Conjugate Allylation of Cyclic α,β-Unsaturated Esters

Abstract

The conjugate allylation of a homologous series of α,β-unsaturated cyclic esters 8-10 by addition of diallylcuprate (method A), fluoride ion catalyzed addition of trimethylallylsilane (method B), and aluminium tris(2,6-diphenylphenoxide) (ATPH)-mediated addition of allyllithium (method C) was investigated. Method A was not selective in all cases. For methods B and C an influence of ester moiety and ring size on the regioselectivity was observed. Meth­yl cyclopentenoate 8c gave mainly the 1,2/1,2-product regardless the allylation method while tert-butyl and benzyl ester moieties favored the 1,4-products. For larger rings 9, 10 and the anellated system 19 methods B and C behave complementary depending on the ester function: Method B gave best results of 1,4-addition products for benzyl esters while method C worked better for tert-butyl esters.

conjugate allylation - cycloalkenecarboxylates - regio­selectivity - pentalene

References and Notes

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18

The initial 1,2-adduct, an enone, is capable of further 1,2-addition, giving the tertiary alcohol.⁵

19

General Procedures for the Allylation According Method B
In a Schlenk flask 4 Å MS (2.00 g) and TBAF (1.31 g, 0.50 mmol) were dried under high vacuum for 30 min. Under N₂ atmosphere DMF (15 mL) was added, the mixture stirred for 30 min, transferred via cannula in a Schlenk flask with 4 Å MS (2.00 g), and stirred for a further 30 min. A solution of the respective ester (1 mmol) in DMF (5 mL) was added followed by HMPA (1.04 mL, 1.07 g, 6.00 mmol) and a solution of trimethylallylsilane (0.95 mL, 685 mg, 6.00 mmol) in DMF (5 mL) at 0 °C. After stirring at 0 °C for 10 min, 1 N HCl in MeOH (5 mL) and H₂O (40 mL) were successively added, and the aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were dried (MgSO₄), concentrated under vacuum, and the crude product was chromatographed on SiO₂ with hexanes-EtOAc.
Benzyl 2-Allylcyclohexanecarboxylate (15b)
R _f = 0.37 (hexanes-EtOAc, 10:1). ¹H NMR (500 MHz, CDCl₃): δ = 0.89-0.98 (m, 1.5 H, CH₂), 1.14-2.03 (m, 13.5 H, H_a-1′, H_a*-1′, H-2, H*-2, H-3, H*-3, H-4, H*-4, H-5, H*-5, H-6, H*-6), 2.06-2.16 (m, 2.5 H, H_b-1′, H_b*-1′, H-1), 2.65 (dt, J = 8.1, 4.1 Hz, 0.5 H, H*-1) 4.90-4.98 (m, 2 H, H-3′), 5.06-5.15 (m, 3 H, ArCH ₂, ArCH ₂*), 5.65-5.76 (m, 1.5 H, H-2′, H*-2′), 7.29-7.38 (m, 7.5 H, Ar, Ar*) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 22.6*, 23.8*, 25.4, 25.4*, 25.6, 28.0*, 30.1, 30.8 (C-3, C-4, C-5, C-6), 37.2*, 38.7 (C-2), 34.9*, 39.3 (C-1′), 44.8*, 49.4 (C-1), 65.8*, 65.9 (ArCH₂), 115.9*, 116.3 (C-3′), 128.09*, 128.1, 128.1*, 128.2, 128.5, 128.5* (Ar), 136.0, 136.1* (Ar), 136.3, 137.3* (C-2′), 174.6*, 175.9 (CO) ppm. (* denotes minor diastereomer). FT-IR (ATR): 2319 (s), 2856 (s), 2360 (s), 1732 (vs), 1259 (s), 1164 (s), 749 (vs) cm^-1. MS (ESI): m/z (%) = 241 (15) [M⁺ - O], 223 (36), 131 (28), 117 (20), 91 (71) [C₇H₇ ⁺]. HRMS (ESI): m/z calcd for C₁₇H₂₂NaO₂ [M + Na]: 281.1512; found: 281.1503.
Benzyl (3a′ R ,4′ R ,5′ R ,6a′ S )-4′-Allylhexahydro-2′ H -spiro[1,3-dioxolane-2,1′-pentalene]-5′-carboxylate (4) R _f = 0.58 (hexanes-EtOAc, 6:1); [α]_D ²⁰ +23 (c 1.00, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ = 1.45 (ddd, J = 12.6, 7.3, 2.7 Hz, 1 H, H_a-2′), 1.66-1.71 (m, 1 H, H_a-3′), 1.74-1.87 (m, 2 H, H_a-6, H_b-2′), 1.89-1.98 (m, 2 H, H-4′, H_b-3′), 2.04 (ddd, J = 12.9, 8.6, 6.3 Hz, 1 H, H_b-6′), 2.10-2.27 (m, 3 H, H-1′′, H-3a′), 2.35-2.44 (m, 2 H, H-5′, H-6a′), 3.79-3.98 (m, 4 H, OCH₂CH₂O), 5.09 (d, J = 5.3 Hz, 2 H, CH ₂Ph), 4.92 (ddt, J = 10.0, 2.1, 1.0 Hz, 1 H, H_a-3′′), 4.98 (ddt, J = 17.1, 2.1, 1.4 Hz, 1 H, H_b-3′′), 5.73 (ddt, J = 17.1, 10.0, 7.2 Hz, 1 H, H-2′′), 7.28-7.38 (m, 5 H, Ph) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 27.8 (C-2′), 32.9, 33.1 (C-6′, C-3′), 37.8 (C-1′′), 46.7 (C-3a′), 48.9, 51.1 (C-5′, C-6a′), 50.4 (C-4′), 63.8, 64.8 (OCH₂CH₂O), 66.1 (CH₂Ph), 116.3 (C-3′′), 118.2 (C-1′), 127.6, 128.1, 128.2 (Ph), 136.1 (CH₂ Ph), 136.4 (C-2′′), 174.6 (CO) ppm. FT-IR (ATR): 2946 (w), 2880 (w), 2362 (w), 2342 (w), 1455 (w), 1338 (w), 1152 (s), 1023 (s), 697 (s) cm^-1. GC-MS (EI): m/z (%) = 342 (2) [M⁺], 301 (8) [M⁺ - C₃H₅], 251 (6) [M⁺ - C₇H₇], 223 (6), 207 (14) [M⁺ - CO₂CH₂C₆H₅], 107 (10) [C₇H₇O⁺], 99 (100), 91 (30) [C₇H₇ ⁺]. HRMS (ESI): m/z calcd for C₂₁H₂₆O₄Νa [M + Na]: 365.1723; found: 365.1722.

