. Odor description: Slightly weaker than 12, but more distinct in

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its musk character, accompanied by fruity-floral facets in the direction of rose. Odor threshold: 6.7 ng L-1 air. Preparation of 1,1-Bis(ethynyldimethylsilyl)ethane (14). A 0.5 M solution of ethynylmagnesium bromide in THF (127 mL, 63.5 mmol of HCtCMgBr) was added at 20 °C within 30 min to a stirred solution of 18 (6.50 g, 30.2 mmol) in THF (20 mL). The resulting mixture was heated under reflux for 4 h, allowed to cool to 20 °C, and then poured into water (150 mL). The aqueous layer was separated and extracted with diethyl ether (275 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (50 mL) and dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by distillation in vacuo to afford compound 14 in 90% yield as a colorless liquid (5.30 g, 27.3 mmol); bp 62-63 °C/10 mbar. 1H NMR (300.1 MHz, C6D6): δ 0.06 (q, 3JH,H=7.5 Hz, 1 H, CHCH3), 0.36 (s, 12 H, SiCH3), 1.31 (d, 3JH,H = 7.5 Hz, 3 H, CHCH3), 2.18 (s, 2 H, CCH). 13C NMR (75.5 MHz, C6D6): δ -1.1 (2 C, SiCH3), -0.9 (2 C, SiCH3), 6.0 (CHCH3), 9.8 (CHCH3), 89.5 (2 C, CCH), 94.7 (2 C, CCH). 29Si NMR (59.6 MHz, C6D6): δ -12.2. Anal. Calcd for C10H18Si2: C, 61.78; H, 9.33. Found: C, 61.5; H, 9.4. Preparation of 1,1-Bis(ethynyldimethylsilyl)ethene (15). A 0.5 M solution of ethynylmagnesium bromide in THF (125 mL, 62.5 mmol of HCtCMgBr) was added at 20 °C within 30 min to a stirred solution of 19 (6.50 g, 30.5 mmol) in THF (25 mL). The resulting mixture was stirred at 20 °C for 5 h and then poured into water (100 mL). The aqueous layer was separated and extracted with diethyl ether (2 60 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (50 mL) and dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by bulb-to-bulb distillation (50-60 °C/10 mbar) to afford compound 15 in 87% yield as a colorless liquid (5.12 g, 26.6 mmol). 1H NMR (300.1 MHz, C6D6): δ 0.45 (s, 12 H, SiCH3), 2.23 (s, 2 H, CCH), 6.73 (s, 2 H, CCH2). 13C NMR (75.5 MHz, C6D6): δ -0.2 (4 C, SiCH3), 88.6 (2 C, CCH), 95.6 (2 C, CCH), 144.8 (CCH2), 147.0 (CCH2). 29Si NMR (59.6 MHz, C6D6): δ -19.9. Anal. Calcd for C10H16Si2: C, 62.42; H, 8.38. Found: C, 62.4; H, 8.4. Preparation of 1,4-Dioxa-5,5,7,7-tetramethyl-6-methylene5,7-disilacycloheptane (16). This compound was synthesized in two steps according to ref 23; in the second step, toluene was used as the solvent instead of working solvent-free. Preparation of 1,4-Dioxa-5,5,6,7,7-pentamethyl-5,7-disilacycloheptane (17). A mixture of 16 (23.7 g, 117 mmol) and palladium on charcoal (830 mg; 10% palladium, 780 μmol of Pd) was stirred at 20 °C under a hydrogen atmosphere for 4 h. The reaction mixture was then filtered through a pad of silica gel (35-70 μm, 25 g), followed by elution with n-hexane/ethyl acetate (4:1 (v/v), 150 mL). The solvent of the filtrate (including the eluate) was removed under reduced pressure, and the residue was purified by distillation in vacuo to afford compound 17 in 81% yield as a colorless liquid (19.4 g, 94.9 mmol); bp 76-78 °C/10 mbar. 1H NMR (300.1 MHz, C6D6): δ 0.22 (q, 3JH,H=7.7 Hz, 1 H, CHCH3), 0.29 (br s, 12 H, SiCH3), 1.05 (d, 3JH,H = 7.7 Hz, 3 H, CHCH3), 3.71-3.73 (m, 4 H, OCH2CH2O). 13C NMR (75.5 MHz, C6D6): δ -2.8 (2 C, SiCH3), -0.7 (2 C, SiCH3), 8.7 (CHCH3), 12.5 (CHCH3), 66.3 (2 C, OCH2CH2O). 