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Synlett 2008(17): 2697-2701  
DOI: 10.1055/s-0028-1083506
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Functionalized Dialkyl Cyclobutane-1,1-dicarboxylates and Alkyl 5,6-Dihydro-4H-pyran-3-carboxylates via Michael-Induced Ring Closure of δ-Chloro-α,β-Unsaturated Diesters and Ketoesters

Sven Mangelinckx, Bruno Vermaut, Roland Verhé, Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium
Fax: +32(9)2646243; e-Mail: norbert.dekimpe@UGent.be;
Further Information

Publication History

Received 6 June 2008
Publication Date:
01 October 2008 (online)

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Abstract

Michael-induced ring closure (MIRC) of dimethyl 2-(3-chloro-2,2-dimethylpropylidene)malonate, upon treatment with sodium tert-butylthiolate, sodium methoxide or sodium cyanide in methanol, provided a short and efficient synthesis of new 2-functionalized cyclobutane-1,1-dicarboxylic esters. Under similar conditions, methyl 2-acetyl-5-chloro-4,4-dimethylpent-2-enoate afforded 4-functionalized methyl 5,6-dihydro-4H-pyran-3-carboxylates as the MIRC products.

Key words

Michael-induced ring closure - cyclobutanes - dihydropyrans - carboxylic esters - cyclizations

1

Postdoctoral fellow of the Research Foundation, Flanders (FWO-Vlaanderen).

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General Procedure: To a three-necked flask equipped with a reflux condenser, dropping funnel and mechanical stirrer was added anhyd THF (200 mL). At 0 ˚C, TiCl4 (0.2 mol) in CCl4 (50 mL) was added, after which, a solution of 3-chloro-2,2-dimethylpropanal (1; 0.1 mol) and dimethyl malonate (2a) or methyl acetoacetate (2b; 0.1 mol) in anhyd THF (50 mL) was added dropwise. Subsequently, at 0 ˚C, anhyd pyridine (0.4 mol) in anhyd THF (50 mL) was added dropwise over a period of 45 min. The reaction was stirred under reflux (6-8 h), poured into crushed ice (500 mL), extracted with Et2O (3 × 100 mL) and washed with brine, sat. NaHCO3 and brine again. After drying (MgSO4), filtration and evaporation under reduced pressure the pure alkylidene ester was obtained via high-vacuum distillation.
Dimethyl 2-(3-Chloro-2,2-dimethylpropylidene)malonate (3a): yield: 72%; bp 85 ˚C/0.01 Torr. ¹H NMR (270 MHz, CDCl3): δ = 1.23 (s, 6 H, CMe2), 3.49 (s, 2 H, CH2), 3.78 (s, 3 H, COOMe), 3.83 (s, 3 H, COOMe), 6.94 (s, 1 H, CH=C). ¹³C NMR (68 MHz, CDCl3): δ = 24.3, 39.1, 52.4, 52.6, 54.4, 127.6, 150.9, 164.3, 166.8. IR (NaCl): 1730 (C=O), 1650 (C=C) cm-¹. MS (EI, 70 eV): m/z (%) = 234 (9) [M+], 219 (39), 185 (35), 167 (83), 153 (100), 135 (78), 125 (39), 67 (39), 59 (57), 41 (52). Anal. Calcd for C10H15ClO4: C, 51.18; H, 6.44. Found: C, 51.01; H, 6.61.
Methyl 2-Acetyl-5-chloro-4,4-dimethylpent-2-enoate (3b): E/Z = 39:61; yield: 69%; bp 68 ˚C/0.02 Torr. ¹H NMR (270 MHz, CDCl3; Z-isomer): δ = 1.25 (s, 6 H, CMe2), 2.32 (s, 3 H, COMe), 3.50 (s, 2 H, CH2), 3.84 (s, 3 H, COOMe), 6.75 (s, 1 H, CH=C). ¹H NMR (270 MHz, CDCl3; E-isomer): δ = 1.22 (s, 6 H, CMe2), 2.44 (s, 3 H, COMe), 3.48 (s, 2 H, CH2), 3.79 (s, 3 H, COOMe), 6.78 (s, 1 H, CH=C). ¹³C NMR (68 MHz, CDCl3; Z-isomer): δ = 25.3, 31.8, 39.3, 52.5, 54.5, 135.4, 149.8, 164.8, 203.1. ¹³C NMR (68 MHz, CDCl3; E-isomer): δ = 24.4, 26.1, 39.0, 52.3, 54.6, 136.5, 149.6, 167.8, 195.2. IR (NaCl): 1675-1730 (C=O), 1635 (C=C) cm-¹. MS (EI, 70 eV): m/z (%) = 218 (<1) [M+], 203 (4), 183 (5), 171 (6), 169 (3), 167 (4), 151 (9), 137 (4), 135 (4), 109 (7), 95 (6), 71 (6), 67 (5), 59 (4), 43 (100). Anal. Calcd for C10H15ClO3: C, 54.92; H, 6.91. Found: C, 54.78; H, 7.07.

