N-Alkylation-Intramolecular Michael Addition: New Reaction Manifold for High Throughput Annulation of Amines

Abstract

Parallel synthesis of α-substituted pyrrolidines, piper­idines, morpholines, piperazines and diazaspirocycles was achieved in a single reaction step via the annulation of primary amines with halo-2-alkenyl esters, amides, nitriles and phenylsulfones.

Key words

heterocycle - amine - annulation - intramolecular - parallel synthesis

References and Notes

• 1 Dolle RE. Le Bourdonnec B. Goodman AJ. Morales GA. Thomas CJ. Zhang W. J. Comb. Chem.  2008,  10:  753 
• 2a Dolle RE. Macleod C. Martinez-Teipel BI. Barker WM. Seida P. Herbetz T. Angew. Chem. Int. Ed.  2005,  44:  5830 
• 2b

  The acronym SPAn is derived from solid/solution-phase annulation.

• 3 Macleod C. Martinez-Teipel BI. Barker WM. Dolle RE. J. Comb. Chem.  2006,  8:  132 
• 4 Bunce RA. Peeples CJ. Jones PB. J. Org. Chem.  1992,  57:  1727 
• SPAn reagents 7-12 and 15-18 were prepared from the requisite chloroalkyl aldehydes and the Horner-Emmons-Wadsworth reaction:
• 5a Kametani T. Higashiyama K. Otomasu H. Honda T. Israel. J. Chem.  1986,  27:  57 
• 5b Lipshutz BH. Chrisman W. Noson K. Papa P. Sclafani JA. Vivian RW. Keith JM. Tetrahedron  2000,  56:  2779 
• 5c SPAn reagents 13 and 14 were obtained and used as a mixture of E- and Z-isomers by the cross-metathesis reaction of 6-chlorohex-1-ene with acrylonitrile and phenyl vinyl sulfone. SPAn reagents 19 and 20 were derived from the modification of experimental procedures described by: Dieter RK. Lu K. J. Org. Chem.  2002,  67:  847 
• 5d

  Because the iodo-based solution-phase reagents gave annulation products in consistently higher yield and purity than the corresponding chloro congeners, the Finkelstein Cl → I exchange reaction was used (5 equiv NaI, acetone, reflux, 3 h) to prepare the final reagent set. SPAn reagents 15 and 16 were obtained via DIC coupling of the corresponding chloroalkenoic acids to Wang resin under standard reaction conditions.

• 6 DeHaven RN. Cassel JA. Windh RT. DeHaven-Hudkins DL. In Current Protocols in Pharmacology   Enna SJ. Williams M. Barrett JF. Ferkany JW. Kenakin T. Porsolt RD. John Wiley and Sons; New York: 2005.  p.1.4.1-1.4.44  

