Weakening C-O Bonds: Ti(III), a New Reagent for. Alcohol Deoxygenation and Carbonyl Coupling. Olefination

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1 Weakening C-O Bonds: Ti(III), a New Reagent for Alcohol Deoxygenation and Carbonyl Coupling Olefination Horacio R. Diéguez, Armando López, Victoriano Domingo, Jesús F. Arteaga, José A. Dobado, M. Mar Herrador, José F. Quílez del Moral, and Alejandro F. Barrero, * Department of Organic Chemistry, Institute of Biotechnology, Facultad de Ciencias, University of Granada, Campus de Fuente Nueva, s/n,18071 Granada, Spain and Department of Chemistry Engineering, Physique Chemistry and Organic Chemistry, Faculty of Experimental Sciences, University of Huelva, Campus el Carmen, Huelva, Spain Supporting Information Table of contents page General Details S2 Experimental Procedures S3 Computacional Details S17 References S52 Spectra S54 S1

2 General Details IR spectra were recorded on a Mattson Satellite FTIR spectrometer. NMR spectra were performed with a Varian Direct-Drive 600 ( 1 H 600 MHz/ 13 C 150 MHz), 500 ( 1 H 500 MHz/ 13 C 125 MHz), Bruker ARX 400 ( 1 H 400 MHz/ 13 C 100 MHz) and Varian Inova Unity 300 ( 1 H 300 MHz/ 13 C 75 MHz) spectrometers. The accurate mass determination was carried out with a AutoSpec-Q mass spectrometer arranged in a EBE geometry (Micromass Instrument, Manchester, UK) and equipped with a FAB (LSIMS) source. The instrument was operated at 8 KV of accelerating voltage and Cs + were used as primary ions. Optical rotations were measured on a Perkin-Elmer 141 polarimeter, using CHCl 3 as the solvent. Silica gel SDS 60 (35-70 µm) was used for flash column chromatography. Reactions were monitored by thin layer chromatography (TLC) carried out on 0.25 mm E. Merck silica gel plates (60F- 254) using UV light as the visualizing agent and a solution of phosphomolybdic acid in ethanol and heat as developing agent. GC-MS analyses were carried out in a Hewlett Packard 6890 chromatograph connected to a Hewlett-Packard 5988A mass spectrometer using an ionization voltage of 70 ev. The GC conditions were: HP-1 methylsilicone capillary column (25 m x0.2 mm); He 1.9 ml/min; the injection and detector heater temperature was 250ºC; temperature program from 50º-300ºC at 10ºC/min. Quantitative chromatographic analysis were carried out on Hewlett Packard 6890 chromatograph equipped with a flame ionization detector (FID) and coupled to an integrator HP-3390A. The column and experimental conditions were the same as those described above, except that the detector heater temperature was 300ºC and the inlet head was 20 psi. The percentage compositions were computed from the GC peak areas without correction factors. HPLC with UV and RI detection was used. Semipreparative HPLC separations were carried out on a column (5 µm Silica, 10 x 250 mm) at a flow rate of 2.0 ml/min in an Agilent Serie 1100 instrument. Reactions were monitored by thin layer chromatography (TLC) carried out on 0.25 mm E. Merck silica gel plates (60F-254) using UV light as the visualizing agent and a solution of phosphomolybdic acid in ethanol and heat as developing agent. All air- and water-sensitive reactions were performed in flaks flame-dried under a positive flow of argon and conducted under an argon atmosphere. The solvents used were purified according to standard S2

3 literature techniques and stored under argon. THF and toluene were freshly distilled immediately prior to use from sodium/benzophenone and strictly deoxygenated for 30 min under argon for each of the Cp 2 TiCl 2 /Mn or Zn reactions. Reagents were purchased at the higher commercial quality and used without further purification, unless otherwise stated. General procedure for stochiometric deoxygenation-reduction reactions (Procedure A): toluene, 8, 10, 12, 14, 16, 18, 20, 23, 25, 27, 29, 31, 33, 35, 37, 38. A mixture of Cp 2 TiCl 2 (998 mg, 3.88 mmol) and Mn dust (154 mg, 2.77 mmol) in strictly deoxygenated THF (7 ml) was heated at reflux under stirring until the red solution turned green. Then, to this mixture was added a solution of the corresponding alcohol (1.85 mmol) in strictly deoxygenated THF (4 ml). The reaction mixture was heated at reflux under stirring until starting material disappearance (TLC monitoring), quenched with 1N HCl and extracted with t-buome. The organic phase was washed with brine, dried over anhydrous Na 2 SO 4, filtered and concentrated in vacuo yielding a. crude which was analyzed by CG-MS, purified by column chromatography over silica gel column and/or subjected to HPLC. General procedure for catalytic deoxygenation- homocoupling carbonyl reactions (Procedure B): 20, 27, 31. A mixture of Cp 2 TiCl 2 (160 mg, mmol) and Mn dust (935 mg, mmol) in thoroughly deoxygenated THF (8 ml) and under Ar atmosphere was stirred until the red solution turned green. This mixture was then heated at reflux and the corresponding TMSCl (1.07 ml, 8.52 mmol) was added, finally the allylic aldehyde (1.92 mmol) in strictly deoxygenated THF (2 ml) was then added. The reaction mixture was stirred until starting material disappearance (TLC monitoring). It was then quenched with t-buome, washed with 1 N HCl, brine, dried over anhydrous Na 2 SO 4 and concentrated S3

