Synthesis of a Novel Octahydro Pyrrolo[3,4-c]pyrrole Cyclic Amidine via 1,3-Dipolar Cycloaddition of Azomethine Ylides

Abstract

A concise synthesis of fused bicyclic pyrrolidines via 1,3-dipolar cycloaddition of azomethine ylides is reported. The exo cycloadduct isomer enables the synthesis of a novel cyclic amidine toward the preparation of a potential human histamine H4 receptor antagonist. The minor endo isomer led to the isolation of a new triazine ring through an intramolecular reductive cyclisation.

Key words

azomethine ylide - 1,3-dipolar cycloaddition - cyclic amidine - amino acid - reductive cyclisation

References and Notes

• 1a Padwa A. Pearson WH. Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products   John Wiley and Sons; New York: 2002.  p.169 
• 1b Grigg R. Sridharan V. In Advances in Cycloaddition   Vol. 3:  Curran DP. JAI Press; Greenwich / CT: 1993.  p.161 
• 1c Padwa A. In Comprehensive Organic Synthesis   Vol. 4:  Trost BM. Flemig I. Pergamon Press; Oxford: UK, 1991.  p.1111 
• 1d Coldham I. Hufton R. Chem. Rev.  2005,  2765 
• 1e Gothelf KV. In Cycloaddition Reactions in Organic Synthesis   Kobayashi S. Jørgensen KA. Wiley-VCH; Weinheim: 2002. 
• 2a Harwood LM. Vickers RJ. In Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Hetero-cycles and Natural Products   John Wiley and Sons; New York: 2002.  Chap. 3. p.169 
• 2b Dondas AH. Fishwick CWG. Grigg R. Kilner C. Tetrahedron  2004,  3473 
• 2c Hanessian S. Yun H. Hou Y. Tintelnot-Blomley M. J. Org. Chem.  2005,  6746 
• 3a Tsuge O. Kanemasa S. Adv. Heterocycl. Chem.  1989,  231 
• 3b Vedejs E. Advances in Cycloaddition   Vol. 1:  Curran DP. JAI Press; Greenwich: 1988.  p.33 
• 4 Karzani Y. Surpateanu G. Heterocycles  1999,  863 
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7

Mowbray, C. The Discovery and Evaluation of PF-3893787: A Novel Histamine H4 Receptor Antagonist, Gordon Research Conference, Medicinal Chemistry Symposium, 12^th August 2010.

9

Synthesis of Amino Cycloadducts 11 and 12 A mixture of N-benzyl glycine (10.2 g, 61.6 mmol), N-Boc-amino acetaldehyde (9.80 g, 61.6 mmol), and N-methyl maleimide (3.42 g, 30.8 mmol) was heated to reflux in toluene (300 mL) for 6 h or until the evolution of CO₂ had ceased. The reaction mixture was diluted with H₂O (150 mL) and extracted with EtOAc (2 × 150 mL). The combined organic layers were washed successively with sat. NaHCO₃ (150 mL) and brine (150 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The isomers obtained were separated by column chromatography (heptane-EtOAc = 9:1 to 2:3) to give exo adduct 9 (5.24g, 46%) and endo adduct 10 (2.72g, 24%) as white solids. TFA (5 equiv) was added to a solution of each cycloadduct in an ice cold solution of CH₂Cl₂ (0.3 M), and the reaction mixture was allowed to stir at r.t. for 3 h. After this time, each mixture was concentrated under reduced pressure, neutralised with sat. NaHCO₃ and extracted with CH₂Cl₂. The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure to give 11 (2.60 g, 68%) and 12 (1.71 g, 86%), respectively.
Compound 11 ( exo): R _f  = 0.43 (CH₂Cl₂-MeOH = 95:5). ^¹H NMR (400 MHz, CD₃OD): δ = 2.55-2.58 (m, 1 H), 2.77-2.83 (m, 1 H), 2.86-2.90 (m, 2 H), 2.92 (s, 3 H), 3.16-3.21 (m, 1 H), 3.27-3.33 (m, 2 H), 3.44 (d, J = 13.3 Hz, 1 H), 3.85 (d, J = 13.3 Hz, 1 H), 7.23-7.32 (m, 5 H). HRMS: m/z calcd for C₁₅H₂₀N₃O₂: 274.1555; found: 274.1566 [MH⁺].
Compound 12 ( endo): R _f  = 0.33 (CH₂Cl₂-MeOH = 95:5). ^¹H NMR (400 MHz, CD₃OD): δ = 2.58-2.61 (m, 1 H), 2.65 (s, 3 H), 2.98-3.00 (m, 1 H), 3.05-3.10 (m, 1 H), 3.26-3.38 (br m, 3 H), 3.42-3.45 (m, 1 H), 3.55 (d, J = 13.3 Hz, 1 H), 3.90 (d, J = 13.3 Hz, 1 H), 7.22-7.38 (m, 5 H). HRMS: m/z calcd for C₁₅H₂₀N₃O₂: 274.1555; found: 274.1551 [MH⁺].

