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

doi:10.1055/s-0028-1083506

LETTER

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;

Abstract

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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

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References

References and Notes

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.

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.

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).