4 under reduced pressure. The resulting crude was purified by column chromatography on silica gel to afford the corresponding coupling products. Toluene: According to the procedure A, the mixture containing benzyl alcohol (1) was heated for 45 min. The resulting crude was analyzed by GC-MS. Toluene (93 %, R t = 4.42 min) was identified by the standard use. 2-Methylnaphthalene (8): According to the procedure A described for deoxygenation-reduction, the mixture containing 2-naphtylmethanol (7) was heated for 60 min. The resulting crude was purified by column chromatography (hexane/t-buome, 6:1) on silica gel to afford 8 (79%). 1 H NMR (CD 3 Cl, 300 MHz): δ 2.56 (s, 3H), 7.37 (d, J = 8.5 Hz, 1H), 7.47 (quintet, J = 6.4 Hz, 2H), 7.66 (bs, 1H), (m, 3H); 13 C NMR (CD 3 Cl, 75 MHz): δ 21.8, 125.0, 125.9, 126.9, 127.3, 127.7, 127.8, 128.2, 131.8, 133.7, H NMR spectroscopic data of this compound were identical to that of a standard. Triphenylmethane (10): According to the procedure A described for deoxygenation-reduction, the mixture containing triphenylmethanol (9) was heated for 60 min. The resulting crude was purified by column chromatography (hexane/t-buome, 6:1) on silica gel to afford 10 (91%). 1 H NMR (CD 3 Cl, 300 S4

5 MHz): δ 7.38 (br s, 15H); 13 C NMR (CD 3 Cl, 75 MHz): δ 82.1, 127.3, 128.0, H NMR spectroscopic data of this compound were identical to that of a standard. MeO MeO OMe 1,2,3-Trimethoxy-5-methylbenzene (12): According to the procedure A described for deoxygenation-reduction, the mixture containing (3,4,5-trimethoxyphenyl)methanol (11) was heated for 50 min. The resulting crude was purified by column chromatography (hexane/t-buome, 4:1) on silica gel to afford 12 (90%). 1 H NMR (CD 3 Cl, 300 MHz): δ 2.32 (s, 3H), 3.83 (s, 3H), 3.85 (s, 6H), 6.41 (s, 2H); 13 C NMR (CD 3 Cl, 300 MHz): δ 21.7, 55.9, 60.8, 105.9, 133.5, 135.7, H NMR spectroscopic data of this compound were identical to that of a standard. MeO OMe Bis(4-methoxyphenyl)methane (14): According to the procedure A described for deoxygenationreduction, the mixture containing bis(4-methoxyphenyl)methanol (13) was heated for 90 min. The resulting crude was purified by column chromatography (hexane/t-buome, 6:1) on silica gel to afford 14 (60%). 1 H NMR (CD 3 Cl, 300 MHz): δ 3.82 (s, 6H), 3.90 (s, 2H), 6.86 (d, J = 8.5 Hz, 4H), 7.12 (d, J = 8.5 Hz, 4H); 13 C NMR (CD 3 Cl, 75 MHz): δ 40.2, 55.3, 113.9, 129.8, 133.8, H NMR spectroscopic data of this compound were identical to that of a standard. MeOOC Methyl p-toluate (16): According to the procedure A described for the deoxygenation-reduction, the mixture containing methyl 4-formolbenzoate 15 was heated at reflux for 55 min. The resulting crude S5