20

General Procedures for the Allylation According Method C Trimethyl aluminium (1.10 mL, 1 M in hexane, 1.10 mmol) was slowly added to a solution of 2,6-diphenylphenol (813 mg, 3.30 mmol) in toluene (6 mL) in a Schlenk flask, and the mixture stirred at r.t. for 30 min. Then a solution of the respective ester (1.00 mmol) in toluene (3 mL) was added. After 5 min, the mixture was cooled to -78 °C and stirred for 1 h. In a further flask n-BuLi (0.88 mL, 1.6 M in hexane, 1.40 mmol) was slowly added to a solution of allyltributyltin (0.43 mL, 463 mg, 1.40 mmol) in THF (4 mL) at -78 °C, and after stirring for 45 min, this allyllithium solution was transferred via cannula to the solution of the ATPH complex, and the reaction mixture stirred at -78 °C for a further 45 min. The reaction was quenched with MeOH (10 mL) and 1 N HCl (5 mL), and the aqueous layer extracted with Et₂O (50 mL). The organic layer was separated, dried (MgSO₄), concentrated, and the crude product chromatographed on SiO₂ with hexanes-EtOAc (50:1).
tert -Butyl 2-Allylcyclopentanecarboxylate (11a)
R _f = 0.74 (hexanes-EtOAc, 10:1). ¹H NMR (300 MHz, CDCl₃): δ = 1.21-1.27 (m, 1 H, H_a-3), 1.44 [s, 9 H, C(CH₃)₃], 1.45 [s, 4.5 H, C(CH₃)₃*], 1.49-1.54 (m, 1 H, H_a*-4, H_a*-3), 1.58-1.69 (m, 2 H, H-4), 1.70-2.00 (m, 5.5 H, H_b-3, H-5, H_a*-1′, H_b*-3, H_b*-4, H*-5), 2.02-2.09 (m, 1 H, H_a-1′), 2.09-2.18 (m, 1.5 H, H-2, H*-2), 2.19-2.29 (m, 2.5 H, H-1, H_b-1′, H_b*-1′), 2.78 (ddd, J = 7.8, 7.8, 5.6 Hz, 0.5 H, H*-1), 4.95-5.05 (m, 3 H, H-3′, H*-3′), 5.75-5.86 (m, 1.5 H, H-2′, H*-2′) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 23.5*, 24.6 (C-4), 28.1, 28.2* [C(CH₃)₃], 28.3*, 30.2 (C-5), 30.7*, 32.1 (C-3), 35.4*, 39.3 (C-1′), 43.3*, 43.7 (C-2), 48.4*, 50.7 (C-1), 79.8, 80.0* [C(CH₃)₃], 115.3*, 115.6 (C-3′), 137.3, 137.9* (C-2′), 174.8*, 175.8 (CO) ppm. (* denotes minor diastereomer). FT-IR (ATR): 1723 (s), 1365 (s), 1256 (s), 1144 (vs) cm^-1. GC-MS (EI): m/z (%) = 210 (1) [M⁺], 154 (60) [M⁺ - C(CH₃)], 137 (28) [M⁺ - OCMe₃], 109 (56)
[M⁺ - CO₂CMe₃], 67 (32), 57 (100) [C₄H₉ ⁺]. HRMS (ESI): m/z calcd for C₁₃H₂₂NaO₂ [M + Na]: 233.1512; found: 233.1510.
tert -Butyl 2-Allylcycloheptanecarboxylate (16a)
