Copper(I) Iodide Catalyzed
Domino Knoevenagel Hetero-Diels-Alder Reaction
of Terminal Acetylenes: Synthesis of Pyrano[2,3-c]pyrazoles

Malihe Javan Khoshkholgh; Saeed Balalaie; Hamid Reza Bijanzadeh; Jürgen H. Gross

doi:10.1055/s-0028-1087380

LETTER

Copper(I) Iodide Catalyzed Domino Knoevenagel Hetero-Diels-Alder Reaction of Terminal Acetylenes: Synthesis of Pyrano[2,3-c]pyrazoles

Malihe Javan Khoshkholgh^a, Saeed Balalaie*^a, Hamid Reza Bijanzadeh^b, Jürgen H. Gross^c
^a Department of Chemistry, K. N. Toosi University of Technology, P.O. Box 15875-4416, Tehran, Iran
Fax: +98(21)22853650; e-Mail: balalaie@kntu.ac.ir; e-Mail: balalaie@yahoo.com;
^b Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran 18716, Iran
^c Organisch-Chemisches Institut, Universitaet Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany

Abstract

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Abstract

A new and efficient CuI-catalyzed domino Knoevenagel hetero-Diels-Alder reaction of 1-oxa-1,3-butadienes with terminal unactivated acetylenes as building blocks to afford pyrano[2,3-c]pyrazoles has been developed. The products were obtained in good to high yields in most cases. Synthesis of polycyclic compounds in one-pot, with easy workup, and mild reaction conditions are advantages of our reported method.

Key words

domino Reaction - hetero-Diels-Alder reaction - Knoe-venagel condensation - cuprous iodide - alkynes - pyran