6 was purified by column chromatography using hexane as eluent on silica gel to afford 16 (83 %) as brown prisms. IR (film): 2952, 2925, 2855, 1725, 1614, 1435, 1310, 1108, 1021, 840, 754, 691 cm H NMR (400 MHz; CDCl 3 ) δ 2.31 (s, 3H), 3.81 (s, 3H), 7.14 (d, J = 7.8 Hz, 2H), 7.85 (d, J = 7.8 Hz, 2H). 13 C NMR (100 MHz; CDCl 3 ) δ 21.6, 51.9, 127.5, (2C), (2C), 143.5, HREIMS (m/z): [M] + calcd. for C 9 H 10 O found Dodecene (18): According to the procedure A described for deoxygenation-reduction, the mixture containing (E)-2-dodecen-1-ol (17) was heated for 50 min. The resulting crude was purified by column chromatography (hexane/t-buome, 9:1) on silica gel to afford 18 (91%). 1 H NMR (CD 3 Cl, 500 MHz): δ 0.88 (t, J = 6.8 Hz, 3H), (m, 16H), 2.04 (q, J = 6.8 Hz, 2H), 4.92 (br d, J = 10.0 Hz, 1H), 4.99 (br d, J = 17.0 Hz, 1H), 5.81 (ddt, J = 6.8 Hz, 10.0 Hz, 17.0 Hz, 1H); 13 C NMR (CD 3 Cl, 125 MHz): δ 14.1, 22.6, 28.9, 29.1, 29.3, 29.4, 29.6, 31.9, 33.8, 114.0, H NMR spectroscopic data of this compound were identical to that of a standard. (E)-3,7,11-Trimethyldodeca-1,6,10-triene (20): According to the procedure A described for deoxygenation-reduction, the mixture containing trans-trans-farnesol (19) was heated for 60 min. The resulting crude was purified by column chromatography (hexane/t-buome, 8:1) on silica gel to afford a mixture of 20 2 (80%). According to the procedure B described for catalytic deoxygenation-reduction, the mixture containing trans-trans-farnesol (19) was heated for 55 min. The resulting crude was purified by column chromatography (hexane/t-buome, 8:1) on silica gel to afford a mixture of 20 2 (92%). 1 H NMR (CD 3 Cl, 500 MHz): δ 0.99 (d, J = 7.0 Hz, 3H), (m, 2H), 1.59 (s, 3H), 1.61 (s, 3H), 1.69 (s, S6

7 3H), (m, 2H), (m, 4H), 2.13 (sept, J = 7.2 Hz, 1H), 4.92 (br d, J = 10.0 Hz, 1H), 4.96 (br d, J = 17.4 Hz, 1H), (m, 2H), 5.70 (ddd, J = 7.2 Hz, 10.0 Hz, 17.4 Hz, 1H); 13 C NMR (CD 3 Cl, 125 MHz): δ 15.9, 17.6, 20.1, 25.6, 25.7, 26.6, 36.7, 37.3, 39.7, 112.4, 124.4, 124.5, 131.2, 134.8, Methyl-3-butenyl benzoate (23): According to the procedure A described for deoxygenationreduction, the mixture containing (E)-4-hydroxy-3-methyl-2-butenyl benzoate (22) was heated for 60 min. The resulting crude was purified by column chromatography (hexane/t-buome, 5:1) on silica gel to afford 23 1 (70%). 1 H NMR (CD 3 Cl, 500 MHz): δ 1.82 (s, 3H), 2.49 (t, J = 6.8 Hz, 2H), 4.44 (t, J = 6.8 Hz, 2H), 4.81 (br s, 1H), 4.84 (br s, 1H), 7.43 (br t, J = 7.9 Hz, 2H), 7.55 (tt, J = 1.1 Hz, 7.9 Hz, 1H), 8.03 (dd, J = 1.1 Hz, 7.9 Hz, 1H); 13 C NMR (CD 3 Cl, 300 MHz): δ 14.1, 29.6, 63.1, 112.4, 128.3, 129.5, 132.8, 141.7, OBz OPiv (2E)-3,7-Dimethylocta-2,7-dienyl pivalate (25): According to the procedure A described for the deoxygenation-reduction, the mixture containing (3E,7E)-8-hydroxy-3,7-dimethylocta-2,6-dienyl pivaloate 24 was heated at reflux for 2 h. The resulting crude was purified by column chromatography using hexane as eluent on silica gel to afford 25 as colorless oil. IR (film): 2971, 2935, 1729, 1480, 1459, 1397, 1282, 1151, 1032, 955, 887 cm H NMR (400 MHz; CDCl 3 ) δ 5.32 (t, J = 7.0 Hz, 1H), 4.70 (s, 1H), 4.66 (s, 1H), 4.56 (d, J = 7.0 Hz, 2H), 2.01 (m, 4H), 1.71 ( s, 3H), 1.69 (s, 3H), 1.55 (qt, J = 8.0 Hz, 2H), 1.18 (s, 9H). 13 C NMR (100 MHz; CDCl 3 ) δ 16.3, 22.3, 25.4, 27.2 (3C), 37.2, 38.8, 38.9, 61.3, 109.9, 118.8, 141.7, 145.7, HRCIMS (m/z): [M-H] + calcd. for C 15 H 26 O found S7