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Synthesis of Dimethyl 2- tert -Butylsulfanyl-3,3-dimethylcyclobutane-1,1-dicarboxylate (4); Representative Procedure: A solution of 2 M NaOMe in MeOH (2.5 mL, 5 mmol) was added to tert-butanethiol (5 mmol). The obtained solution of sodium tert-butylthiolate was added at r.t. to a solution of dimethyl 2-(3-chloro-2,2-dimethylpropylidene)malonate (3a; 5 mmol) in anhyd MeOH (5 mL). The reaction mixture was stirred for 4 h, during which NaCl precipitated, poured into H2O (100 mL) and extracted with Et2O (3 × 50 mL). The combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure. High-vacuum distillation afforded the pure dimethyl 2-tert-butylsulfanyl-3,3-dimethylcyclo-butane-1,1-dicarboxylate(4); yield: 79%; bp 64-65 ˚C/0.02 Torr. ¹H NMR (270 MHz, CDCl3): δ = 1.12 [s, 3 H, C(Me)Me], 1.16 [s, 3 H, C(Me)Me], 1.31 (s, 9 H, SCMe3), 1.95 [d, 1 H, J = 12.2 Hz, CH(H)], 2.63 [dd, 1 H, J = 12.4, 0.8 Hz, CH(H)], 3.75 (s, 3 H, COOMe), 3.77 (s, 3 H, COOMe), 3.99 (s, 1 H, CHSt-Bu). ¹³C NMR (68 MHz, CDCl3): δ = 24.1, 30.3, 31.4, 36.9, 39.7, 42.8, 50.9, 52.1, 52.6, 56.5, 170.3, 172.3. IR (NaCl): 1735 (C=O) cm-¹. MS (EI, 70 eV): m/z (%) = 288 (2) [M+], 258 (1), 232 (8), 231 (8), 201 (8), 176 (54), 145 (23), 144 (77), 116 (8), 113 (23), 88 (100), 59 (31), 57 (92). Anal. Calcd for C14H24O4S: C, 58.30; H, 8.39. Found: C, 58.15; H, 8.54.
Dimethyl 2-Methoxy-3,3-dimethylcyclobutane-1,1-dicarboxylate (5): yield: 67%; bp 60 ˚C/0.02 Torr. ¹H NMR (270 MHz, CDCl3): δ = 1.10 [s, 3 H, C(Me)Me], 1.14 [s, 3 H, C(Me)Me], 1.65 (d, 1 H, J = 12.2 Hz, CH(H)], 2.55 [d, 1 H, J = 12.2 Hz, CH(H)], 3.41 (s, 3 H, OMe), 3.74 (s, 3 H, COOMe), 