10

Synthesis of Cyclic Amidine 15 To an ice cold solution of Red-Al^® (3.5 M in toluene) in THF (50 mL) was added dropwise a solution of exo adduct 11 (2.6g, 9.51mmol) in THF (25 mL). Once added, the reaction mixture was left stirring at r.t. After 3 h, the mixture was cooled with an ice bath and carefully quenched by dropwise addition of 3 N NaOH solution until effervescence had ceased. The mixture was diluted with H₂O (50 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography (CH₂Cl₂-MeOH-NH₃ = 100:0:0 to 90:10:1) to give exo adduct 13 (1.92 g, 82%) as an amber oil. A solution of exo cycloadduct 13 (725 mg, 2.96 mmol) in EtOH (3 mL) was treated 1-methyl-1,4-cyclohexadiene (4.98 mL, 44.3 mmol) and 20 mol% Pd(OH)₂/C (42 mg, 0.29 mmol). The resulting mixture was heated to 80 ˚C for 3 h. After this time, the solution was cooled to r.t. and loaded onto an ion-exchange cartridge (SCX-2), eluting with 2 N NH₃ (2 × 5 mL) to give 14 (445 mg, 97%) as a colorless oil. ^¹H NMR (400MHz, CD₃OD): δ = 2.31 (s, 3 H), 2.30-2.37 (m, 1 H), 2.42-2.67 (m, 6 H), 2.72-2.85 (m, 3 H), 3.11-3.16 (m, 1 H). HRMS: m/z calcd for C₈H₁₈N₃: 156.1501; found: 156.1498 [MH⁺].
A suspension of exo cycloadduct 14 (158 mg, 1.02 mmol) and benzimidazole-2-carbonitrile 4 (182 mg, 1.02 mmol) in 2-PrOH (3 mL) was heated at reflux. After 8 h, the reaction mixture was cooled to r.t. and evaporated under reduced pressure. The residue was purified by column chromatog-raphy (CH₂Cl₂-MeOH-NH₃ = 97:3:0.3 to 90:10:1) to give 15 (206 mg, 64%) as a pale yellow solid. ^¹H NMR (400 MHz, CDCl₃): δ = 2.17 (dd, J = 6.6, 2.7 Hz, 1 H), 2.24 (dd, J = 6.6, 2.7 Hz, 1 H), 2.37 (s, 3 H), 2.49-2.56 (m, 1 H), 2.62-2.68 (m, 1 H), 2.71 (d, J = 9.8 Hz, 1 H), 2.81 (d, J = 9.8 Hz, 1 H), 3.29 (dd, J = 8.2, 4.7 Hz, 1 H), 3.91-3.97 (m, 2 H), 4.10-4.16 (m, 1 H), 5.18 (dd, J = 9.0, 3.9 Hz, 1 H), 7.34-7.39 (m, 2 H). HRMS: m/z calcd for C₁₆H₁₈F₂N₅: 318.1530; found: 318.1533 [MH⁺].

11

Synthesis of Triazacyclopenta[ cd ]pentalene 3 To an ice cold solution of Red-Al^® (6.6 mL, 23.3 mmol) in THF (5 mL) was added a solution of 12 (637 mg, 2.33 mmol) in THF (5 mL), and the reaction was allowed to stir at r.t. After 16 h, the reaction was quenched with 1 N NaOH (20 mL), diluted with H₂O (20 mL) and extracted with EtOAc (20 mL). The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography (CH₂Cl₂-MeOH-NH₃ = 100:0:0 to 90:10:1) to give 3 (200 mg, 35%) as a colorless oil. ^¹H NMR(400 MHz, CD₃OD): δ = 2.38 (s, 3 H), 2.49-2.51 (m, 1 H), 2.60-2.69 (m, 4 H), 2.78-2.80 (m, 1 H), 2.90-2.93 (m, 1 H), 3.15-3.20 (m, 2 H), 3.48 (d, J = 13.3 Hz, 1 H), 3.82 (d, J = 13.3 Hz, 1 H), 4.13 (d, J = 3.5 Hz, 1 H), 7.22-7.29 (m, 5 H). LRMS: m/z = 244 [MH⁺].