8 O (5E,9E)-6,10,14-Trimethylpentadeca-5,9,14-trien-2-one (27): According to the procedure A described for the deoxygenation-reduction, (5E,9E,13Z)-15-hydroxy-6,10,14-trimethylpentadeca- 5,9,13-trien-2-one 26 was heated at reflux for 2 h. The resulting crude was purified by column chromatography using (4:1) hexanes: t-buome as eluent on silica gel to afford 27(38 %) as a colorless oil. According to the procedure B described for the catalytic deoxygenation-reduction, the compound 26 was heated at reflux for 4 h. The resulting crude was purified by column chromatography (hexane/t- BuOMe 4:1) as eluent on silica gel to afford 27(85 %). IR (film): 3073, 2933, 1719, 1649, 1441, 1358, 1158, 885 cm H NMR (400 MHz; CDCl 3 ) δ 1.39 (quintuplet, J = 7.4 Hz, 2H), 1.47 (s, 3H), 1.49 (s, 3H), 1.59 (s, 3H), 1.85 (m, 6H), 1.95 (t, J = 7.4 Hz, 2H), 2.01 (s, 3H), 2.15 (t, J = 7.4 Hz, 2H), 2.33 (t, J = 7.4 Hz, 2H), 4.54 (s, 1H), 4.58 (s, 1H), 4.96 (m, 2H). 13 C NMR (100 MHz; CDCl 3 ) δ 15.8, 15.9, 22.3, 22.4, 25.9, 26.4, 29.8, 37.3, 39.2, 39.6, 43.7, 109.7, 122.5, 124.1, 134.9, 136.2, 145.9, HRFABMS (m/z): [M+ Na] + calcd. for C 18 H 30 ONa found trans-stilbene (29): According to the procedure A described for deoxygenation-reduction, the mixture containing 1,2-diphenylethane-1,2-diol (28) was heated for 65 min, the resulting crude was purified by column chromatography (hexane/t-buome, 6:1) on silica gel to afford 29 3 (94 %). 1 H NMR (CD 3 Cl, 300 MHz): δ 7.22 (s, 2H), 7.37 (t, J = 7.3 Hz, 2H), 7.47 (t, J = 7.3 Hz, 4H), 7.62 (d, J = 7.3 Hz, 4H); 13 C NMR (CD 3 Cl, 75 MHz): δ 126.6, 127.7, 128.7, 128.8, S8

9 Cl Cl (E)-4,4 -Dichlorostilbene (31): According to the procedure A described for the deoxygenationreduction, the mixture containing 1,2-bis(4-chlorophenyl)ethane-1,2-diol 30 was heated at reflux for 1 h. The resulting crude was purified by column chromatography using (hexane/t-buome 1:1) as eluent on silica gel to afford 31 (79 %) as a white powder. According to the procedure B described for the catalytic deoxygenation-reduction, the mixture containing 1,2-bis(4-chlorophenyl)ethane-1,2-diol 30 was heated at reflux for 1.5 h. The resulting crude was purified by column chromatography using (hexane/t-buome 1:1) as eluent on silica gel to afford 31 (86 %). IR (film):3040, 3010, 2938, 1701, 1600, 1497, 1405, 1102 cm H NMR (400 MHz; CDCl 3 ) δ 7.02 (s, 2H), 7.33 (d, J = 8.2 Hz, 4H), 7.43 (d, J = 8.2 Hz, 4H). 13 C NMR (100 MHz; CDCl 3 ) δ 135.5, 133.4, 128.9, 127.9, HREIMS (m/z): [M] + calcd. for C 14 H 10 Cl found Tetradecene (33): According to the procedure A described for deoxygenation-reduction, the mixture containing tetradecane-1,2-diol (32) was heated for 90 min. The resulting crude was purified by column chromatography on silica gel to afford 33 (68 %). 1 H NMR (CD 3 Cl, 500 MHz): δ 0.88 (t, J = 6.8 Hz, 3H), (m, 20H), 2.04 (q, J = 6.8 Hz, 2H), 4.93 (br d, J = 10.2 Hz, 1H), 4.99 (br d, J = 17.1 Hz, 1H), 5.81 (ddt, J = 6.8 Hz, 10.2 Hz, 17.1 Hz, 1 H); 13 C NMR (CD 3 Cl, 125 MHz): δ 14.2, 22.8, 29.0, 29.3, 29.4, 29.6, 29.7, 29.8, 32.0, 33.9, 114.1, H NMR spectroscopic data of this compound were identical to that of a standard. 10 S9

10 β-pinene (35): According to the procedure A described for deoxygenation-reduction, the mixture containing pinane-2α,10-diol (34) was heated for 90 min. The resulting crude was analyzed by GC-MS. 35 (92%, RT = 6.32 min) was identified by the standard use. Octadecane (37) and 1-octadecene (38): A mixture of Cp 2 TiCl 2 (200 mg, 0.77 mmol) and Zn dust (36.72 mg, 0.55 mmol) in strictly deoxygenated toluene (2 ml) was heated at reflux under stirring until the red solution turned green. Then, to this mixture was added a solution of octadecan-1-ol (36) (100 mg, 0.37 mmol) in strictly deoxygenated toluene (1 ml). The reaction mixture was heated at reflux under stirring for 120 min. It was then quenched with 1N HCl and extracted with t-buome. The organic phase was washed with brine, dried over anhydrous Na 2 SO 4, filtered and concentrated in vacuo yielding a. crude was purified by column chromatography (hexane/t-buome, 9:1) on silica gel to afford a mixture (90%) that was analyzed by GC-MS. This mixture was constituted for 37 (RT = min) and 38 (RT = min) at a ratio 1:1. These compounds were identified by the standard use. When the procedure A described for deoxygenation-reduction was followed, starting compound 36 was recovered. General procedure for stochiometric homocoupling carbonyl reactions (Procedure C): 29, 31, 41, 43, 45, 48, 50, 52, 54, 56, 58. A mixture of Cp 2 TiCl 2 (392 mg, 1.57 mmol) and Mn dust (172 mg, 3.15 mmol) or Zn dust (206 mg, 3.15 mmol) in thoroughly deoxygenated THF (6.5 ml) and under Ar atmosphere was stirred until the red solution turned green. This mixture was then heated at reflux and the corresponding allylic aldehyde (1.31 mmol) in strictly deoxygenated THF (2 ml) was then added. The reaction mixture was stirred until starting material disappearance (TLC monitoring). It was then quenched with t-buome, washed S10