29Si NMR (59.6 MHz, C6D6): δ 20.7. Anal. Calcd for C8H20O2Si2: C, 47.01; H, 9.86. Found: C, 47.0; H, 9.8. Preparation of 1,1-Bis(chlorodimethylsilyl)ethane (18). Oxalyl chloride (10.3 g, 81.1 mmol) was added dropwise at 20 °C (water bath) within 5 min to a stirred mixture of 17 (16.2 g, 79.2 mmol) and aluminum trichloride (528 mg, 3.96 mmol). The reaction mixture was stirred at 50 °C for 2 h and was then allowed to cool to 20 °C. n-Pentane (50 mL) was added, and the resulting suspension was stirred at 20 °C for 15 min. The insoluble solid

was removed by centrifugation and discarded, the solvent of the supernatant was removed by distillation at normal pressure, and the residue was purified by distillation in vacuo to afford compound 18 in 50% yield as a colorless liquid (8.51 g, 39.5 mmol); bp 74-75 °C/10 mbar. 1H NMR (300.1 MHz, C6D6): δ 0.20 (q, 3JH,H=7.5 Hz, 1 H, CHCH3), 0.38 (s, 6 H, SiCH3), 0.39 (s, 6 H, SiCH3), 1.14 (d, 3JH,H=7.5 Hz, 3 H, CHCH3). 13C NMR (75.5 MHz, C6D6): δ 1.8 (2 C, SiCH3), 2.2 (2 C, SiCH3), 8.7 (CHCH3), 13.2 (CHCH3). 29Si NMR (59.6 MHz, C6D6): δ 31.9. Anal. Calcd for C6H16Cl2Si2: C, 33.48; H, 7.49. Found: C, 33.4; H, 7.5. Preparation of 1,1-Bis(chlorodimethylsilyl)ethene (19). Oxalyl chloride (6.40 g, 50.4 mmol) was added dropwise at 20 °C (water bath) within 45 min to a stirred mixture of 16 (10.0 g, 49.4 mmol) and aluminum trichloride (329 mg, 2.47 mmol). The reaction mixture was stirred at 20 °C for 4 h, n-pentane (30 mL) was added, and the resulting suspension was stirred at 20 °C for 15 min. The insoluble solid was removed by centrifugation and discarded, the solvent of the supernatant was removed by distillation at normal pressure, and the residue was purified by distillation in vacuo to afford compound 19 in 33% yield as a colorless liquid (3.50 g, 16.4 mmol); bp 75-76 °C/20 mbar. 1H NMR (300.1 MHz, C6D6): δ 0.49 (s, 12 H, SiCH3), 6.48 (s, 2 H, CCH2). 13C NMR (75.5 MHz, C6D6): δ 2.9 (4 C, SiCH3), 145.8 (CCH2), 148.0 (CCH2). 29 Si NMR (59.6 MHz, C6D6): δ 21.4. Anal. Calcd for C6H14Cl2Si2: C, 33.79; H, 6.62. Found: C, 33.4; H, 6.6. Preparation of 1-(1,1,2,3,3,6-Hexamethyl-1,3-disilaindan-5yl)ethanol (20). Compound 14 (1.00 g, 5.14 mmol), 30 (519 mg, 6.17 mmol), and a 0.1 M solution of cobalt(II) iodide in acetonitrile (1.29 mL, 129 μmol of CoI2) were added in single portions one after another at 45 °C to a stirred suspension of zinc powder (42 mg, 642 μmol) in acetonitrile (12 mL).24 The reaction mixture was stirred at 45 °C for 30 min and then cooled to 20 °C, followed by the addition of sodium carbonate (100 mg, 943 μmol). The reaction mixture was filtered through a pad of silica gel (35-70 μm, 50 g), followed by elution with n-hexane/ ethyl acetate (4:1 (v/v), 100 mL). The solvent of the filtrate (including the eluate) was removed under reduced pressure, and the residue was purified by column chromatography (silica gel (35-70 μm); eluent, n-hexane/ethyl acetate (9:1 (v/v))). The relevant fractions (GC control) were combined, the solvent was removed under reduced pressure, and the solid residue was recrystallized from n-hexane (4 mL; slow cooling of a hot solution to 20 °C) to afford compound 20 in 39% yield as a colorless solid (565 mg, 2.03 mmol); mp 106-109 °C. 1H NMR (500.1 MHz, C6D6); data for the (R,R)/(S,S) and (R,S)/(S,R) diastereomers (molar ratio ca. 1:1): δ 