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DOI: 10.1055/s-0030-1260768
Synthesis of a Novel Octahydro Pyrrolo[3,4-c]pyrrole Cyclic Amidine via 1,3-Dipolar Cycloaddition of Azomethine Ylides
Publikationsverlauf
Publikationsdatum:
01. Juni 2011 (online)
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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
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References and Notes
Mowbray, C. The Discovery and Evaluation of PF-3893787: A Novel Histamine H4 Receptor Antagonist, Gordon Research Conference, Medicinal Chemistry Symposium, 12th 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+].
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+].
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+].