11 with 1 N HCl, brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The resulting crude was purified by column chromatography on silica gel to afford the corresponding coupling products. trans-stilbene (29): According to the procedure C described for the carbonyl homocoupling, the mixture containing benzaldehyde (39) was heated at reflux for 1 h. The resulting crude was purified by column chromatography (hexane) on silica gel to afford 29 (93%). Cl Cl (E)-4,4 -Dichlorostilbene (31): According to the procedure C described for the carbonyl homocoupling, the mixture containing 4-chlorobenzaldehyde 46 was heated at reflux for 1.5 h. The resulting crude was purified by column chromatography using (hexane/t-buome 1:1) as eluent on silica gel to afford 31 (74 %) as a white powder. According to the procedure B described for the catalytic carbonyl homocoupling, the mixture containing 4-chlorobenzaldehyde 46 was heated at reflux for 2 h. The resulting crude was purified by column chromatography using (hexane/t-buome 1:1) as eluent on silica gel to afford 31 (95 %). MeO OMe MeO OMe (E)-3,3,5,5 -Tetramethoxystilbene (41): According to the procedure C described for the carbonyl homocoupling, the mixture containing 3,5-dimethoxybenzaldehyde (40) was heated at reflux for 1 h. S11

12 The resulting crude was purified by column chromatography (hexane) on silica gel to afford 41 4 (87%). 1 H NMR (300 MHz; CDCl 3 ): δ 3.75 (s, 12H), 6.33 (t, J = 2.3 Hz, 2H), 6.60 (d, J = 2.3 Hz, 4H), 6.94 (s, 2H); 13 C NMR (75 MHz; CDCl 3 ): δ 55.5, 100.3, 104.8, 129.3, 139.3, MeOOC COOMe Dimethyl (E)-4,4'-stilbenedicarboxylate (43): According to the procedure C described for the carbonyl homocoupling, the mixture containing methyl 4-formylbenzoate 42 was heated at reflux for 2 h. The resulting crude was purified by column chromatography using EtOAc as eluent on silica gel to afford 43 (94%) as a white powder. IR (film): 1721, 1284, 1108, 965, 858, 774 cm H NMR (400 MHz; CDCl 3 ) δ 3.93 (s, 6H), 7.25 (s, 2H), 7.59 (d, J = 8.6 Hz, 4H), 8.04(d, J = 8.6 Hz, 4H). 13 C NMR (100 MHz; CDCl 3 ) δ 26.9, 52.1, 86.6, 126.6, 130.1, 141.2, HREIMS (m/z): [M] + calcd. for C 18 H 16 O found HO OH (E)-4,4 -Dihydroxystilbene(45): According to the procedure C described for the carbonyl homocoupling, the mixture containing 4-Hydroxybenzaldehyde 44 was heated at reflux for 4 h. The resulting crude was purified by column chromatography using t-buome as eluent on silica gel to afford 45 (93 %) as a white powder. IR (film): 3333, 2926, 1510, 1439, 1270, 825 cm H NMR (500 MHz; CDCl 3 ) δ 6.82 (d, J = 8.7 Hz, 4H), 6.96 (s, 2H), 7.39 (d, J = 8.7 Hz, 4H), 8.37 (s, 2H). 13 C NMR (125 MHz; CDCl 3 ) δ 116.3, , 130.5, ppm. HREIMS (m/z): [M] + calcd. for C 14 H 12 O found S12