0.30 (q, 3JH,H = 7.7 Hz, 1 H, SiCHCH3), 0.31 (q, 3JH,H =7.7 Hz, 1 H, SiCHCH3), 0.37 (br s, 6 H, SiCH3), 0.38 (s, 3 H, SiCH3), 0.39 (s, 3 H, SiCH3), 0.42 (s, 3 H, SiCH3), 0.43 (s, 3 H, SiCH3), 0.44 (s, 3 H, SiCH3), 0.45 (s, 3 H, SiCH3), 1.21 (d, 3JH,H =3.2 Hz, 2 H, OH), 1.24-1.28 (m, 6 H, SiCHCH3), 1.42 (d, 3JH,H = 6.4 Hz, 3 H, C(OH)CH3), 1.43 (d, 3JH,H=6.4 Hz, 3 H, C(OH)CH3), 2.26-2.27 (m, 6 H, CCH3), 4.92 (dq, 3JH,H =6.4 Hz, 3JH,H =3.2 Hz, 2 H, CH(OH)), 7.467.48 (m, 2 H, H-7), 8.02 (s, 2 H, H-4). 13C NMR (125.8 MHz, C6D6): δ -2.74 (SiCH3), -2.68 (2 C, SiCH3), -2.6 (SiCH3), -0.50 (SiCH3), -0.48 (SiCH3), -0.40 (SiCH3), -0.36 (SiCH3), 4.0 (SiCHCH3), 4.1 (SiCHCH3), 8.6 (SiCHCH3), 8.7 (SiCHCH3), 19.1 (2 C, CCH3), 24.28 (C(OH)CH3), 24.30 (C(OH)CH3), 67.07 (C(OH)CH3), 67.10 (C(OH)CH3), 128.40 (C-4), 128.41 (C-4), 134.3 (2 C, C-7), 134.9 (C-6), 135.0 (C-6), 145.4 (C-5), 145.5 (C5), 147.33 (C-3a or C-7a), 147.34 (C-3a or C-7a), 148.236 (C-3a or C-7a), 148.245 (C-3a or C-7a). 29Si NMR (99.4 MHz, C6D6): δ 9.25, 9.34, 9.5, and 9.6. Anal. Calcd for C15H26OSi2: C, 64.68; H, 9.41. Found: C, 64.7; H, 9.7. Preparation of 1-(1,1,2,3,3-Pentamethyl-1,3-disilaindan-5yl)ethanol (21). Compound 14 (2.00 g, 10.3 mmol), 31 (1.78 g,

(23) Pawluc, P.; Marciniec, B.; Hreczycho, G.; Gaczewska, B.; Itami, Y. J. Org. Chem. 2005, 70, 370–372.

(24) A suspension of zinc powder in acetonitrile was treated with catalytic amounts of iodine and heated until a colorless mixture resulted.

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12.5 mmol), and a 0.1 M solution of cobalt(II) iodide in acetonitrile (2.57 mL, 257 μmol of CoI2) were added in single portions one after another at 20 °C to a stirred suspension of zinc powder (67 mg, 1.02 mmol) in acetonitrile (20 mL).24 The reaction mixture was stirred at ca. 40 °C for 5 min, cooled with a water bath (20 °C), and then stirred at 20 °C for a further 30 min, followed by the addition of sodium carbonate (200 mg, 1.89 mmol). The reaction mixture was filtered through a pad of silica gel (35-70 μm, 80 g), followed by elution with n-hexane/ethyl acetate (4:1 (v/v), 200 mL). The solvent of the filtrate (including the eluate) was removed under reduced pressure, and the residue was dissolved in a mixture of ethanol (20 mL) and acetic acid (309 mg, 5.15 mmol). The resulting mixture was heated under reflux for 3 h, cooled to 20 °C, and then poured into a mixture of water (15 mL), a saturated aqueous solution of sodium carbonate (5 mL), and diethyl ether (20 mL). The organic layer was separated, the aqueous layer was extracted with diethyl ether (2 20 mL), the combined organic extracts were dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (silica gel (35-70 μm), 180 g; eluent, n-hexane/ethyl acetate (9:1 (v/v))). The relevant fractions (GC control) were combined, the solvent was removed under reduced pressure, and the residue was purified by bulb-to-bulb distillation (100-125 °C/0.02 mbar) to afford compound 21 in 47% yield as a colorless oily liquid (1.27 g, 4.80 mmol). 1H NMR (500.1 MHz, C6D6); data for the (R,R)/(S,S) and (R,S)/(S,R) diastereomers (molar ratio ca. 1:1): δ 0.29 (q, 3JH,H =7.7 Hz, 2 H, SiCHCH3), 0.340 (s, 3 H, SiCH3), 0.342 (s, 3 H, SiCH3), 0.35 (s, 3 H, SiCH3), 0.36 (s, 3 H, SiCH3), 0.400 (s, 3 H, SiCH3), 0.401 (s, 3 H, SiCH3), 0.410 (s, 3 H, SiCH3), 0.415 (s, 3 H, SiCH3), 1.23 (d, 3JH,H=7.7 Hz, 6 H, SiCHCH3), 1.36 (d, 3JH,H=3.4 Hz, 2 H, OH), 1.45 (d, 3JH,H = 6.5 Hz, 6 H, C(OH)CH3), 4.72 (dq, 3JH,H = 6.5 Hz, 3JH,H=3.4 Hz, 2 H, CH(OH)), 7.42-7.47 (m, 2 H, H6), 7.60-7.64 (m, 2 H, H-7), 7.72-7.76 (m, 2 H, H-4). 