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References

References and Notes

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8

General Procedures for the Intramolecular Domino Knoevenagel-Hetero-Diels-Alder Reaction
A solution of compounds 1a-g (1 mmol), 2a,b (1.2 mmol), CuI (0.2 equiv, 38 mg), and Et₃N (1 mmol, 0.06 mL) in MeOH (25 mL) was refluxed for 8 h. The progress of reaction was monitored by TLC. The precipitated solid was filtered, washed with cold EtOH, and recrystallized in CH₂Cl₂.
Selected Spectroscopic Data
3-(3-Chlorophenyl)-1-methyl-3,11b-dihydro-6 H -chromeno[4′,3′:4,5]pyrano[2,3- c ]pyrazole (3a) White solid; mp 167-168 ˚C. IR (KBr): 1686, 1596 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 2.49 (s, 3 H, Me), 4.70 (d, J = 12.0 Hz, 1 H, OCH), 4.71 (s, 1 H, CH), 4.86 (d, J = 12.0 Hz, 1 H, OCH), 6.69 (s, 1 H, =CH), 6.85 (d, J = 8.0 Hz, 1 H, H_Ar), 6.91 (t, J = 7.3 Hz, 1 H, H_Ar), 7.07 (d, J = 7.6 Hz, 1 H, H_Ar), 7.17 (t, J = 7.6 Hz, 1 H, H_Ar), 7.22 (d, J = 7.9 Hz, 1 H, H_Ar), 7.33 (t, J = 8.0 Hz, 1 H, H_Ar), 7.64 (d, J = 8.1, 1 H, H_Ar), 7.78 (s, 1 H, H_Ar) ppm. ^¹³C NMR (125 MHz, CDCl₃): δ = 8.4, 15.2, 62.7, 63.0, 83.9, 117.6, 118.9, 121.1, 121.7, 126.6, 129.3, 130.1, 130.7, 134.9, 153.2 ppm. HRMS (EI, 70 eV): m/z calcd for C₂₀H₁₅N₂O₅ ^³5Cl [M]⁺ : 350.0822; found: 350.0822; m/z calcd for C₂₀H₁₅N₂O₅ ^³7Cl [M + 2]⁺ : 352.0792; found: 352.0783.
10-Bromo-1-methyl-3-phenyl-3,11b-dihydro-6 H -chromeno[4′,3′:4,5]pyrano[2,3- c ]pyrazole (3b)
Light brown solid; mp 195-196 ˚C. IR (KBr): 1683, 1600 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 2.49 (s, 3 H, Me), 4.70 (d, J = 12.0 Hz, 1 H, OCH), 4.71 (s, 1 H, CH), 4.83 (d, J = 12.0 Hz, 1 H, OCH), 6.69 (s, 1 H, =CH), 6.72 (d, J = 8.6 Hz, 1 H, H_Ar), 7.18 (d, J = 2.2 Hz, 1 H, H_Ar), 7.24 (dd, J = 8.6, 2.2 Hz, 1 H, H_Ar), 7.28 (t, J = 7.5 Hz, 1 H, H_Ar), 7.44 (t, J = 7.9 Hz, 1 H, H_Ar), 7.70 (d, J = 7.9 Hz, 2 H, H_Ar) ppm. ^¹³C NMR (125 MHz, CDCl₃): δ = 13.5, 31.1, 67.2, 94.8, 109.7, 112.3, 118.4, 120.5, 125.9, 128.2, 128.5, 129.2, 134.9, 137.3, 145.7, 146.0, 152.3 ppm. HRMS (EI, 70 eV): m/z calcd for C₂₀H₁₅N₂O₅ ⁷⁹Br [M]⁺ : 394.0317; found: 394.0357; m/z calcd for C₂₀H₁₅N₂O₅ ^8¹Br [M + 2]⁺ : 396.0297; found: 396.0314.
10-Bromo-3-(3-chlorophenyl)-1-methyl-3,11b-dihydro-6 H -chromeno[4′,3′:4,5]pyrano[2,3- c ]pyrazole (3c) White solid. IR (KBr): 1474 cm^-¹. ^¹H NMR (500 MHz, DMSO-d ₆): δ = 2.39 (s, 3 H, Me), 4.80 (s, 2 H, OCH₂), 4.88 (s, 1 H, CH), 6.77 (d, J = 8.5 Hz, 1 H, H_Ar), 7.00 (s, 1 H, =CH), 7.14 (s, 1 H, H_Ar), 7.29 (d, J = 8.5 Hz, 1 H, H_Ar), 7.36 (d, J = 7.9 Hz, 1 H, H_Ar), 7.49 (t, J = 7.9 Hz, 1 H, H_Ar), 7.67 (d, J = 7.9 Hz, 1 H, H_Ar), 7.73 (s, 1 H, H_Ar) ppm. ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 13.4, 30.1, 66.4, 95.4, 109.2, 110.9, 118.2, 118.7, 119.4, 125.6, 127.5, 129.3, 130.2, 130.6, 133.1, 135.7, 138.2, 145.5, 146.3, 152.3 ppm. HRMS (EI, 70 eV): m/z calcd for C₂₀H₁₄N₂O₂ ^³5Cl⁷⁹Br [M]⁺ : 427.9937; found: 427.9948; m/z calcd for C₂₀H₁₄N₂O₂ ^³5Cl^8¹Br [M + 2]⁺ : 429.9907; found: 429.9931; m/z calcd for C₂₀H₁₄N₂O₂ ^³7Cl^8¹Br [M + 4]⁺ : 431.9877; found: 431.9912.
