References and Notes
1a
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Pearson WH.
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Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles
and Natural Products
John Wiley and Sons;
New
York:
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1b
Grigg R.
Sridharan V.
In Advances
in Cycloaddition
Vol. 3:
Curran DP.
JAI Press;
Greenwich / CT:
1993.
p.161
1c
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p.1111
1d
Coldham I.
Hufton R.
Chem. Rev.
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1e
Gothelf KV. In
Cycloaddition Reactions
in Organic Synthesis
Kobayashi S.
Jørgensen KA.
Wiley-VCH;
Weinheim:
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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:
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Chap.
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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,
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3a
Tsuge O.
Kanemasa S.
Adv.
Heterocycl. Chem.
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3b
Vedejs E.
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1988.
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4
Karzani Y.
Surpateanu G.
Heterocycles
1999,
863
5a
Garner P.
Dogan .
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Chem.
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4
5b
Toyota M.
Nishikawa Y.
Fukumoto K.
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Kanemasa S.
Ohe M.
Takenaka S.
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Antagonist, Gordon Research Conference, Medicinal Chemistry Symposium,
12th August 2010.
8
Pellegrino S.
Clerici F.
Contini A.
Leone S.
Pilati T.
Gelmi ML.
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2009,
1995
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+].
12a
Porter MJ.
Nandra GS.
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12b
Thorsett ED.
Harris EE.
Patchett AA.
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1978,
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