Synlett 2008(3): 405-409  
DOI: 10.1055/s-2008-1032054
LETTER
© Georg Thieme Verlag Stuttgart · New York

Transannular Cyclization with Grignard Reagents: Facile Synthetic Routes to Oxaadamantane and Protoadamantane Derivatives

Kata Mlinarić-Majerski*, Goran Kragol, Tatjana Šumanovac Ramljak
Department of Organic Chemistry and Biochemistry, Ruđer Boković Institute, Bijenička cesta 54, P.O. Box 180, 10 002 Zagreb, Croatia
Fax: +385(1)4680195; e-Mail: [email protected];
Further Information

Publication History

Received 26 October 2007
Publication Date:
16 January 2008 (online)

Abstract

A simple and efficient synthetic route to different adamantanoid derivatives such as disubstituted oxaadamantane derivatives, trisubstituted protoadamantane, and trisubstituted adamantane derivatives starting from same precursor, 7-exo-epoxymethylene[3.3.1]nonan-3-one, is described.

    References and Notes

  • 2 Cage Hydrocarbons   Olah GA. Wiley; New York: 1990. 
  • 3 Yurchenko A. In Cage Hydrocarbons   Olah GA. Wiley; New York: 1990.  p.Chap. 5 
  • 4a Zefirov NS. Averina NV. Zh. Org. Khim.  1969,  5:  190 
  • 4b Averina NV. Zafirev NS. Zh. Org. Khim.  1969,  5:  1991 
  • 4c Zefirov NS. Tartakovski VA. Averina NV. Zh. Org. Khim.  1971,  7:  504 
  • 5a Stetter H. Mayer J. Chem. Ber.  1959,  92:  2664 
  • 5b Schaefer JP. Honig LM. J. Org. Chem.  1968,  33:  2655 
  • 6a Black RM. Gill GB. Hands D. J. Chem. Soc., Chem. Commun.  1972,  311 
  • 6b Krasutsky PA. Kolomitsin IV. Carlson RM. Jones MJr. Tetrahedron Lett.  1996,  37:  5673 
  • 7 Grignard Reagents: New Developments   Richey HG. Wiley; Chichester: 2000. 
  • 8a Gagneux AR. Meier R. Tetrahedron Lett.  1969,  1365 
  • 8b Mori T. Yang KH. Kimoto K. Nozaki H. Tetrahedron Lett.  1970,  2419 
  • 8c Stepanov FN. Utochka TN. Yurchenko AG. Z. Org. Khim.  1972,  8:  1183 
  • Reaction of Epoxy Ketone 7 with Grignard Reagent - General Procedure
  • 9a

    Method A: A solution of 7-exo-epoxymethylenbicy-clo[3.3.1]nonan-3-one (1.00 mmol) in anhyd THF (10 mL) was heated to 55 °C and then the Grinard reagent (3.00 mmol) was added. The reaction mixture was heated for 1 h at 55 °C. After cooling to r.t., sat. aq NH4Cl (50 mL) was added, the product was extracted with CH2Cl2 (4 × 25 mL), and the resulting organic extracts were dried over anhyd MgSO4. The solvent was evaporated under reduced pressure and crude product was purified on silica gel column.

  • 9b

    Method B: A solution of 7-exo-epoxymethylenbicy-clo[3.3.1]nonan-3-one (7) in anhyd THF was added to a solution of Grignard reagent preheated to 55 °C. The reaction mixture was heated for 1 h at 55 °C, and after workup the products were separated by column chromatography.