13C NMR (125.8 MHz, C6D6): δ -2.79 (2 C, SiCH3), -2.77 (2 C, SiCH3), -0.57 (SiCH3), -0.56 (SiCH3), -0.54 (SiCH3), -0.53 (SiCH3), 4.02 (SiCHCH3), 4.03 (SiCHCH3), 8.54 (SiCHCH3), 8.55 (SiCHCH3), 25.738 (C(OH)CH3), 25.742 (C(OH)CH3), 70.49 (C(OH)CH3), 70.50 (C(OH)CH3), 126.49 (C-6), 126.51 (C-6), 129.16 (C-4), 129.18 (C-4), 132.46 (C-7), 132.47 (C-7), 147.2 (2 C, C-5), 148.5 (2 C, C-3a or C-7a), 149.94 (C-3a or C-7a), 149.95 (C-3a or C-7a). 29Si NMR (99.4 MHz, C6D6): δ 9.3 (2 Si), 9.66, and 9.67. Anal. Calcd for C14H24OSi2: C, 63.57; H, 9.15. Found: C, 63.5; H, 9.3. Preparation of 1-(1,1,3,3,6-Pentamethyl-2-methylene-1,3-disilaindan-5-yl)ethanol (22). Compound 15 (2.00 g, 10.4 mmol), 30 (1.05 g, 12.5 mmol), and a 0.1 M solution of cobalt(II) iodide in acetonitrile (4.16 mL, 416 μmol of CoI2) were added in single portions one after another at 40 °C to a stirred suspension of zinc powder (85 mg, 1.30 mmol) in acetonitrile (25 mL).24 The reaction mixture was stirred at 40 °C for 2 h and then cooled to 20 °C, followed by the addition of sodium carbonate (200 mg, 1.89 mmol). The reaction mixture was filtered through a pad of silica gel (35-70 μm, 70 g), followed by elution with n-hexane/ ethyl acetate (4:1 (v/v), 200 mL). The solvent of the filtrate (including the eluate) was removed under reduced pressure, and the residue was purified by column chromatography (silica gel (35-70 μm), 180 g; eluent, n-hexane/ethyl acetate (85:15 (v/v))). The relevant fractions (GC control) were combined, the solvent was removed under reduced pressure, and the solid residue was recrystallized from n-hexane (3 mL; slow cooling of a hot solution to 20 °C) to afford compound 22 in 31% yield as a colorless solid (900 mg, 3.25 mmol); mp 107-109 °C. 1H NMR (500.1 MHz, C6D6): δ 0.46 (s, 3 H, SiCH3), 0.47 (s, 3 H, SiCH3), 0.478 (s, 3 H, SiCH3), 0.484 (s, 3 H, SiCH3), 1.22 (d, 3JH,H =3.0 Hz, 1 H, OH), 1.43 (d, 3JH,H = 6.4 Hz, 3 H, C(OH)CH3), 2.27 (d, 4 JH,H=0.3 Hz, 3 H, CCH3), 4.92 (dq, 3JH,H=6.4 Hz, 3JH,H=3.0 Hz, 1 H, CH(OH)), 6.66 (s, 2 H, CCH2), 7.50-7.51 (m, 1 H, H7), 8.06 (s, 1 H, H-4). 13C NMR (125.8 MHz, C6D6): δ -0.83

Metz et al. (SiCH3), -0.79 (SiCH3), -0.74 (SiCH3), -0.68 (SiCH3), 19.1 (CCH3), 24.3 (C(OH)CH3), 67.1 (C(OH)CH3), 128.9 (C-4), 134.7 (C-7), 135.1 (C-5 or C-6), 139.8 (CCH2), 145.6 (C-5 or C-6), 147.2 (C-3a or C-7a), 148.0 (C-3a or C-7a), 154.1 (CCH2). 29 Si NMR (99.4 MHz, C6D6): δ -4.5, -4.2. Anal. Calcd for C15H24OSi2: C, 65.15; H, 8.75. Found: C, 65.2; H, 8.9. Preparation of 1-(1,1,3,3-Tetramethyl-2-methylene-1,3-disilaindan-5-yl)ethanol (23). Compound 15 (1.00 g, 5.20 mmol), 31 (961 mg, 6.75 mmol), and a 0.1 M solution of cobalt(II) iodide in acetonitrile (1.30 mL, 130 μmol of CoI2) were added in single portions one after another at 40 °C to a stirred suspension of zinc powder (43 mg, 658 μmol) in acetonitrile (13 mL).24 The reaction mixture was stirred at 40 °C for 2 h and then cooled to 20 °C, followed by the addition of sodium carbonate (100 mg, 943 μmol). The reaction mixture was filtered through a pad of silica gel (35-70 μm, 50 g), followed by elution with n-hexane/ ethyl acetate (4:1 (v/v), 150 mL). The solvent of the filtrate (including the eluate) was removed under reduced pressure, and the residue was dissolved in a mixture of ethanol (13 mL) and acetic acid (156 mg, 2.60 mmol). The resulting mixture was heated under reflux for 1 h, cooled to 20 °C, and then poured into a mixture of water (12 mL), a saturated aqueous solution of sodium carbonate (3 mL), and diethyl ether (15 mL). The organic layer was separated, the aqueous layer was extracted with diethyl ether (2 15 mL), the combined organic extracts were dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (silica gel (35-70 μm); eluent, n-hexane/ethyl acetate (85:15 (v/v))). The relevant fractions (GC control) were combined, the solvent was removed under reduced pressure, and the residue was purified by bulb-to-bulb distillation (110-130 °C/0.02 mbar) to afford compound 23 in 42% yield as a colorless oily liquid (573 mg, 2.18 mmol). 1H NMR (300.1 MHz, C6D6): δ 0.44 (s, 6 H, SiCH3), 0.45 (s, 3 H, SiCH3), 0.46 (s, 3 H, SiCH3), 1.37 (d, 3JH,H=3.2 Hz, 1 H, OH), 1.46 (d, 3JH,H=6.4 Hz, 3 H, C(OH)CH3), 4.72 (dq, 3JH,H = 6.4 Hz, 3JH,H =3.2 Hz, 1 H, CH(OH)), 6.65 (s, 2 H, CCH2), 7.447.47 (m, 1 H, H-6), 7.63-7.66 (m, 1 H, H-7), 7.77-7.78 (m, 1 H, H-4). 13C NMR (75.5 MHz, C6D6): δ -0.9 (4 C, SiCH3), 25.7 (C(OH)CH3), 70.4 (C(OH)CH3), 126.6 (C-6), 129.6 (C-4), 132.9 (C-7), 140.0 (CCH2), 147.3 (C-5), 148.3 (C-3a or C-7a), 149.7 (C3a or C-7a), 153.8 (CCH2). 29Si NMR (59.6 MHz, C6D6): δ -4.4, -4.1. Anal. Calcd for C14H22OSi2: C, 64.06; H, 8.45. Found: C, 64.1; H, 8.2. Preparation of 1-(1,1,3,3,6-Pentamethyl-1,3-disilaindan-5yl)ethanol (24). Compound 28 (1.80 g, 9.98 mmol), 30 (1.18 g, 14.0 mmol), and a 0.1 M solution of cobalt(II) iodide in acetonitrile (2.50 mL, 250 μmol of CoI2) were added in single portions one after another at 20 °C to a stirred suspension of zinc powder (65 mg, 994 μmol) in acetonitrile (20 mL).24 As the reaction did not start, further zinc powder (10 mg, 153 μmol) and iodine (5 mg) were added, and the resulting mixture was heated at ca. 60 °C for 2 min and then stirred at 20 °C for 19 h. The reaction mixture was filtered through a pad of silica gel (63-200 μm, 80 g), followed by elution with diethyl ether/nhexane (4:1 (v/v), 160 mL). The solvent of the filtrate (including the eluate) was removed under reduced pressure, the residue was dried in vacuo (10 mbar, 50 °C, 1 h), triethylamine (2 mL) was added, and the resulting mixture was subjected to column chromatography (silica gel (32-63 μm); eluent, n-hexane/ethyl acetate (10:3.5 (v/v))). The relevant fractions (GC control) were combined, the solvent was removed under reduced pressure, and the solid residue was recrystallized from n-hexane (8 mL; slow cooling of a hot solution to 20 °C) to afford compound 24 in 39% yield as a colorless solid (1.04 g, 3.93 mmol); mp 103104 °C. 1H NMR (500.1 MHz, C6D6): δ 0.08 (br s, 2 H, SiCH2Si), 0.43 (s, 6 H, SiCH3), 0.44 (s, 3 H, SiCH3), 0.45 (s, 3 H, SiCH3), 1.25 (d, 3JH,H=3.2 Hz, 1 H, OH), 1.43 (d, 3JH,H=6.4 Hz, 3 H, C(OH)CH3), 2.27 (s, 3 H, CCH3), 4.90-4.95 (m, 1 H, CH(OH)), 7.48 (br s, 1 H, H-7), 8.03 (br s, 1 H, H-4). 13C NMR