13 (1E,3E,5E)-1,6-Diphenylhexa-1,3,5-triene (48): According to the procedure C described for the carbonyl homocoupling, the mixture including E-cinnamaldehyde (47) was heated at reflux for 2 h. The resulting crude was purified by column chromatography (hexane) on silica gel to afford 48 5 (65%). 1 H NMR (CDCl 3, 500 MHz): δ 6.53 (dd, J = 7.0, 2.9 Hz, 2H), 6.61 (d, J = 15.5 Hz, 2H), 6.90 (ddd, J = 15.5, 7.0, 3.0 Hz, 2H), 7.24 (t, J = 7.3 Hz, 2H), 7.33 ( t, J = 7.4 Hz, 4H), 7.43 (d, J = 7.5 Hz, 4H); 13 C NMR (CDCl 3, 125 MHz): δ 126.4, 127.5, 128.6, 129.1, 132.7, 133.6, (6E,8E,10E)- and (6E,8Z,10E)-2,6,11,15-Tetramethylhexadeca-2,6,8,10,14-pentaene (50): According to the procedure C described for the carbonyl homocoupling, the mixture including citral (49) was heated at reflux for 1 h. The resulting crude was purified by column chromatography (hexane) on silica gel to afford 50 6 (76%) as a mixture of (6E,8E,10E) and (6E,8Z,10E) isomers at a 6:1 ratio. (6E,8E,10E) isomer: 1 H NMR (CDCl 3, 500 MHz): δ 1.59 (s, 6H), 1.67 (s, 6H), 1.76 (s, 6H), 2.07 (m, 8H), 5.09 (bt, J = 6.7 Hz, 2H), 5.90 (bd, J = 7.5 Hz, 1H), 6.33 (m, 1H); 13 C NMR (CDCl 3, 125 MHz): δ 16.7, 17.7, 25.7, 26.7, 40.1, 124.1, 125.4, 127.2, 131.6, (6E,8Z,10E) isomer: 1 H NMR (CDCl 3, 500 MHz): δ 1.59 (s, 3H), 1.67 (s, 3H), 1.76 (s, 3H), 2.07 (m, 4H), 5.09 (bt, J = 6.7 Hz, 1H), 6.10 (m, 1H), 6.33 (m, 1H); 13 C NMR (CDCl 3, 125 MHz): δ 16.5, 17.7, 25.7, 26.7, 40.4, 120.3, 123.4, 124.0, 131.6, S13

14 Mini-3-β-carotene (52): According to the procedure C described for the carbonyl homocoupling, the mixture including β-cyclocitral (51) was heated at reflux for 2 h 30 min. The resulting crude was purified by column chromatography (hexane) on silica gel to afford 52 (74%). IR (film) 2960, 2923, 2849, 2823, 1652, 1452, 1378, 1357, 1032, 971, 740 cm -1 ; 1 H NMR (CDCl 3, 500 MHz): δ 1.03 (s, 12H), (m, 4H), (m, 4H), 1.76 (s, 6H), 2.01 (t, J = 6.3 Hz, 4H), 5.81 (s, 2H); 13 C NMR (CDCl 3, 125 MHz): δ 19.5, 22.0, 29.0, 29.9, 33.0, 34.4, 39.7, 128.4, 132.3, 139.3; HRFABMS (m/z): [M+Na] + calcd for C 20 H 32 Na , found OPiv PivO (2E,6E,10E)-2,6,11,15-Tetramethylhexadeca-2,6,8,10,14-pentaene-1,16-pivaloate (54): According to the procedure C described for the carbonyl homocoupling, the mixture containing the corresponding aldehyde 53 was heated at reflux for 1.15 h. The resulting crude was purified by column chromatography using hexane as eluent on silica gel to afford 54 (73 %) as a colorless oil. IR (film): 2969, 2931, 2872, 1726, 1281, 1151, 955 cm H NMR (600 MHz; CDCl 3 ) δ 1.19 (s, 18H), 1.71 (s, 6H), 1.76 (s, 6H), 2.10 (t, J = 7.7 Hz, 4H), 2.28(q, J = 7.1 Hz, 4H), 4.57 (d, J = 6.9 Hz, 4H), 5.33 (d, J = 6.9, 2H), 5.34 (d, J = 6.9 Hz, 2H), 5.45 (t, J = 7.2 Hz, 2 H). 13 C NMR (150 MHz; CDCl 3 ) δ 12.4, 16.4, 26.6, 27.2 (3C), 38.7, 39.2, 61.2, 119.1, 130.9, 131.2, 134.2, 141.2, ppm.. HRFABMS (m/z): [M+ Na] + calcd. for C 30 H 48 O 4 Na found S14

15 (E)-α,β-Dimethylstilbene (56): According to the procedure C described for the carbonyl homocoupling, the mixture including acetophenone (55) was heated at reflux for 4 h. The resulting crude was purified by column chromatography (hexane) on silica gel to afford 56 7 (71%). 1 H NMR (CDCl 3, 500 MHz): δ 1.89 (s, 6H), 7.27 (m, 6H), 7.37 (t, J = 7.6 Hz, 4H); 13 C NMR (CDCl 3, 125 MHz): δ 22.5, 126.3, 128.2, 128.3, 133.1, (6E,14E)-2,6,10,11,15,19-hexamethylicosa-2,6,10,14,18-pentaene (58): According to the procedure C described for the carbonyl homocoupling, the mixture including geranylacetone (57) was heated at reflux for 4 h. The resulting crude was purified by column chromatography (hexane) on silica gel to afford 58 (62%). IR (film) 2964, 2923, 2855, 1705, 1630, 1448, 1375, 1260, 1105, 1079, 979, 894, 746 cm -1 ; 1 H NMR (CDCl 3, 500 MHz): δ 1.60 (bs, 15H), 1.68 (bs, 9H), (m, 16H), (m, 4H); 13 C NMR (CDCl 3, 125 MHz): δ 16.1, 17.8, 25.8, 26.8, 27.1, 39.8, 124.5, 124.6, 124.7, 131.4, 135.1, HRFABMS (m/z): [M + Na] + calcd for C 26 H 44 Na , found General procedure for heterocoupling carbonyl reactions: 61, 62. S15