7

General Procedure for High-Throughput Annulation: DMSO (750 µL) and diisopropylethylamine (DIPEA, 150 µL) were added to Milestone CombiCHEM Microwave reaction vials containing the individual SPAn reagents (0.30 mmol). The amines (0.30 mmol) were then added and the reaction vials transferred to a 48-well Milestone CombiCHEM plate. The unit was securely fitted to the Milestone CombiCHEM rotor and inserted into the Milestone Microwave (equipped with thermocouple). A microwave program (with rotation of the CombiCHEM block) was applied: full power (500 W) ramping from 25 ˚C → 150 ˚C over a period of 25 min and holding at 150 ˚C for 15 min. Upon cooling, the CombiCHEM block was removed and transferred to a Genevac. The vials were concentrated in vacuo and the resulting residues were purified by silica gel chromatography to give the annulation products.
2-{1-[2-(1 H -Indol-3-yl)methyl]pyrrolidin-2-yl}- N -benzylacetamide (1g): ^¹H NMR (400 MHz, CDC1₃): δ = 8.55 (s, 1 H), 8.20 (s, 1 H), 6.95-7.55 (m, 9 H), 5.65 (m, 1 H), 4.00, 4.34 (m, 2 × 1 H), 2.45-3.45 (m, 6 H), 0.90-2.05 (m, 7 H). ^¹³C NMR (75 MHz, CDC1₃): δ = 172.7, 137.7, 136.8, 128.5, 127.4, 127.1, 123.0, 121.5, 119.8, 118.5, 113.0, 110.8, 65.5, 56.1, 55.1, 44.0, 32.5, 30.8, 23.4, 21.5. MS (ESI): m/z = 362 [M + H]⁺. HRMS (TOF): m/z [M + H]⁺ calcd for C₂₃H₂₈N₃O: 362.2232; found: 362.2245.
2-{1-[2-(1 H -Indol-3-yl)ethyl]piperidin-2-yl}- N -benzyl- N -methylacetamide (2i): ^¹H NMR (400 MHz, CDC1₃) δ = 8.68, 8.78 (m, 1 H), 6.95-7.55 (m, 9 H), 4.52 (m, 2 H), 4.00 (m, 1 H), 2.95-3.70 (m, 6 H), 2.80, 2.95 (2 × s, 3 H, NMe rotomers), 0.90-2.20 (m, 9 H). MS (ESI): m/z = 390 [M + H]⁺. HRMS (TOF): m/z [M + H]⁺ calcd for C₂₅H₃₂N₃O: 390.2545; found: 390.2561.
2-[1-(2,2-Diphenylethyl)piperidin-2-yl]acetonitrile (2l): ^¹H NMR (400 MHz, CDC1₃): δ = 7.10-7.35 (m, 10 H), 4.15 (m, 1 H), 3.12 (m, 1 H), 2.95 (m, 1 H), 2.75 (m, 1 H), 2.65 (m, 1 H), 2.30 (m, 3 H), 1.30-1.75 (m, 6 H). ^¹³C NMR (75 MHz, CDC1₃): δ = 144.0, 129.3, 128.5, 126.0, 117.9, 59.8, 59.5, 57.9, 49.3, 31.1, 26.2, 22.8, 22.3. MS (ESI): m/z = 305 [M + H]⁺. HRMS (TOF): m/z [M + H]⁺ calcd for C₂₁H₂₅N₂: 305.2018; found: 305.2050.
3-{[2-(Phenylsulfonylmethyl)piperidin-1-yl]methyl}pyridine (2n): ^¹H NMR (400 MHz, CDC1₃): δ = 8.45 (m, 1 H), 7.98 (m, 1 H), 7.50-7.75 (m, 6 H), 7.20 (m, 1 H), 3.25-3.60 (m, 5 H), 2.30 (m, 2 H), 1.40-1.90 (m, 6 H). ^¹³C NMR (75 MHz, CDC1₃): δ = 150.8, 146.9, 145.5, 139.5, 137.0, 133.1, 129.5, 128.0, 122.5, 64.8, 65.9, 59.4, 55.6, 55.5, 29.9, 26.8, 22.5. MS (ESI): m/z = 331 [M + H]⁺. HRMS (TOF): m/z [M + H]⁺ calcd for C₁₈H₂₃N₂O₂S: 331.1480; found: 331.1492.