  • 14 Kolocouris N. Zoidis G. Fytas C. Synlett  2007,  1063 
  • 15 Majerski Z. Hamerak Z. Org. Synth., Coll. Vol. VI  1988,  958 
  • 17a Lenoir D. Raber DJ. Schleyer Pvon R. J. Am. Chem. Soc.  1974,  96:  2149 
  • 17b Lenoir D. Schleyer Pvon R. J. Chem. Soc., Chem. Commun.  1970,  941 
  • 18 Muraoka O. Wang Y. Okumura M. Nishiura S. Tanabe G. Momose T. Synth. Commun.  1996,  26:  1555 
  • 19 Yurchenko AG. Melnik NN. Likhotvorik IR. Tetrahedron Lett.  1989,  30:  3653 
  • 20a Liu J.-H. Kovacic P. J. Org. Chem.  1973,  38:  3462 
  • 20b Wiesmann RF. Rademacher P. Chem. Ber.  1994,  127:  1517 
  • 22a Herpers E. Kirmse W. J. Chem. Soc., Chem. Commun.  1993,  160 
  • 22b Gappa A. Herpers E. Herrmann R. Hülsewede V. Kappert W. Klar M. Kirmse W. J. Am. Chem. Soc.  1995,  117:  12096 
  • 24a Schleyer Pvon R. Lenoir D. Mison P. Liang G. Surya Prakash GK. Olah GA. J. Am. Chem. Soc.  1980,  102:  683 
  • 24b Dutler R. Rauk A. Withworth SM. Sorensen TS. J. Am. Chem. Soc.  1991,  113:  411 
  • 24c Gomann K. Herpers E. Kirmse W. Eur. J. Org. Chem.  1998,  2245 
  • 25a Imamoto T. Takiyama N. Nakamura K. Hatajima T. Kamiya Y. J. Am. Chem. Soc.  1989,  111:  4392 
  • 25b Bartoli G. Marcatoni E. Petrini M. Angew. Chem., Int. Ed. Engl.  1993,  32:  1061 
  • 25c Dimitrov V. Bratovanov S. Simova S. Kostova K. Tetrahedron Lett.  1994,  35:  6713 
  • 25d Dimitrov V. Kostova K. Genov M. Tetrahedron Lett.  1996,  37:  6787 
1

Current Address: GlaxoSmithKline Research Centre Zagreb, Prilaz baruna Filipovića 29, 10000 Zagreb, Croatia.

10

Reaction of Epoxy Ketone 7 with Vinylmagnesium BromideBy following method A, the products were obtained via reaction of epoxyketone 7 (0.50 g, 3.00 mmol) with vinyl magnesium bromide (10 mL, 10.00 mmol). The crude reaction product was purified via column chromatography on silica gel by eluting with 0-15% EtOAc in CH2Cl2 to afford 0.17 g (29%) of 4-endo-vinylprotoadamantan-1,4-exo-diol (4); mp 149-152 °C. IR (KBr): ν = 3360 (s), 3100 (w), 3020 (w), 2940 (s), 2920 (s), 2870 (m), 1640 (w), 1310 (m), 1100 (s), 1060 (m), 990 (m) cm-1. 1H NMR (300 MHz, CD3OD): δ = 1.22-1.27 (m, 1 H), 1.41-1.82 (m, 5 H), 1.86-1.96 (m, 3 H), 2.15-2.37 (m, 4 H), 5.02 (dd, J = 10.9, 1.4 Hz, 1 H), 5.20 (dd, J = 17.4, 1.4 Hz, 1 H), 5.99 (dd, J = 17.4, 10.9 Hz, 1 H). 13C NMR (75 MHz, CD3OD): δ = 30.2 (d), 33.2 (t), 35.2 (d), 41.7 (t), 42.3 (t), 44.9 (d), 48.8 (t), 49.8 (t), 76.1 (s), 78.4 (s), 113.1 (t), 148.5 (d). Anal. Calcd for C12H18O2: C, 74.19; H, 9.34. Found: C, 74.28; H, 9.22. Further elution with 25% EtOAc in CH2Cl2 afforded 0.20 g (35%) of 4-exo-vinylprotoadamantan-1,4-endo-diol (3); mp 182-184 °C. IR (KBr): ν = 3340 (s), 3240 (s), 3080 (w), 2980 (w), 2940 (s), 2915 (s), 2870 (m), 2840 (m), 1645 (w), 1320 (m), 1230 (m), 1080 (s), 925 (s) cm-1. 1H NMR (300 MHz, CD3OD): δ = 1.17-1.21 (m, 1 H), 1.44 (dd, J = 10.2, 2.8 Hz, 1 H), 1.66-2.56 (m, 11 H), 5.04 (d, J = 17.6 Hz, 1 H), 5.28 (d, J = 10.9 Hz, 1 H), 6.06 (dd, J = 17.6, 10.9 Hz, 1 H). 13C NMR (75 MHz, CD3OD): δ = 30.0 (d), 32.3 (t), 35.1 (d), 40.6 (t), 42.7 (t), 44.1 (d), 48.5 (t), 49.5 (t), 73.8 (s), 77.7 (s), 113.1 (t), 148.9 (d). Anal. Calcd for C12H18O2: C, 74.19; H, 9.34. Found: C, 74.23; H, 9.13. In the Grignard reaction done by method B, besides products 3 and 4, 1 was isolated in the yield of 4.5%. 1-Hydroxymethyl-3-vinyl-2-oxaadamantane (1); mp 58-60 °C. IR (KBr): ν = 3220 (s, OH), 3000 (w), 2980 (w), 2840 (s), 1640 (s), 1440 (s), 1195 (s), 1080 (s), 990 (s) cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.47 (d, J = 12.3 Hz, 2 H), 1.60-1.85 (m, 10 H), 2.27 (br s, 2 H), 2.41 (s, OH), 3.38 (s, 2 H), 5.04 (dd, J = 10.8, 1.3 Hz, 1 H), 5.15 (dd, J = 17.4, 1.3 Hz, 1 H), 5.85 (dd, J = 17.4, 10.8 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ = 27.0 (d), 34.8 (t), 35.8 (t), 39.2 (t), 70.1 (t), 72.1 (s), 72.4 (s), 111.7 (t), 144.2 (d). Anal. Calcd for C12H18O2: C, 74.19; H, 9.34. Found: C, 74.19; H, 9.21.

