Organic Lewis Acid Assisted Elimination: Ortho Esters as Surrogates for Ketene Acetals

Abstract

A one-pot elimination/hetero-Diels-Alder addition cascade has been developed whereby certain α,β-unsaturated carbonyl compounds, acting as organic Lewis acids, induce conversion of ortho esters into ketene acetals in situ. The ketene acetals then react with enones or acrylamides to yield derivatives of cyclic ortho esters.

Key words

acetals - Diels-Alder reactions - enones - heterocycles - tandem reactions

References and Notes

• 1 Bitter J. Leitich J. Partale H. Polansky OE. Riemer W. Ritter-Thomas U. Schlamann B. Stilkerieg B. Chem. Ber.  1980,  113:  1020 
• 2 Schuster P. Polansky OE. Wesseley F. Tetrahedron  1966,  22:  463 ; Suppl. 8, Part II
• 3a McElvain SM. Davie WR. J. Am. Chem. Soc.  1951,  73:  1400 
• 3b Comprehensive Organic Functional Group Transformations   Vol. 4:  Katritzky AR. Meth-Cohn O. Rees CW. Pergamon; New York: 1995.  p.225-826  
• 3c Johnson WS. Werthemann L. Bartlett WR. Brocksom TJ. Li T. Faulkner DJ. Petersen MR. J. Am. Chem. Soc.  1970,  92:  741 
• 4 Belanger A. Brassard P. J. Chem. Soc., Chem. Commun.  1972,  863 
• 5 McElvain SM. Degginger ER. Behun JD. J. Am. Chem. Soc.  1954,  76:  5736 
• 6 Vu Moc T. Bull. Soc. Chim. Fr.  1970,  4429 
• 7 Jones G. Organic Reactions   Vol. 15:  Adams R. John Wiley and Sons; New York: 1967.  Chap. 2. p.204 
• 15 Davies S. Smith AD. Cowley AR. Synlett  2004,  1957 

8

General Procedure
A mixture of the heterodiene in an excess of ortho ester was heated at 100 °C for 1-3 d. The excess ortho ester was removed in vacuo to give the crude products, which were purified either by column chromatography or recrystallisation.

9

This was confirmed by reacting enone 3a with dimethyl ketene acetal at r.t. for 20 h. The volatile components were removed in vacuo. The product was purified by column chromatography. The NMR spectrum of 6 was identical with the product from the reaction with the ketene acetal. Compound 11 (Table [2] ) was prepared similarly, either by heating 4a (Figure [1] , R = Me, Y = Cl) with trimethyl orthoacetate or by reacting it with the dimethyl ketene acetal at r.t.

10

The stability of the ortho esters at the reaction temperatures used was confirmed by monitoring a sample of the triethyl orthopropionate at 150 °C over a period of 24 h. No evidence for the decomposition of the ortho ester or the formation of the ketene acetal was detected by NMR.

11

Synthesis of Ethyl 4-(4-Chlorophenyl)-6,6-dimethoxy-2-methyl-5,6-dihydro-4 H -pyran-3-carboxylate (6) A mixture of enone 3a (1.00 g, 3.5 mmol) and trimethyl orthoacetate (4 mL) was heated at 80 °C. After 3 d the volatiles were left to evaporate (over 1 d) and the crude material was purified by column chromatography (SiO₂) to give product 6 (0.91 g, 76%) as a colourless oil which slowly crystallised, mp 75-76 °C. Anal. Calcd (%) for C₁₇H₂₁ClO₅: C, 59.9; H, 6.2; Cl, 10.4. Found: C, 60.0; H, 6.5; Cl, 10.5. ¹H NMR (400 MHz, CDCl₃): δ = 7.19 (2 H, d, J = 8.4 Hz, ArH), 7.08 (2 H, d, J = 8.4 Hz, ArH), 3.93-3.78 (3 H, m, CHAr and OCH ₂CH₃), 3.30 (3 H, s, OCH₃), 3.14 (3 H, s, OCH₃), 2.29 (3 H, s, OCCH₃), 2.24 (1 H, dd, J = 7.0, 13.5 Hz, CH _AH_B), 1.91 (1 H, dd, J = 9.1, 13.5 Hz, CH_A H _B), 0.84 (3 H, t, J = 7.2 Hz, CO₂CH₂CH ₃). ¹³C NMR (100.6 MHz, CDCl₃): δ = 167.4, 160.5, 143.3, 131.7, 128.6, 128.3, 112.3, 106.2, 59.7, 49.8, 48.8, 38.1, 36.0, 19.1, 13.7. The identity of the product was confirmed by comparison of the NMR spectra with the product formed from 3a (0.88 g, 3.5 mmol) and ketene dimethyl acetal (3 mL) by stirring the mixture at r.t. for 20 h. The excess ketene acetal was removed in vacuo to afford 6 (0.98 g, 82%) as a colourless solid, mp 76 °C.