2-{1-[2-(1 H -Indol-3-yl)ethyl]piperidin-2-yl}acetic Acid (2q): ^¹H NMR (400 MHz, CDC1₃): δ = 10.95 (s, 1 H), 7.38, 7.60 (2 × d, J = 7.4 Hz, 2 × 1 H), 6.85-7.20 (m, 3 H), 1.50-3.50 (m, 15 H). ^¹³C NMR (75 MHz, CDC1₃): δ = 180.0, 136.2, 127.0, 123.1, 121.1, 120.2, 119.5, 113.9, 110.5, 67.0, 58.1, 57.9, 55.0, 32.3, 26.1, 23.8, 23.5. MS (ESI): m/z = 287 [M + H]⁺. HRMS (TOF): m/z [M + H]⁺ calcd for C₁₇H₂₃N₂O₂: 287.1793; found: 287.1810.
Methyl 2-[4-(2,2-Diphenylethyl)morpholin-3-yl]acetate (3b): ^¹H NMR (400 MHz, CDC1₃): δ = 7.10-7.35 (m, 10 H), 4.10 (m, 1 H), 3.65 (s, 3 H), 3.40-3.60 (m, 4 H), 2.90-3.10 (m, 3 H), 2.65 (m, 1 H), 2.50 (m, 2 H), 2.30 (m, 1 H). ^¹³C NMR (75 MHz, CDC1₃): d = 174.1, 144.8, 129.9, 129.1, 126.6, 72.3, 69.0, 64.1, 660.9, 52.3, 51.8, 38.1. MS (ESI): m/z = 340 [M + H]⁺. HRMS (TOF): m/z [M + H]⁺ calcd for C₂₁H₂₆NO₃: 340.1913; found: 340.1944.
Methyl 2-[4-(Methylsulfonyl)-1-(pyridin-3-ylmethyl)piperazin-2-yl]acetate (4a): ^¹H NMR (400 MHz, CDC1₃): δ = 8.50 (m, 2 H), 7.35, 7.75 (m, 2 × 1 H), 3.70 (s, 3 H), 3.62 (m, 2 H), 3.50 (m, 1 H), 2.92 (s, 3 H), 2.20-2.75 (m, 8 H). ^¹³C NMR (75 MHz, CDC1₃): δ = 173.8, 152.0, 147.8, 156.1, 137.0, 123.2, 60.8, 60.1, 54.7, 51.8, 51.1, 48.5, 40.2, 38.3. MS (ESI): m/z = 328 [M + H]⁺. HRMS (TOF): m/z [M + H]⁺ calcd for C₁₄H₂₂N₃O₄S: 328.1331; found: 328.1362.
1-(2,2-Diphenylethyl)-7-methyl-1,7-diazaspiro[4.4]nonan-8-one (5b): ^¹H NMR (400 MHz, CDC1₃): δ = 7.10-7.35 (m, 10 H), 4.05 (t, J = 7.5, 1 H), 3.40 (s, 3 H), 3.17 (d, J = 10.2 Hz, 1 H), 2.65-3.00 (m, 5 H), 2.50, 2.12 (2 × d, J = 17.2 Hz, 2 × 1 H), 1.75 (m, 4 H). MS (ESI): m/z = 335 [M + H]⁺. HRMS (TOF): m/z [M + H]⁺ calcd for C₂₂H₂₇N₂O: 335.2123; found: 335.2148.
Ethyl {6β-[17-(Cyclopropylmethyl)-3,14-dihydroxy-4,5-epoxymorphinan-6β-yl]pyrrolidin-2-yl}acetate (1m): mixture of diastereomers. ^¹H NMR (400 MHz, CDC1₃): δ = 6.71, 6.74 (2 × d, J = 8.1 Hz, 2 × 0.5 H), 6.52, 6.54 (2 × d,
J = 8.1 Hz, 2 × 0.5 H), 4.75 (d, J = 7.4, 0.5 H), 4.53 (d, J = 8.2 Hz, 0.5 H), 4.21 (m, 1 H), 4.07 (dd, J = 7.0, 14.0 Hz, 1 H), 3.60 (br s, 1 H), 1.38-3.20 (m, 24 H), 1.30, 1.21 (2 × t,
J = 7.1 Hz, 2 × 1.5 H), 0.85 (m, 1 H), 0.54 (s, 2 H), 0.15 (s, 2 H). MS (ESI): m/z = 483 [M + H]⁺. HRMS (TOF): m/z [M + H]⁺ calcd for C₂₈H₃₉N₂O₅: 483.2859; found: 483.2885.