11

Reaction of Epoxy Ketone 7 with Methylmagnesium Iodide By following the method A the products were obtained via reaction of epoxy ketone 7 (0.25 g, 1.50 mmol) and MeMgI (5.20 mmol). The crude reaction mixture was purified via column chromatography on silica gel by eluting with 0-10% of EtOAc in CH2Cl2 to afford 0.013 g (5%) of 1-hydroxy­-methyl-3-methyl-2-oxaadamantane (2); mp 59-60 °C. IR (KBr): ν = 3220 (s), 2920 (s), 2840 (s), 1440 (s), 1150 (s), 1080 (s). 1H NMR (300 MHz, CDCl3): δ = 1.10 (s, 3 H, CH3), 1.41 (d, J = 11.8 Hz, 2 H), 1.51-1.76 (m, 8 H), 2.20 (br s, 2 H), 2.41 (s, OH), 3.33 (s, 2 H). 13C NMR (75 MHz, CDCl3): δ = 27.2 (d), 29.1 (q), 34.8 (t), 35.9 (t), 41.1 (t), 70.2 (t), 70.3 (s), 72.2 (s). Anal. Calcd for C11H18O2: C, 72.49; H, 9.95. Found: C, 72.55; H, 10.01. Further elution with 15% EtOAC in CH2Cl2 afforded 0.08 g (31%) of 4-endo-methylprotoadamantan-1,4-exo-diol (6); mp 144-147 °C. IR (KBr): ν = 3320 (s, OH), 2900 (s), 2850 (s), 1450 (s), 1355 (s), 1160 (s), 1040 (s) cm-1. 1H NMR (300 MHz, CD3OD): δ = 1.22-1.38 (m, 4 H, with distinguished singlet at 1.23 ppm, CH3), 1.51 (d, J = 10.0 Hz, 2 H), 1.66 (d, J = 12.3 Hz, 1 H), 1.76-2.43 (m, 9 H). 13C NMR (75 MHz, CD3OD): δ = 29.9 (d), 31.5 (q), 32.5 (t), 34.7 (d), 42.4 (t), 43.4 (t), 45.7 (d), 48.2 (t), 49.3 (t), 73.5 (s), 77.7 (s). Anal. Calcd for C11H18O2: C, 72.49; H, 9.95. Found: C, 72.60; H, 10.02. Elution with 5% MeOH in CH2Cl2 afforded 0.06 g (24%) of 4-exo-methyl­-protoadamantan-1,4-endo-diol (5); mp 181-183 °C. IR (KBr): ν = 3270 (s, OH), 2920 (s), 1320 (s), 1120 (s), 1080 (s), 930 (s) cm-1. 1H NMR (300 MHz, CD3OD): δ = 1.24-1.31 (m, 4 H, with distinguished singlet at 1.31 ppm, CH3), 1.45 (d, J = 10.1 Hz, 1 H), 1.59-2.27 (m, 11 H). 13C NMR (75 MHz, CD3OD): δ = 30.4 (d), 32.5 (t), 32.9 (q), 34.6 (d), 41.0 (t), 44.3 (t), 46.6 (d), 48.5 (t), 49.8 (t), 72.5 (s), 77.7 (s). Anal. Calcd for C11H18O2: C, 72.49; H, 9.95. Found: C, 72.57; H, 9.86.Method BA solution of epoxy ketone 7 (0.50 g, 3.00 mmol)was added to a solution of MeMgI (10.40 mmol) preheated to 35 °C. After column chromatography there was obtained 0.035 g (7%) of oxaadamantane 2, 0.23 g (45%) of exo-diol 6, and 0.14 g (27%) of endo-diol 5.