10-Nitro-1-methyl-3-phenyl-3,11b-dihydro-6 H -chromeno[4′,3′:4,5]pyrano[2,3- c ]pyrazole (3d) Light brown solid; mp 208-209 ˚C. IR (KBr): 1678, 1601, 1514 cm^-¹; ^¹H NMR (500 MHz, CDCl₃): δ = 2.59 (s, 3 H, Me), 4.80 (s, 1 H, CH), 4.83 (d, J = 12.1 Hz, 1 H, OCH), 4.93 (d, J = 12.1 Hz, 1 H, OCH), 6.78 (s, 1 H, =CH), 6.90 (d, J = 8.9 Hz, 1 H, H_Ar), 7.29 (t, J = 7.7 Hz, 1 H, H_Ar), 7.44 (t, J = 7.7 Hz, 2 H, H_Ar), 7.70 (d, J = 7.7 Hz, 2 H, H_Ar), 8.06 (dd, J = 2.0, 8.9 Hz, 1 H, H_Ar), 8.09 (d, J = 2.0 Hz, 1 H, H_Ar) ppm. ^¹³C NMR (125 MHz, CDCl₃): δ = 14.3, 31.8, 68.5, 108.6, 117.7, 121.1, 122.9, 124.3, 126.6, 127.7, 129.1, 136.5, 137.8, 159.2 ppm. HRMS (EI, 70 eV): m/z calcd for C₂₀H₁₅N₃O₄ [M]⁺ : 361.1063; found: 361.1066.
10-Nitro-3-(3-chlorophenyl)-1-methyl-3,11b-dihydro-6 H -chromeno[4′,3′:4,5]pyrano[2,3- c ]pyrazole (3e) Light brown solid; mp 215-216 ˚C. IR (KBr): 1686, 1599, 1580, 1510 cm^-¹. ^¹H NMR (500 MHz, DMSO-d ₆): δ = 2.48 (s, 3 H, Me), 4.97 (s, 2 H, OCH and CH), 5.01 (s, 1 H, OCH), 7.00 (d, J = 9.0 Hz, 1 H, H_Ar), 7.24 (s, 1 H, =CH), 7.37 (dd, J = 6.5, 1.0 Hz, 1 H, H_Ar), 7.51 (t, J = 8.0 Hz, 1 H, H_Ar), 7.67 (dd, J = 8.0, 1.0 Hz, 1 H, H_Ar), 7.74 (t, J = 2.0 Hz, 1 H, H_Ar), 7.87 (d, J = 1.8 Hz, 1 H, H_Ar), 8.05 (dd, J = 9.0, 2.8 Hz, 1 H, H_Ar) ppm. ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 13.9, 30.6, 66.3, 67.6, 95.5, 108.3, 117.8, 118.7, 119.9, 121.9, 124.1, 126.2, 127.7, 131.0, 133.6, 136.9, 138.5, 140.3, 145.9, 146.6, 159.2 ppm. HRMS (EI, 70 eV): m/z calcd for C₂₀H₁₄N₃O₄ ^³5Cl [M]⁺ : 395.0673; found: 395.0663; m/z calcd for C₂₀H₁₄N₃O₄ ^³7Cl [M + 2]⁺ : 397.0643; found: 397.0622.
3-(3-Chlorophenyl)-1,10-dimethyl-3,11b-dihydro-6 H -chromeno[4′,3′:4,5]pyrano[2,3- c ]pyrazole (3f) White solid; mp 194-195 ˚C. IR (KBr): 1683, 1597, 1512 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 2.26 (s, 3 H, Me), 2.50 (s, 3 H, Me), 4.68 (d, J = 11.9 Hz, 1 H, OCH), 4.69 (s, 1 H, CH), 4.83 (d, J = 11.9 Hz, 1 H, OCH), 6.67 (s, 1 H, =CH), 6.76 (d, J = 8.2 Hz, 1 H, H_Ar), 6.86 (s, 1 H, H_Ar), 6.97 (dd, J = 8.2, 1.7 Hz, 1 H, H_Ar), 7.23 (m, 1 H, H_Ar), 7.35 (t, J = 8.0 Hz, 1 H, H_Ar), 7.65 (dd, J = 8.0, 1.7 Hz, 1 H, H_Ar), 7.79 (t, J = 2.0 Hz, 1 H, H_Ar) ppm. ^¹³C NMR (125 MHz, CDCl₃): δ = 14.2, 20.7, 31.5, 67.3, 96.4, 111.7, 117.0, 118.4, 120.6, 126.0, 126.1, 127.5, 128.7, 130.1, 130.2, 134.7, 134.8, 139.1, 146.5, 1147.4, 151.4 ppm. HRMS (EI, 70 eV): m/z calcd for C21H17N2O235Cl [M]+: 364.0970; found 364.0959; m/z calcd for C21H17N2O237Cl [M + 2]+: 366.0949; found 366.0964.