R _f = 0.68 (hexanes-EtOAc, 10:1). ¹H NMR (500 MHz, CDCl₃): δ = 1.25-1.34 (m, 1 H, H_a-3), 1.37-1.51 (m, 3 H, H_a-4, CH₂), 1.46 [s, 9 H, C(CH₃)₃], 1.53-1.75 (m, 6 H, H_b-3, H_b-4, H-7, CH₂), 1.89-1.99 (m, 2 H, H_a-1′, H-2), 2.00-2.22 (m, 2 H, H-1, H_b-1′), 4.96-5.04 (m, 2 H, H-3′), 5.72-5.81 (m, 1 H, H-2′) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 26.1, 26.2, 26.3*, 26.5* (C-5, C-6), 28.1, 28.2* [C(CH₃)₃], 28.3*, 29.3 (C-4), 28.6*, 30.3 (C-7), 30.7, 30.7* (C-3), 37.7*, 40.6 (C-1′), 40.2*, 40.5 (C-2), 48.2*, 51.8 (C-1), 79.7, 79.8* [C(CH₃)₃], 115.7*, 116.3 (C-3′), 137.1, 138.0* (C-2′), 175.1*, 176.4 (CO) ppm. FT-IR (ATR): 2923 (s), 1723 (vs), 1366 (s), 1142 (vs), 910 (s) cm^-1. GC-MS (EI): m/z (%) = 238 (4) [M⁺], 181 (100) [M⁺ - CMe₃], 165 (24) [M⁺ - OCMe₃], 140 (14), 136 (16) [M⁺ - CO₂CMe₃], 122 (10), 109 (20), 95 (56), 81 (24), 67 (12), 57 (90) [C₄H₉ ⁺], 41 (24) [C₃H₅ ⁺], 29 (10). HRMS (ESI): m/z calcd for C₁₅H₂₇O₂ [M + H]: 239.2006; found: 239.2017.
1-{(3a′ R ,6a′ S )-3′,3a′6′,6a′-tetrahydro-2′ H -spiro[1,3-dioxolane-2,1′-pentalen]-5′-yl}but-3-en-1-one (20)
R _f = 0.38 (hexanes-EtOAc, 6:1). ¹H NMR (500 MHz, CDCl₃): δ = 1.54-1.72 (m, 3 H, H_a-3′, H-2), 1.98 (dddd, J = 12.1, 10.7, 9.1, 6.5 Hz, 1 H, H_b-3′), 2.59-2.68 (m, 2 H, H_a-6′, H-6a′), 2.76 (dddd, J = 12.6, 2.9, 1.9, 1.9 Hz, 1 H, H_b-6′), 3.44 (dddd, J = 6.7, 2.2, 1.4, 1.4 Hz, 2 H, CH ₂CH=CH₂), 3.44-3.51 (m, 1 H, H-3a′), 3.85-3.95 (m, 4 H, OCH₂CH₂O), 5.09-5.20 (m, 2 H, CH₂CH=CH ₂), 5.96 (ddt, J = 17.2, 10.3, 6.7 Hz, 1 H, CH₂CH=CH₂), 6.52 (dddd, J = 3.7, 1.9, 1.9, 0.9 Hz, 1 H, H-4′) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 27.7 (C-3′), 32.9 (C-6′), 33.4 (C-2′), 44.2 (CH₂CH=CH₂), 46.3 (C-6a′), 49.6 (C-3a′), 63.9, 64.9 (OCH₂CH₂O), 118.2 (CH₂ CH=CH₂), 127.7 (C-1′), 131.4 (CH=), 143.6 (C-5′), 145.3 (C-4′), 197.6 (CO) ppm. FT-IR (ATR): 2952 (s), 2875 (s), 1665 (vs), 1617 (s), 1202 (s), 1105 (vs), 1028 (vs), 993 (s), 914 (s), 735 (s) cm^-1. MS (ESI): m/z (%) = 257 (100)
[M + Na], 235 (6) [M + H], 211 (8), 193 (16) [M⁺ - C₃H₅], 173 (8), 149 (76) [C₁₁H₁₇ ⁺], 131 (8), 121 (8) [C₉H₁₃ ⁺], 105 (16), 99 (8). HRMS (ESI): m/z calcd for C₁₄H₁₉O₃ [M + H]: 235.1329; found: 235.1320.

