Spiro[4.5]decane-7-carboxylic acid, 6-oxo-, methyl ester synthesis

Yield:1093270-59-7 93%

Reaction Conditions:

with sodium hydride in tetrahydrofuran;Reflux;

Steps:

15.3

Method 3.(E)-1-(7-methylspiro[4.5]dec-6-en-6-yl)but-2-en-1-one. Spiro[4.5]decan-6-one was transformed in three steps into 7-methylspiro[4.5]decan-6-one by methoxycarbonylation (MeOCO₂Me, NaH, THF, reflux, 93%) followed by methylation of the resulting ketoester (MeI, K₂CO₃, acetone, reflux, 2.5 d) and subsequent demethoxycarbonylation of the crude product (AcOH/H₂O/H₂SO₄ 10:4:3, reflux, 2 h, 79%). The required intermediate 1-(7-methylspiro[4.5]dec-6-en-6-yl)ethanone was then prepared from 7-methylspiro[4.5]decan-6-one according to the Example 10 via 6-ethynyl-7-methylspiro[4.5]decan-6-ol (lithium acetylide ethylenediamine complex, THF, 2 h, 0-20° C., 75%, 78:22 diastereomeric mixture) and 6-ethynyl-7-methylspiro[4.5]dec-6-ene (POCl₃, pyridine, 100° C., 19 h, 45%) that was treated with AcOH/H₂SO₄ (20° C., 50 min., 34%) to give 1-(7-methylspiro[4.5]dec-6-en-6-yl)ethanone. Subsequent aldol condensation with acetaldehyde (LDA, THF; according to the Example 10) followed by treatment of the crude with acetic anhydride/sodium acetate (80° C., 5 h, 59%; according to the Example 10) gave (E)-1-(7-methylspiro[4.5]dec-6-en-6-yl)but-2-en-1-one.7-methylspiro[4.5]decan-6-oneBoiling point: 57° C. (0.09 mbar)¹³C-NMR (100 MHz, CDCl₃): δ215.63 (s), 56.79 (s, C(5)), 41.98 (d), 40.48 (t), 36.50 (t), 36.39 (t), 34.16 (t), 25.37 (t), 24.81 (t), 22.78 (t), 15.01 (q).6-ethynyl-7-methylspiro[4.5]decan-6-olMS (EI): 192 (1), 191 (1), 177 (9), 166 (5), 164 (5), 163 (10), 159 (22), 151 (40), 149 (23), 145 (15), 135 (77), 131 (21), 125 (12), 121 (26), 117 (21), 110 (73), 108 (63), 97 (50), 95 (100), 93 (66), 91 (49), 82 (86), 81 (72), 79 (61), 77 (41), 67 (98), 55 (71), 53 (74), 41 (75), 39 (43).6-ethynyl-7-methylspiro[4.5]dec-6-ene¹H-NMR (400 MHz, CDCl₃): δ3.03-3.02 (br. m, H-CC(6)), 2.01 (tm, J=6.2, 0.9, 2H), 1.97-1.86 (m, 1H), 1.90 (m, Me), 1.76-1.53 (m, 7H), 1.47-1.36 (m, 4H).¹³C-NMR (100 MHz, CDCl₃): δ143.25 (s, C(7)), 122.62 (s, C(6)), 82.87 (s, CCH), 80.16 (d, CCH), 45.02 (s, C(5)), 38.70 (t, 2C), 35.41 (t), 31.72 (t), 25.17 (t, 2C), 22.72 (q), 19.75 (t).MS (EI): 174 (44), 159 (22), 146 (12), 145 (36), 132 (100), 131 (42), 117 (81), 115 (42), 105 (20), 103 (23), 91 (67), 79 (13), 77 (24), 67 (9), 65 (13), 53 (11), 51 (12), 41 (16), 39 (16).1-(7-Methylspiro[4.5]dec-6-en-6-yl)ethanone¹H-NMR (400 MHz, CDCl₃): δ2.29 (s, MeCO), 1.95 (br. t, J=0.6, 6.4, C(8)H₂), 1.77-1.56 (m, 8H), 1.60 (t, J=0.9, MeC(7)), 1.52-1.40 (m, 4H).¹³C-NMR (100 MHz, CDCl₃): δ210.41 (s, CO), 142.38 (s), 129.15 (s), 44.62 (s, C(5)), 37.52 (t, 2C), 34.87 (t), 33.61 (q), 30.89 (t), 24.10 (t, 2C), 20.95 (q), 19.37 (t).MS (EI): 192 (3), 177 (9), 163 (7), 159 (2), 150 (18), 149 (100), 135 (16), 121 (7), 107 (17), 93 (18), 91 (18), 81 (13), 79 (15), 77 (12), 67 (9), 55 (8), 43 (32).

References:

US2010/292128,2010,A1 Location in patent:Page/Page column 15-16