16 Diphenylmethylenecyclohexane (61). A mixture of Cp 2 TiCl 2 (845 mg, 3.29 mmol) and Mn dust (487 mg, 8.78 mmol) or Zn dust (573 mg, 8.78 mmol) in thoroughly deoxygenated THF (4 ml) and under Ar atmosphere was stirred until the red solution turned green. This mixture was then heated at reflux and the corresponding mixture of benzophenone (60) (200 mg, 1.10 mmol) and cyclohexanone (59) (431 mg, 4.40 mmol) in strictly deoxygenated THF (2 ml) were then added. The reaction mixture was stirred until starting material disappearance (TLC monitoring). It was then quenched with t-buome, washed twice with 1N HCl, brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The resulting crude was purified by column chromatography (hexane) on silica gel to afford 61 8 (65%). 1 H NMR (CDCl 3, 500 MHz): δ (m, 6H), (m, 4H), (m, 10H); 13 C NMR (CDCl 3, 125 MHz): δ 26.8, 28.7, 32.4, 126.0, 127.8, 129.8, 134.5, 139.1, (le,3e)-4,8-dimethyl-l-pheny1-1,3,7-nonatriene (62). A mixture of Cp 2 TiCl 2 (2.45 g, 9.85 mmol) and Mn dust (1.44 g, mmol) or Zn dust (1.71 g, mmol) in thoroughly deoxygenated THF (140 ml) and under Ar atmosphere was stirred until the red solution turned green. This mixture was then heated at reflux and the corresponding mixture of citral (49) (500 mg, 3.28 mmol) and benzaldehyde (39) (1.743 g, mmol) in strictly deoxygenated THF (23 ml) were then added. The reaction mixture was stirred until starting material disappearance (TLC monitoring). It was then quenched with t-buome, washed twice with 1N HCl, brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The resulting crude was purified, by column chromatography (hexane) on silica gel to afford 62 9 (77%). 1 H NMR (CDCl 3, 500 MHz): δ 1.62 (s, 3 H), 1.69 (s, 3 H), S16

17 1.85 (s, 3 H), 2.13 (m, 4 H), 5.12 (bs, 1 H), 6.00 (d, J = 11.0 Hz, 1 H), 6.44 (d, J = 15.4 Hz, 1 H), 7.02 (dd, J = 15.4, 11.0 Hz, 1 H), 7.18 (t, J = 7.3 Hz, 1H), 7.29 (t, J = 7.3 Hz, 2H), 7.39 (d, J = 7.3 Hz, 2H); 13 C NMR (CDCl 3, 125 MHz): δ 16.9, 17.7, 25.7, 26.6, 40.1, 123.9, 125.1, 125.7, 126.1, 126.9, 128.5, 129.9, 131.8, 138.1, Computational Details Calculations based on density functional theory (DFT) were performed with Gaussian 03 package. We have used the M05 functional from the Truhlar group together with the Ahlrichs VDZ basis set, for the geometry optimization and for the calculation of the Gibbs free energy of activation and free energy of reactions. The local stability of all structures was checked through the eigenvalues of the matrix of second derivatives (Hessian); all energetic minima presented no imaginary frequencies, while transition states (TS) presented a single imaginary frequency. Unrestricted calculations (UM05) were carried out for all the structures, being the electronic state doublet for the reactives, TS's and products and singlet for the Cp 2 TiClOH compound. DFT energies (a.u.), first frequency value (cm -1 ) in parentheses, zero point vibrational energy (ZPVE a.u.), and cartesian coordinates (Å) of the optimized structures discussed: 1prod. E(UM05/Ahlrichs-VDZ) = a.u. / (441 cm -1 ) / ZPVE = a.u. C C C S17