Article (125.8 MHz, C6D6): δ -2.1 (SiCH2Si), 0.73 (SiCH3), 0.79 (2 C, SiCH3), 0.85 (SiCH3), 19.2 (CCH3), 24.3 (C(OH)CH3), 67.1 (C(OH)CH3), 128.1 (C-4), 134.0 (C-7), 134.9 (C-6), 145.4 (C-5), 148.1 (C-3a), 149.0 (C-7a). 29Si NMR (99.4 MHz, C6D6): δ 8.1, 8.3. Anal. Calcd for C14H24OSi2: C, 63.57; H, 9.15. Found: C, 63.5; H, 9.4. Preparation of 1-(1,1,3,3-Tetramethyl-1,3-disilaindan-5-yl)ethanol (25). Compound 28 (902 mg, 5.00 mmol), 32 (491 mg, 7.01 mmol), and a 0.1 M solution of cobalt(II) iodide in acetonitrile (1.25 mL, 125 μmol of CoI2) were added in single portions one after another at 20 °C to a stirred suspension of zinc powder (32 mg, 489 μmol) in acetonitrile (10 mL).24 As the reaction did not start, further zinc powder (10 mg, 153 μmol) and iodine (5 mg) were added, and the resulting mixture was heated at ca. 60 °C for 5 min and then stirred at 20 °C for 2 h. The reaction mixture was filtered through a pad of silica gel (63-200 μm, 80 g), followed by elution with diethyl ether/n-hexane (4:1 (v/v), 160 mL). The solvent of the filtrate (including the eluate) was removed under reduced pressure, the residue was dried in vacuo (10 mbar, 50 °C, 1 h), triethylamine (1 mL) was added, and the resulting mixture was subjected to column chromatography (silica gel (32-63 μm); eluent, n-hexane/ethyl acetate (100:35 (v/v))). The relevant fractions (GC control) were combined, the solvent was removed under reduced pressure, and the solid residue was recrystallized from nhexane (5 mL; slow cooling of a hot solution to 20 °C) to afford compound 25 in 51% yield as a colorless solid (642 mg, 2.56 mmol); mp 42-44 °C. 1H NMR (500.1 MHz, C6D6): δ 0.07 (s, 2 H, SiCH2Si), 0.41 (br s, 6 H, SiCH3), 0.422 (s, 3 H, SiCH3), 0.428 (s, 3 H, SiCH3), 1.44 (d, 3JH,H=3.4 Hz, 1 H, OH), 1.46 (d, 3JH,H= 6.4 Hz, 3 H, C(OH)CH3), 4.70-4.76 (m, 1 H, CH(OH)), 7.447.47 (m, 1 H, H-6), 7.61-7.64 (m, 1 H, H-7), 7.74-7.75 (m, 1 H, H-4). 13C NMR (125.8 MHz, C6D6): δ -2.20 (SiCH2Si), 0.66 (2 C, SiCH3), 0.68 (2 C, SiCH3), 25.7 (C(OH)CH3), 70.5 (C(OH)CH3), 126.4 (C-6), 128.9 (C-4), 132.2 (C-7), 147.1 (C-5), 149.2 (C-7a), 150.6 (C-3a). 29Si NMR (99.4 MHz, C6D6): δ 8.1, 8.5. Anal. Calcd for C13H22OSi2: C, 62.34; H, 8.85. Found: C, 62.0 H, 9.0. Preparation of 1-(1,1,3,3,6-Pentamethyl-2-oxa-1,3-disilaindan-5-yl)ethanol (26). Compound 29 (912 mg, 5.00 mmol), 30 (588 mg, 6.99 mmol), and a 0.1 M solution of cobalt(II) iodide in acetonitrile (1.25 mL, 125 μmol of CoI2) were added in single portions one after another at 20 °C to a stirred suspension of zinc powder (32 mg, 489 μmol) in acetonitrile (10 mL).24 The reaction mixture was stirred at 20 °C for 2 h and was then filtered through a pad of silica gel (63-200 μm, 80 g), followed by elution with diethyl ether/n-hexane (4:1 (v/v), 160 mL). The solvent of the filtrate (including the eluate) was removed under reduced pressure, the residue was dried in vacuo (0.01 mbar, 20 °C, 1 h), triethylamine (1 mL) was added, and the resulting mixture was subjected to column chromatography (silica gel (32-63 μm); eluent, n-hexane/ethyl acetate (5:1 (v/v))). The relevant fractions (GC control) were combined, the solvent was removed under reduced pressure, and the solid residue was recrystallized from n-hexane (5 mL; slow cooling of a hot solution to 20 °C) to afford compound 26 in 27% yield as a colorless solid (354 mg, 1.33 mmol); mp 88-89 °C. 1H NMR (500.1 MHz, C6D6): δ 0.33 (s, 3 H, SiCH3), 0.34 (s, 3 H, SiCH3), 0.35 (br s, 6 H, SiCH3), 1.25 (d, 3JH,H = 3.5 Hz, 1 H, OH), 1.42 (d, 3JH,H = 6.4 Hz, 3 H, C(OH)CH3), 2.26 (s, 3 H, CCH3), 4.90-4.94 (m, 1 H, CH(OH)), 7.41 (br s, 1 H, H-7), 8.01 (br s, 1 H, H-4). 