12

Synthesis of 4 R* -(4-Chlorophenyl)-2-(3,4-dichloro-phenyl)-6,6-diethoxy-5 S* -methyl-5,6-dihydro-4 H -pyran-3-carbonitrile (8)
A mixture of enone 3b (1.00 g, 3 mmol) and triethyl orthoacetate (3 mL) was heated at 100 °C for 20 h. Excess ortho ester was removed in vacuo to give the crude product. Then, i-PrOH was added and the resultant solid was filtered off to give the product 8 (0.55 g, 40%) as beige crystals. Recrystallisation from i-PrOH gave fine colourless needles, mp 165-166 °C. Anal. Calcd (%) for C₂₃H₁₂Cl₃NO₃: C, 59.2; H, 4.8; N, 3.0; Cl, 22.8. Found: C, 59.4; H, 4.6; N, 3.0; Cl, 22.8. ¹H NMR (400 MHz, CDCl₃): δ = 7.75-7.77 (2 H, m, ArH), 7.41-7.45 (3 H, m, ArH), 7.26-7.27 (2 H, m, ArH), 4.23 (1 H, br s, CHAr), 3.60-3.90 (4 H, m, 2 × OCH₂), 2.31 (1 H, br s, CH₃CH), 1.24 (3 H, t, J = 7.3 Hz, CH₃), 1.19 (3 H, br s, CH₃), 1.01 (3 H, br s, CH₃). ¹³C NMR (100.6 MHz, CDCl₃): δ = 162.1, 137.0, 136.5, 135.5, 133.7, 131.0, 130.2, 129.6, 129.3, 128.8, 127.6, 118.8, 115.8, 87.9, 59.2, 57.8, 42.8, 38.5, 15.1, 15.0, 12.8.

13

Synthesis of 7,7-Diethoxy-5 S* -(4-methoxyphenyl)-6 R* -methyl-1,5,6,7-tetrahydropyrano[2,3- d ]pyrimidine-2,4-dione (17) The condensation product 4c (1.10 g, 4.5 mmol) in triethyl orthopropionate (4.5 mL) was heated at 120 °C until the intense yellow colour faded (10 h). The mixture was cooled, stirred with i-PrOH (5 mL) for 2 h, filtered and the solid washed with i-PrOH to afford product 17 (0.86 g, 51%). A portion was recrystallised from MeOH to give pale yellow plates, mp 195 °C (dec). Anal. Calcd (%) for C₁₉H₂₄N₂O₆: C, 60.6; H, 6.4; N, 7.4. Found: C, 60.7; H, 6.2; N, 7.4. ¹¹H NMR (400 MHz, CDCl₃): δ = 9.17 (1 H, br s, NH), 8.28 (1 H, br s, NH), 7.09 (2 H, d, J = 8.4 Hz, ArH), 6.82 (2 H, d, J = 8.4 Hz, ArH), 3.81-3.88 (1 H, m, OCH _AH_B), 3.77 (3 H, s, OCH₃), 3.61-3.69 (1 H, m, OCH_A H _B), 3.53-3.59 (3 H, m, OCH₂ and CHAr), 2.21 (1 H, dq, J = 6.7, 8.4 Hz, CHCH₃), 1.18 (3 H, t, J = 7.0 Hz, OCH₂CH ₃), 1.16 (3 H, t, J = 7.0 Hz, OCH₂CH ₃), 0.94 (3 H, d, J = 6.7 Hz, CHCH ₃). ¹³C NMR (100.6 MHz, DMSO): δ = 163.2, 157.3, 155.5, 150.0, 135.3, 128.6, 116.6, 113.0, 88.3, 58.6, 57.0, 54.3 (2 × CH₂), 41.4, 14.9, 14.7, 13.3.

14

Synthesis of Ethyl 3 R* -(4-Methoxyphenyl)-2 R*- methyl-3-(2,4,6-trioxo-hexahydropyrimidin-5-yl)propionate (18)
TFA (0.5 mL) was added to cycloadduct 17 (0.50 g, 1.43 mmol) in CH₂Cl₂ (2 mL) and the solution was stirred at r.t. for 5 min. The volatiles were removed in vacuo and the residue was purified by chromatography (20% Et₂O-CH₂Cl₂) to give product 18 (0.41 g, 83%) as a colourless glass. Anal. Calcd (%) for C₁₇H₂₀N₂O₆: C, 58.6; H, 5.8; N, 8.0. Found: C, 58.3; H, 5.8; N, 7.8. ¹H NMR (400 MHz, CDCl₃): δ = 7.95 (1 H, br s, NH), 7.81 (1 H, br s, NH), 7.07 (2 H, d, J = 8.5 Hz, ArH), 6.81 (2 H, d, J = 8.5 Hz, ArH), 4.23 (2 H, q, J = 7.0 Hz, OCH ₂CH₃), 4.03 (1 H, d, J = 3.7 Hz, OCCHCO), 3.74-3.80 (1 H, m, CHAr), 3.77 (3 H, s, OCH₃), 3.38-3.47 (1 H, m, CHCH₃), 1.31 (3 H, t, J = 7.0 Hz, OCH₂CH ₃), 1.01 (3 H, d, J = 7.0 Hz, CHCH ₃). ¹³C NMR (100.6 MHz, CDCl₃): δ = 176.1, 169.0, 168.6, 159.2, 149.3, 129.6, 128.5, 114.4, 61.0, 55.1, 51.4, 49.2, 40.8, 17.1, 14.1.