18 H H H H H reac. E(UM05/Ahlrichs-VDZ) = a.u. / (11 cm -1 ) / ZPVE = a.u. Ti Cl O C H H H C C S18

19 C C C H H H H H C C C C C H H H H H C S19

20 C H H H ts. E(UM05/Ahlrichs-VDZ) = a.u. / (731i cm -1 ) / ZPVE = a.u. Ti Cl O C H H H C C S20

21 C C C H H H H H C C C C C H H H H H C S21

22 C H H H prod. E(UM05/Ahlrichs-VDZ) = a.u. / (49 cm -1 ) / ZPVE = a.u. C C H C H C C H C H C S22

23 C H H H H H reac. E(UM05/Ahlrichs-VDZ) = a.u. / (16 cm -1 ) / ZPVE = a.u. Ti Cl O C H H C C S23

24 C C C H H H H H C C C C C H H H H H C S24

25 C C C H C H C H H H C H H H ts. E(UM05/Ahlrichs-VDZ) = a.u. / (623i cm -1 ) / ZPVE = a.u. S25

26 Ti Cl O C H H C C C C C H H H S26

27 H H C C C C C H H H H H C C C C H C H S27

28 C H H H C H H H prod. E(UM05/Ahlrichs-VDZ) = a.u. / (116 cm -1 ) / ZPVE = a.u. C C C C C C H S28

29 H C H H H C C C C H H H H reac. E(UM05/Ahlrichs-VDZ) = a.u. / (6 cm -1 ) / ZPVE = a.u. Ti Cl S29

30 C C C C C H H H H H C C C C C H H H H S30

31 H C C C C C C C C C C H H H C H H O H S31

32 H H H H ts. E(UM05/Ahlrichs-VDZ) = a.u. / (697i cm -1 ) / ZPVE = a.u. Ti Cl C C C C C H H H S32

33 H H C C C C C H H H H H C C C C C C C S33

34 C C C H H H C H H O H H H H H prod. E(UM05/Ahlrichs-VDZ) = a.u. / (205 cm -1 ) / ZPVE = a.u. S34

35 C H H C C C C H C H C H H H reac. E(UM05/Ahlrichs-VDZ) = a.u. / (4 cm -1 ) / ZPVE = a.u. S35

36 Ti Cl C C C C C H H H H H C C C S36

37 C C H H H H H C C C C C C H H H C H H S37

38 O H H H ts. E(UM05/Ahlrichs-VDZ) = a.u. / (683i cm -1 ) / ZPVE = a.u. Ti Cl C C C C C H H H S38

39 H H C C C C C H H H H H C C C C C C H S39

40 H H C H H O H H H prod. E(UM05/Ahlrichs-VDZ) = a.u. / (38 cm -1 ) / ZPVE = a.u. C H H C C H S40

41 H H H H reac. E(UM05/Ahlrichs-VDZ) = a.u. / (4 cm -1 ) / ZPVE = a.u. Ti Cl O C H H H C C S41

42 C C C H H H H H C C C C C H H H H H C S42

43 C H H H H H ts. E(UM05/Ahlrichs-VDZ) = a.u. / (505i cm -1 ) / ZPVE = a.u. Ti Cl O C H H H S43

44 C C C C C H H H H H C C C C C H H H H S44

45 H C C H H H H H prod. E(UM05/Ahlrichs-VDZ) = a.u. / (408 cm -1 ) / ZPVE = a.u. C C C C H S45

46 C H C H H H reac. E(UM05/Ahlrichs-VDZ) = a.u. / (6 cm -1 ) / ZPVE = a.u. Ti Cl C C C C C H S46

47 H H H H C C C C C H H H H H C C C C C S47

48 C H H H H H O H ts. E(UM05/Ahlrichs-VDZ) = a.u. / (437i cm -1 ) / ZPVE = a.u. Ti Cl C C C C S48

49 C H H H H H C C C C C H H H H H C C C S49

50 C C C H H H H H O H (TiCp 2 ClOH). E(UM05/Ahlrichs-VDZ) = a.u. / (38 cm -1 ) / ZPVE = a.u. Ti Cl O S50

51 H C C C C C H H H H H C C C C C H H H S51

52 H H References (1) Sakurai, H.; Sakata, Y.; Hosomi, A. Chem. Lett. 1983, (2) McMurry, J. E.; Silvestri, M. G.; Fleming, M.P.; Hoz, T.; Grayston, M. W. J. Org. Chem. 1978, 43, (3) Yanlong, Q.; Guisheng, L.; Huang, Y-Z. J. Organomet. Chem. 1990, 381, (4) Murias, M.; Handler, N.; Erker, T.; Pleban, K.; Ecker, G.; Saiko, P.; Szekeres, T.; Jäger, W. Bioorg. Med. Chem. 2004, 12, (5) Sonoda, Y.; Suzuki, Y. J. Chem. Soc., Perkin Trans. II. 1996, (6) Tsukahara, Y.; Kinoshita, H.; Inomata, K.; Kotake, H. Bull. Chem. Soc. Jpn. 1984, 57, (7) Rele, S. M.; Nayak, S. K.; Chattopadhyay, S. Tetrahedron, 2008, 64, (8) McMurry, J. E.; Fleming, M. P.; Kees, K. L.; Krepski, L. R. J. Org. Chem. 1978, 43, (9) Tamura, R. J. Org. Chem. 1987, 52, (10) Reference 8a of the manuscript: 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.; S52