13C NMR (125.8 MHz, C6D6): δ 1.21 (SiCH3), 1.23 (SiCH3), 1.27 (SiCH3), 1.29 (SiCH3), 19.2 (C(OH)CH3), 24.3 (CCH3), 67.0 (C(OH)CH3), 127.4 (C-4), 133.2 (C-7), 135.2 (C-6), 145.8 (C-5), 146.3 (C-3a or C-7a), 147.1 (C-3a or C-7a). 29Si NMR (99.4 MHz, C6D6): δ 14.2, 14.6. Anal. Calcd for C13H22O2Si2: C, 58.59; H, 8.32. Found: C, 58.6; H, 8.2. Preparation of 1-(1,1,3,3-Tetramethyl-2-oxa-1,3-disilaindan5-yl)ethanol (27). Compound 29 (3.65 g, 20.0 mmol), 32 (1.96 g, 28.0 mmol), and a 0.1 M solution of cobalt(II) iodide in acetonitrile (5.0 mL, 500 μmol of CoI2) were added in single portions one after another at 20 °C to stirred suspension of zinc powder


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(130 mg, 1.99 mmol) in acetonitrile (40 mL).24 The reaction mixture was heated under reflux for 70 min, cooled to 20 °C, stirred at 20 °C for 3 days, and then filtered through a pad of silica gel (63-200 μm, 80 g), followed by elution with diethyl ether/nhexane (4:1 (v/v), 240 mL). The solvent of the filtrate (including the eluate) was removed under reduced pressure, triethylamine (5 mL) was added, and the resulting mixture was subjected to column chromatography (silica gel (32-63 μm); eluent, n-hexane/ethyl acetate (10:3.5 (v/v))). The relevant fractions (GC control) were combined, the solvent was removed under reduced pressure, and the residue was recrystallized from n-hexane (15 mL; slow cooling of a hot solution to 20 °C) to afford compound 27 in 43% yield as a colorless solid (2.19 g, 8.67 mmol); mp 65-66 °C. 1H NMR (500.1 MHz, CD2Cl2): δ 0.34 (s, 6 H, SiCH3), 0.345 (s, 3 H, SiCH3), 0.347 (s, 3 H, SiCH3), 1.48 (d, 3JH,H =6.5 Hz, 3 H, C(OH)CH3), 1.91 (br s, 1 H, OH), 4.90 (q, 3JH,H=6.5 Hz, 1 H, CH(OH)), 7.39-7.43 (m, 1 H, H-6), 7.54-7.58 (m, 1 H, H-7), 7.58-7.60 (m, 1 H, H-4). 13 C NMR (125.8 MHz, CD2Cl2): δ 1.1 (4 C, SiCH3), 25.6 (C(OH)CH3), 70.7 (C(OH)CH3), 126.7 (C-6), 128.2 (C-4), 131.4 (C-7), 147.1 (C-5), 147.6 (C-7a), 149.0 (C-3a). 29Si NMR (99.4 MHz, CD2Cl2): δ 14.8 (2 Si). Anal. Calcd for C12H20O2Si2: C, 57.09; H, 7.98. Found: C, 57.1; H, 8.1. Preparation of 1,1-Bis(ethynyldimethylsilyl)methane (28). This compound was synthesized according to ref 25. Preparation of 1,3-Diethynyl-1,1,3,3-tetramethyldisiloxane (29). This compound was synthesized according to ref 26. Preparation of Pent-3-yn-2-ol (30). This compound was synthesized according to ref 27; however, a 2.5 M solution of n-butyllithium in hexanes was used instead of a solution of ethylmagnesium bromide in THF. Preparation of (Trimethylsilyloxy)but-1-yne (31). This compound was synthesized according to ref 28. But-3-yn-2-ol (32). This compound was commercially available (Acros). 1,1,2,3,3-Pentamethylindan-2-ol (34). This compound was synthesized according to refs 29 and 30. 1,1,3,3-Tetramethyl-2-methyleneindane (35). This compound was synthesized according to ref 30. 