3.78 (s, 3 H, COOMe), 4.12 (s, 1 H, CHOMe). ¹³C NMR (68 MHz, CDCl3): δ = 20.9, 29.8, 35.9, 37.3, 52.58, 52.63, 56.0, 58.5, 85.1, 169.5, 171.9. IR (NaCl): 1730 (C=O) cm-¹. MS (EI, 70 eV): m/z (%) = no [M+], 199 (6), 143 (38), 113 (23), 86 (100), 75 (19), 71 (38), 59 (14), 46 (14), 45 (19). Anal. Calcd for C11H18O5: C, 57.38; H, 7.88. Found: C, 57.09; H, 8.04.
Dimethyl 2-Cyano-3,3-dimethylcyclobutane-1,1-dicarboxylate (6): yield: 63%; bp 85 ˚C/0.04 Torr. ¹H NMR (270 MHz, CDCl3): δ = 1.25 [s, 3 H, C(Me)Me], 1.31 [s, 3 H, C(Me)Me], 2.11 [d, 1 H, J = 12.5 Hz, CH(H)], 2.79 [d, 1 H, J = 12.5 Hz, CH(H)], 3.78 (s, 3 H, COOMe), 3.80 (s, 1 H, CHCN), 3.84 (s, 3 H, COOMe). ¹³C NMR (68 MHz, CDCl3): δ = 25.6, 29.7, 34.0, 38.7, 39.6, 49.7, 53.4, 53.5, 116.5, 168.5, 170.0. IR (NaCl): 2230 (C≡N), 1735 (C=O) cm-¹. MS (EI, 70 eV): m/z (%) = no [M+], 194 (17), 170 (39), 166 (100), 138 (33), 134 (61), 113 (28), 106 (25), 79 (25), 59 (28), 56 (61), 54 (72).
Dimethyl 2-(3-Chloro-1-cyano-2,2-dimethylpropyl)malonate (7): yield: 58%; bp 88-89 ˚C/0.01 Torr. ¹H NMR (270 MHz, CDCl3): δ = 1.11 [s, 3 H, C(Me)Me], 1.20 [s, 3 H, C(Me)Me], 3.47 [d, 1 H, J = 11.9 Hz, CH(H)Cl], 3.60 [d, 1 H, J = 11.6 Hz, CH(H)Cl], 3.67, 3.71 [2 × d, 2 × 1 H, J = 5.4 Hz, CH(CN)CH], 3.82 (s, 3 H, COOMe), 3.83 (s, 3 H, COOMe). ¹³C NMR (68 MHz, CDCl3): δ = 22.4, 23.7, 38.3 (2 × C), 49.4, 52.8, 53.3, 53.6, 117.4, 167.0, 167.1. IR (NaCl): 2240 (C≡N), 1750, 1735 (C=O) cm-¹. MS (EI, 70 eV): m/z (%): no [M+], 230 (7), 212 (17), 171 (50), 152 (17), 148 (14), 139 (10), 112 (100), 91 (10), 80 (16), 59 (16), 55 (28). Anal. Calcd for C11H16ClNO4: C, 50.48; H, 6.16; N, 5.35. Found: C, 50.32; H, 6.33; N, 5.24.