21

tert -Butyl 2-(2-Hydroxyethyl)cyclopentane-carboxylate (13)
Ozone was passed through a solution of 11a (70 mg, 0.33 mmol) in MeOH-CH₂Cl₂-pyridine (4:4:1) at -78 °C. Then N₂ was passed for 1 min, NaBH₄ (33 mg, 0.84 mmol) was added, and the reaction mixture warmed to 0 °C and stirred for 3 h. After quenching with a sat. NH₄Cl soln (5 mL), the reaction mixture was extracted with EtOAc (20 mL). The combined organic layers were washed with brine (10 mL), dried (MgSO₄), and concentrated under vacuum. The residue was chromatographed on SiO₂ with hexanes-EtOAc (3:1, R _f = 0.34) to give 13 as a colorless oil (52 mg, 74%, dr 67:33). ¹H NMR (500 MHz, CDCl₃): δ = 1.18-1.28 (m, 1 H, H_a-3), 1.45 [s, 13.5 H, C(CH₃)₃, C(CH₃)₃*], 1.52-1.96 (m, 11 H, H-1′, H*-1′, H_b-3, H*-3, H-4, H*-4, H-5, H*-5), 2.11-2.25 (m, 1.5 H, H-2, H-2*), 2.29 (dt, J = 8.8, 7.8 Hz, 1 H, H-1), 2.76 (dt, J = 7.8, 4.6 Hz, 0.5 H, H*-1), 3.60-3.76 (m, 3 H, H-2′, H*-2′) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 23.6*, 24.8 (C-4), 28.1, 28.2* [C(CH₃)₃], 28.5*, 30.6 (C-5), 31.2*, 33.3 (C-3), 34.1*, 38.4 (C-1′), 40.2, 40.6* (C-2), 48.4, 50.9 (C-1), 61.6, 62.2 (C-2′), 80.2*, 80.3 [C(CH₃)₃], 175.1*, 175.5 (CO) ppm. FT-IR (ATR): 2935 (s), 2871 (s), 1722 (vs), 1366 (s), 1145 (vs), 1051 (s), 847 (s) cm^-1. GC-MS (EI): m/z (%) = 184 (1), 158 (18) [M⁺ - C(CH₃)], 141 (44) [M⁺ - OCMe₃], 129 (12), 112 (8) [M⁺ - CO₂CMe₃], 95 (50), 67 (16), 57 (100) [C₄H₉ ⁺], 41 (18) [C₃H₅ ⁺]. HRMS (ESI): m/z calcd for C₁₂H₂₂NaO₃ [M + Na]: 237.1461; found: 237.1453.

22 Tsunoi S. Ryu I. Okuda T. Tanaka M. Komatsu M. Sonoda N. J. Am. Chem. Soc.  1998,  120:  8692 

23

Compound 19 was obtained from enantiomerically pure pentalene-1,4-dione monoacetal^1b via α-acylation, reduction of the carbonyl group, and subsequent dehydration following the method by Burgess.²⁴

24 Burgess EM. Penton HR. Taylor EA. J. Org. Chem.  1973,  38:  26