12

Reaction of Epoxyketone 7 with MethyllithiumA solution of 7 (0.20 g, 1.20 mmol) in anhyd THF (5 mL) was cooled to 0 °C and then methyllithium (2 mL, 4.00 mmol) was added. The reaction mixture was stirred for 1 h at 0 °C. After warming to r.t., sat. aq soln of NH4Cl (20 mL) was added. The mixture of products was extracted with CH2Cl2 (4 × 15 mL) and organic extracts were dried over anhyd MgSO4. After column chromatography 0.02 g (10%) of oxaadamantane 2, 0.09 g (44%) of exo-diol 6, and 0.05 g (25%) of endo-diol 5 were obtained.

13

The calculations were performed by AM1 and PM3 methods implemented in HyperChem 5.0, Hypercube, Gainsville, Florida, USA. The enthalpy of formation for endo-derivatives were found to be higher approximately 1.27 (AM1) or 1.15 (PM3) kcal/mol for 3 and 0.37 (AM1) or 0.88 (PM3) kcal/mol for derivative 5, respectively.

16

Reaction of protoadamantan-4-one with vinylmagnesium bromide was performed according to the method B. The crude product obtained from protoadamantan-4-one [15] (0.45 g, 3.00 mmol) was purified on silica gel column by eluting with 0-10% EtOAc in pentane to afford 0.15 g (28%) of 4-endo-vinylprotoadamantan-4-exo-ol and 0.18 g (34%) of 4-exo-vinylprotoadamantan-4-endo-ol.4- endo- Vinylprotoadamantan-4- exo -olMp 64-66 °C. IR (KBr): ν = 3350 (s, OH), 3090 (w), 3020 (w), 2920 (s), 1635 (w), 1460 (m), 1130 (m) cm-1. 1H NMR (300 MHz, CD3OD): δ = 1.40-1.52 (m, 2 H), 1.56-1.68 (m, 2 H), 1.70-2.55 (m, 10 H), 5.10 (dd, J = 10.8, 1.5 Hz, 1 H), 5.30 (dd, J = 17.3, 1.5 Hz, 1 H), 6.14 (dd, J = 17.3, 10.8 Hz, 1 H). 13C NMR (75 MHz, CD3OD): δ = 30.3 (d), 33.7 (t), 35.2 (d), 36.5 (t), 37.5 (d), 41.3 (t), 41.8 (t), 43.6 (t), 46.9 (d), 76.0 (s), 112.0 (t), 148.3 (d). HRMS: m/z calcd for C12H18O [M+]: 178.135216; found: 178.139600.4- exo- Vinylprotoadamantan-4- endo -olMp 71-73 °C. IR (KBr): ν = 3485 (s, OH), 3090 (w), 2920 (s), 2850 (s), 1630 (w), 1445 (m), 1110 (m). 1H NMR (300 MHz, CD3OD): δ = 1.34-1.45 (m, 2 H), 1.51-1.65 (m, 2 H), 1.70-1.93 (m, 4 H), 1.99-2.39 (m, 5 H), 2.43-2.50 (m, 1 H), 5.12 (dd, J = 10.8, 1.2 Hz, 1 H), 5.40 (dd, J = 17.5, 1.2 Hz, 1 H), 6.21 (dd, J = 17.5, 10.8 Hz, 1 H). 13C NMR (75 MHz, CD3OD): δ = 31.0 (d), 33.4 (t), 35.4 (t), 35.6 (d), 37.1 (d), 41.6 (t), 43.4 (t), 43.9 (t), 46.5 (d), 74.4 (s), 112.7 (t), 149.3 (d). HRMS: m/z calcd for C12H18O [M+]: 178.135216; found: 178.129036.