2,2,3,3-Tetramethyl-1-methyleneindane (36). This compound was obtained by treatment of 34 with aluminum trichloride and acetyl chloride or by reaction of 35 with aluminum trichloride. The NMR data of the product were identical with those reported in ref 30. Preparation of 1-(2,2,3,3-Tetramethylindan-1-ylidene)acetone (37). Graphite (750 mg) was dried in vacuo for 2 h, followed by addition of 1,2-dichloroethane (10 mL), 36 (250 mg, 1.34 mmol), and acetyl bromide (510 mg, 4.15 mmol), and the resulting suspension was heated under reflux for 2 days. The reaction mixture was allowed to cool to 20 °C, and the solid was filtered off, washed with diethyl ether (10 mL), and discarded. The combined organic extracts were washed with a saturated aqueous solution of sodium hydrogen carbonate (10 mL) and dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (silica gel (35-70 μm); eluent, n-hexane/ethyl acetate (93:7 (v/v))). The chromatographic purification step was repeated, the relevant fractions (GC control) were combined, the solvent was removed under reduced pressure, and the residue was dried in vacuo (0.02 mbar, 2 h) to afford compound 37 in 34% yield as a yellowish oily liquid (105 mg, 460 μmol). (25) Kusumoto, T.; Hiyama, T. Chem. Lett. 1988, 17, 1149–1152. (26) Wong, W.-Y.; Wong, C.-K.; Lu, G.-L. J. Organomet. Chem. 2003, 671, 27–34. (27) Fleming, I.; Takaki, K.; Thomas, A. P. J. Chem. Soc., Perkin Trans. 1 1987, 2269–2273. (28) Hoffmann, R. W.; Dresely, S. Synthesis 1988, 103–106. (29) Knorr, R.; Mehlst€aubl, J.; B€ ohrer, P. Chem. Ber. 1989, 122, 1791–1793. (30) Knorr, R.; Freudenreich, J.; von Roman, T.; Mehlst€aubl, J.; B€ ohrer, P. Tetrahedron 1993, 49, 8837–8854.

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The analytical data of the product were identical with those reported in ref 30 (molar ratio of the Z/E isomers, 96:4). Odor description: Spicy, peppery-woody odor, with reminiscence to cashmeran (1,1,2,3,3-pentamethyl-2,3,6,7-tetrahydro-1H-inden-4(5H)-one), resinous, fir-type aspects and slight ionone facets in the dry-down. Odor threshold: 7.2 ng L-1 air. Crystal Structure Analyses. Suitable single crystals of compounds 7 and 11 were isolated as described in the respective synthetic protocols. The crystals were mounted in inert oil (perfluoropolyalkyl ether, ABCR) on a glass fiber and then transferred to the cold nitrogen gas stream of the diffractometer (Bruker Nonius KAPPA APEX II (7; Montel mirror, Mo KR radiation, λ = 0.71073 A˚) and Stoe IPDS (11; graphite-monochromated Mo KR radiation, λ = 0.71073 A˚)). The structures were solved by direct methods (SHELXS-97).31 The non-hydrogen atoms were refined anisotropically (SHELXL-97).31 A riding model was employed in the refinement of the CH hydro(31) Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112–122.

Metz et al. gen atoms. Crystallographic data (excluding structure factors) for the structures reported in this paper have been deposited with The Cambridge Crystallographic Data Centre as supplementary publication nos. CCDC-736723 (7) and CCDC-736722 (11). Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, U.K. (fax, (þ44)1223/336033; e-mail, [email protected]).

Acknowledgment. We are indebted to Alain E. Alchenberger and Dominique Lelievre for the olfactory evaluations, and to Katarina Grman and all her panelists for the determination of odor threshold values. Supporting Information Available: Details of the computational structure optimizations of 4-13, crystallographic data of 7 and 11, and CIF files providing the crystallographic data for 7 and 11. This material is available free of charge via the Internet at http://pubs.acs.org.

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