8-Bromo-10-chloro-3-(3-chlorophenyl)-1-methyl-3,11b-dihydro-6 H -chromeno[4′,3′:4,5]pyrano[2,3- c ]pyrazole (3g) Light brown solid; mp 208.5-209.5 ˚C. IR (KBr): 1682, 1596 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): d = 2.46 (s, 3 H, Me), 4.69 (s, 1 H, CH), 4.85 (d, J = 12.0 Hz, 1 H, OCH), 4.95 (d, J = 12.0 Hz, 1 H, OCH), 6.74 (s, 1 H, =CH), 6.96 (s, 1 H, H_Ar), 7.23-7.42 (m, 3 H, H_Ar), 7.64 (d, J = 2.0 Hz, 1 H, H_Ar), 7.78 (d, J = 2.0 Hz, 1 H, H_Ar) ppm. ^¹³C NMR (125 MHz, CDCl₃): d = 14.0, 31.7, 68.5, 95.2, 109.7, 111.5, 118.5, 120.7, 125.0, 125.8, 126.3, 130.1, 130.2, 131.2, 134.8, 135.6, 138.9, 146.3, 146.9, 149.1 ppm. HRMS (EI, 70 eV): m/z calcd for C₂₀H₁₄N₂O₂ ^³5Cl₂ ⁷⁹Br [M]⁺ : 461.9538; found: 461.9547; m/z calcd for C₂₀H₁₄N₂O₂ ^³5Cl₂ ^8¹Br [M + 2]⁺ : 463.9517; found: 463.9500; m/z calcd for C₂₀H₁₄N₂O₂ ^³5Cl^³7Cl^8¹Br [M + 4]⁺ : 465.9487; found: 465.9485.
8-Bromo-10-chloro-1-methyl-3-phenyl-3,11b-dihydro-6 H -chromeno[4′,3′:4,5]pyrano[2,3- c ]pyrazole (3h) White solid; mp 197.5-199 ˚C. IR (KBr): 1683, 1597, 1518 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): d = 2.47 (s, 3 H, Me), 4.68 (s, 1 H, CH), 4.84 (d, J = 12.0 Hz, 1 H, OCH), 4.95 (d, J = 12.0 Hz, 1 H, OCH), 6.70 (s, 1 H, =CH), 6.99 (d, J = 2.1 Hz, 1 H, H_Ar), 7.28 (t, J = 7.7 Hz, 1 H, H_Ar),7.41 (d, J = 2.1 Hz, 1 H, H_Ar), 7.43 (t, J = 7.7 Hz, 2 H, H_Ar), 7.70 (d, J = 7.7 Hz, 2 H, H_Ar) ppm. ^¹³C NMR (125 MHz, CDCl₃): d = 14.1, 31.8, 68.6, 94.9, 109.4, 111.5, 120.9, 125.1, 125.8, 126.5, 129.1, 130.3, 131.1, 135.8, 137.8, 146.1, 146.3, 149.1 ppm. HRMS (EI, 70 eV): m/z calcd for C₂₀H₁₄N₂O₂ ^³5Cl⁷⁹Br [M]⁺ : 427.9928; found: 427.9980; m/z calcd for C₂₀H₁₄N₂O₂ ^³5Cl^8¹Br [M + 2]⁺ : 429.9907; found: 429.9946.
8,10-Dichloro-1-methyl-3-phenyl-3,11b-dihydro-6 H -chromeno[4′,3′:4,5]pyrano[2,3- c ]pyrazole (3i) White solid; mp 208-209 ˚C. IR (KBr): 1676, 1598, 1519 cm^-¹. ^¹H NMR (500 MHz, DMSO-d ₆): d = 2.39 (s, 3 H, Me), 4.91 (s, 1 H, CH), 4.92 (d, J = 12.0 Hz, 1 H, OCH), 4.96 (d, J = 12.0 Hz, 1 H, OCH), 6.85 (d, J = 2.0 Hz, 1 H, H_Ar), 7.16 (s, 1 H, =CH), 7.31 (t, J = 7.5 Hz, 1 H, H_Ar),7.44 (d, J = 2.0 Hz, 1 H, H_Ar), 7.48 (t, J = 7.5 Hz, 2 H, H_Ar), 7.67 (d, J = 7.5 Hz, 2 H, H_Ar) ppm. ^¹³C NMR (125 MHz, CDCl₃): d = 13.7, 30.8, 67.8, 94.9, 108.6, 120.4, 121.6, 123.7, 124.0, 126.4, 127.6, 129.2, 130.7, 136.6, 137.3, 145.6, 145.8, 148.0 ppm. HRMS (EI, 70 eV): m/z calcd for C₂₀H₁₄N₂O₂ ^³5Cl₂ [M]⁺ : 384.0432; found: 384.0398; m/z calcd for C₂₀H₁₄N₂O₂ ^³5Cl^³7Cl [M + 2]⁺ : found: 386.0365; 386.0384; m/z calcd for C₂₀H₁₄N₂O₂ ^³7Cl₂ [M + 4]⁺ : 388.0373; found: 388.0368.
8-Methoxy-1-methyl-3-phenyl-3,11b-dihydro-6 H -chromeno[4′,3′:4,5]pyrano[2,3- c ]pyrazole (3j)
Light brown solid; mp 214-215 ˚C. IR (KBr): 1686, 1597 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): d = 2.49 (s, 3 H, Me), 3.88 (s, 3 H, OMe), 4.75 (s, 1 H, CH), 4.83 (d, J = 12.0 Hz, 1 H, OCH₂), 4.91 (d, J = 12.0 Hz, 1 H, OCH₂), 6.68 (s, 1 H, =CH), 6.74 (d, J = 7.7 Hz, 1 H, H_Ar), 6.80 (d, J = 7.7 Hz,
1 H, H_Ar), 6.87 (t, J = 7.9 Hz, 1 H, H_Ar), 7.26 (t, J = 7.3 Hz, 1 H, H_Ar), 7.42 (t, J = 7.8 Hz, 2 H, H_Ar), 7.70 (d, J = 7.9, 2 H, H_Ar) ppm. ^¹³C NMR (125 MHz, CDCl₃): d = 12.0, 56.1, 63.4, 83.7, 115.1, 119.5, 121.1, 121.3, 121.5, 123.1, 126.6, 126.8, 127.7, 128.9, 129, 135.8, 141, 145.7, 147.4, 148.4 ppm. HRMS (EI, 70 eV): m/z calcd for C₂₁H₁₈N₂O₃ [M]⁺ : 346.1318; found: 346.1331.

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