21

Reaction of 1-hydroxyprotoadamantan-4-one (8) with vinyl magnesium bromide was performed according to method B. The crude product obtained from 1-hydroxyproto­-adamantan-4-one (8, 0.20 g, 1.20 mmol) was purified on silica gel column using 0-25% EtOAc in CH2Cl2 as eluent to afford 0.065 g (28%) of exo-diol 4 and 0.08 g (32%) of endo-diol 3.

23

Acid-Catalyzed Rearrangement of 4- endo -Methyl­-protoadamantan-1,4- exo -diol (6) and 4- exo -Methyl­-protoadamantan-1,4- endo -diol (5)A solution of diols 6 (or 5) in 1.75 M HClO4 (10 mL, 0.10 g, 0.55 mmol), in dioxane-H2O (3:2), was heated at 60 °C for 2 h. This reaction was monitored by gas chromatography (capillary column DB-210, 120 °C). After cooling to r.t., a sat. aq soln of NaHCO3 (30 mL) was added. The product was extracted with CH2Cl2 (4 × 15 mL) and organic extracts were dried over anhyd MgSO4. The solvent was evaporated under reduced pressure and crude product was purified on silica gel column using 2% MeOH in CH2Cl2 as eluent to afford 0.80 g (80%) of 3-methyladamantan-1,4-exo-diol (9); mp 164-166 °C. IR (KBr): ν = 3300 (s, OH), 2920 s), 2880 (m), 1450 (m), 1090 (s). 1H NMR (300 MHz, CD3OD): δ = 0.94 (s, 3 H, CH3), 1.17 (d, J = 12.5 Hz, 1 H), 1.39 (d, J = 12.3 Hz, 1 H), 1.45-2.16 (m, 10 H), 3.49 (s, 1 H). 13C NMR (75 MHz, CD3OD): δ = 17.5 (q), 20.7 (t), 22.2 (d), 28.1 (s), 28.2 (t), 28.8 (d), 35.1 (t), 36.0 (t), 42.6 (t), 59.5 (s), 68.9 (d). Anal. Calcd for C11H18O2: C, 72.49; H, 9.95. Found: C, 72.42; H, 9.72.

26

Reaction of Epoxyketone 7 with CeCl 3 and Vinyl­-magnesium BromideA suspension of 7-exo-epoxymethylenbicylo[3.3.1]nonan-3-one (7, 1.50 g, 9.00 mmol) and anhyd CeCl3 [25] (2.45 g, 9.00 mmol) in anhyd THF (40 mL) was stirred at r.t. for 2 h and then 1 M solution of vinylmagnesium bromide (17.0 mL, 17.0 mmol) was added. The reaction mixture was stirred overnight at r.t. and then 10% aq soln of AcOH (75 mL) was added. The product was extracted with CH2Cl2 (4 × 25 mL) and organic extracts were dried over anhyd MgSO4. The solvent was evaporated under reduced pressure and crude product was purified on silica gel column using CH2Cl2 as eluent to afford 1.00 g (58%) of 1-hydroxymethyl-3-vinyl-2-oxaadamantane (1).Reaction of Epoxy Ketone 7 with CeCl 3 and Methylmagnesium IodideA suspension of 7-exo-epoxymethylenbicylo[3.3.1]nonan-3-one (7, 0.50 g, 3.00 mmol) and anhyd CeCl3 [24] (0.75 g, 3.00 mmol) in anhyd THF (12 mL) was stirred at r.t. for 2 h and then a solution (10 mL) of MeMgI was added [prepared from magnesium turnings (0.30 g, 12.00 mmol) and MeI (0.65 mL, 10.30 mmol) in Et2O (13.5 mL)]. The reaction mixture was stirred 1.5 h at r.t. and then a sat. aq soln of NH4Cl (50 mL) was added. The product was extracted with CH2Cl2 (4 × 25 mL) and the organic extracts were dried over anhyd MgSO4. The solvent was evaporated under reduced pressure and crude product was purified on silica gel column using 5% EtOAc in CH2Cl2 as eluent to afford 0.415 g (80%) of 1-hydroxymethyl-3-methyl-2-oxaadamantane (2).

27

Since in the reaction with CeCl3 only method A could be applied, the sensitivity of vinyl magnesium bromide plays the main role for the lower yield.

28

Results to be published.