16

Synthesis of 4 R* -(4-Chlorophenyl)-6,6-diethoxy-1-(4-fluorophenyl)-5 S*- methyl-2-oxo-piperidine-3 R*- carbonitrile (21Aa)
A mixture of the cyano compound 5a (0.90 g, 3.0 mmol) and triethyl orthopropionate (2 mL) was heated at 120 °C for 6 h and then left to cool overnight. The next day the mixture was diluted with i-PrOH (5 mL), stirred 1 h and then filtered to give product 21Aa (1.07g, 83%) as yellow needles. A portion was recrystallised from i-PrOH to give pale yellow blades, mp 164-166 °C. Anal. Calcd (%) for C₂₃H₂₄ClFN₂O₃: C, 64.1; H, 5.6; N, 6.5. Found: C, 64.2; H, 5.7; N, 6.6. ¹H NMR (400 MHz, CDCl₃): δ = 7.46-7.52 (4 H, m, ArH), 7.21-7.28 (4 H, m, ArH), 4.75 (1 H, d, J = 12.4 Hz, CHCN), 3.42-3.71 (4 H, m, 2 × OCH ₂CH₃), 3.23 (1 H, dd, J = 7.0, 12.4 Hz, CHAr), 2.64 (1 H, quintet, J = 7.0 Hz, CHCH₃), 1.08 (3 H, t, J = 7.0 Hz, OCH₂CH ₃), 0.97 (3 H, t, J = 7.0 Hz, OCH₂CH ₃), 0.88 (3 H, d, J = 7.0 Hz, CH ₃CH). ¹³C NMR (100.6 MHz, CDCl₃): δ = 164.1, 160.9 (J = 243.8 Hz), 139.3, 133.0 (J = 3.1 Hz), 132.2, 131.3 (J = 9.2 Hz), 129.9, 128.7, 116.9, 115.0 (J = 22.2 Hz), 107.9, 58.9, 57.7, 45.1, 42.3, 41.8, 14.7 (2 overlapping signals), 14.2.

17

Synthesis of Ethyl 3 R* -(4-Chlorophenyl)-4 R* -cyano-4-(4-fluorophenylcarbamoyl)-2 S* -methylbutyrate (22) A portion of 21Aa (0.50 g, 1.2 mmol) was suspended in aq i-PrOH (80%, 5 mL) containing one drop of concd HCl and the mixture was heated at reflux for 30 min. Cooling followed by filtration gave product 22 (0.32 g, 68%) as pale yellow needles, mp 145-147 °C. Anal. Calcd (%) for C₂₁H₂₀ClFN₂O₃: C, 62.6; H, 5.0; Cl, 8.8; N, 7.0. Found: C, 62.5; H, 4.8; Cl, 9.0; N, 7.1. ¹H NMR (400 MHz, CDCl₃): δ = 7.76 (1 H, br s, NH), 7.26-7.32 (4 H, m, ArH), 7.14-7.18 (2 H, m, ArH), 6.93-6.98 (2 H, m, ArH), 4.24 (2 H, q, J = 7.1 Hz, OCH ₂CH₃), 4.12 (1 H, d, J = 4.8 Hz, CHCN), 3.66 (1 H, dd, J = 4.8, 11.3 Hz, CHAr), 3.14 (1 H, dq, J = 7.0, 11.3 Hz, CHCH₃), 1.32 (3 H, t, J = 7.1 Hz, OCH₂CH ₃), 1.04 (3 H, d, J = 7.0 Hz, CH ₃CH). ¹³C NMR (100.6 MHz, CDCl₃): δ = 174.9, 161.3, 160.0 (J = 245.4 Hz), 134.2, 134.3, 132.0 (J = 3.1 Hz), 130.0, 129.2, 122.7 (J = 8.4 Hz), 116.5, 115.7 (J = 23.0 Hz), 61.4, 47.4, 44.0, 42.0, 16.6, 14.1.