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Methyl 4- tert -Butylsulfanyl-2,5,5-trimethyl-5,6-dihydro-4 H -pyran-3-carboxylate (8): yield: 70%; bp 80-83 ˚C/0.02 Torr. ¹H NMR (270 MHz, CDCl3): δ = 1.01 [s, 3 H, C(Me)Me], 1.10 [s, 3 H, C(Me)Me], 1.34 (s, 9 H, SCMe3], 2.12 (s, 3 H, C=CMe], 3.45-3.46 (m, 1 H, CHSt -Bu), 3.54 [dd, 1 H, J = 10.7, 2.8 Hz, CH(H)O], 3.73 (s, 3 H, COOMe), 3.73 [d, 1 H, J = 10.8 Hz, CH(H)O]. ¹³C NMR (68 MHz, CDCl3): δ = 19.8, 24.1, 24.2, 31.9, 32.2, 44.0, 46.0, 51.0, 72.3, 105.5, 160.0, 168.3. IR (NaCl): 1700 (C=O), 1615 (C=C) cm-¹. MS (EI, 70 eV): m/z (%) = 272 (8) [M+], 183 (100), 182 (31), 151 (41), 141 (31), 109 (23), 90 (21), 59 (18), 57 (44), 43 (79), 41 (67). Anal. Calcd for C14H24O3S: C, 61.73; H, 8.88. Found: C, 61.54; H, 8.97.
Methyl 4-Methoxy-2,5,5-trimethyl-5,6-dihydro-4 H -pyran-3-carboxylate (9): yield: 61%; bp 52-54 ˚C/0.02 Torr. ¹H NMR (270 MHz, CDCl3): δ = 0.84 [s, 3 H, C(Me)Me], 1.01 [s, 3 H, C(Me)Me], 2.23 [s, 3 H, C=C(Me)], 3.46 [s, 3 H, OMe], 3.58 [dd, 1 H, J = 10.2, 2.0 Hz, CH(H)O], 3.66 (br s, 1 H, CHOMe), 3.74 (s, 3 H, COOMe), 3.83 [d, 1 H, J = 10.2 Hz, CH(H)O]. ¹³C NMR (68 MHz, CDCl3): δ = 20.2, 20.9, 22.5, 33.2, 51.0, 59.6, 71.5, 77.6, 102.9, 165.9, 169.0. IR (NaCl): 1710 (C=O), 1620 (C=C) cm-¹. MS (EI, 70 eV): m/z (%) = 214 (7) [M+], 183 (33), 159 (26), 155 (7), 151 (11), 143 (56), 127 (44), 85 (26), 75 (41), 59 (7), 43 (100). Anal. Calcd for C11H18O4: C, 61.66; H, 8.47. Found: C, 61.51; H, 8.59.
Methyl 4-Cyano-2,5,5-trimethyl-5,6-dihydro-4 H -pyran-3-carboxylate(10): yield: 64%; bp 82-83 ˚C/0.01 Torr. ¹H NMR (270 MHz, CDCl3): δ = 1.03 [s, 3 H, C(Me)Me], 1.24 [s, 3 H, C(Me)Me], 2.31 (s, 3 H, C=CMe), 3.31 (br s, 1 H, CHC≡N), 3.74 (dd, 1 H, J = 11.2, 2.3 Hz, OCHH], 3.77 (s, 3 H, COOMe), 3.86 (d, 1 H, J = 11.2 Hz, OCHH). ¹³C NMR (68 MHz, CDCl3): δ = 20.2, 23.1, 23.3, 29.8, 36.2, 51.6, 72.6, 96.6, 119.6, 166.7, 167.0. IR (NaCl): 2235 (C≡N), 1710 (C=O), 1610 (C=C) cm-¹. MS (EI, 70 eV): m/z (%) = 209 (18) [M+], 194 (15), 178 (15), 154 (15), 150 (10), 122 (5), 113 (6), 97 (10), 56 (100). Anal. Calcd for C11H15NO3: C, 63.14; H, 7.23; N, 6.69. Found: C, 63.01; H, 7.51; N 6.56.

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Dimethyl 2-(3-Chloro-2,2-dimethylpropyl)malonate (13): Sample was isolated via preparative GC from a distillation fraction (bp 88-91 ˚C/0.02 Torr). ¹H NMR (270 MHz, CDCl3): δ = 0.98 (s, 6 H, CMe2), 2.08 (d, 2 H, J = 6.6 Hz, CH 2CH), 3.34 (s, 2 H, ClCH2), 3.42 (t, 1 H, J = 6.4 Hz, CH2CH), 3.75 [s, 6 H, (COOMe)2]. ¹³C NMR (68 MHz, CDCl3): δ = 24.7, 35.2, 37.5, 47.9, 52.8, 54.9, 170.2. IR (NaCl): 1735 (C=O) cm-¹. MS (EI, 70 eV): m/z (%) = no [M+], 221 (<1), 205 (15), 187 (100), 155 (26), 145 (78), 127 (96), 123 (56), 95 (48), 59 (44), 55 (96), 41 (67).