Light-Triggered Release of NO from Nitrosamines
FULL PAPER
(m, 2H), 2.19–2.13 (m, 1H), 1.91–1.85 (m, 1H), 1.70–1.63 (m, 1H; CH2 ꢁ
1H), 2.43–2.33 (m, 1H; H-C(2)), 2.0–1.54 (m, 6H; CH2 ꢁ3), 1.43 (s, 9H;
3), 1.41 ppm (s, 9H; -C
Synthesis of 30: Methyltriphenylphosphonium bromide (17.993 g,
50.37 mmol) at 08C was added to solution of tBuOK (5.139 g,
(CH3)3).
-CACHTNGUTERNU(NG CH3)3), 1.35 ppm (brs, 1H).
Synthesis of 34: DMSO (7.6 mL, 107.00 mmol) at ꢀ788C was added to a
a
solution of oxalyl chloride (7.0 mL, 82.72 mmol) in CH2Cl2 (370 mL).
45.80 mmol) in Et2O (130 mL). The reaction mixture was heated at
reflux with stirring for 1 h, and then cooled to RT. A solution of 29
(6.608 g, 24.84 mmol) in Et2O (130 mL) was added to the above mixture
at RT, and the reaction mixture was stirred for an additional 4 h at RT.
The reaction mixture was quenched by the addition of water, and the
whole was extracted with Et2O (3ꢁ50 mL). The combined organic phase
was washed with brine, dried over Na2SO4, and evaporated. Purification
of the residue by column chromatography (n-hexane/AcOEt=5:1) gave
The reaction mixture was stirred for 20 min and a solution of 33
(6774.0 mg, 17.95 mmol, obtained in the above reaction) in CH2Cl2
(180 mL) was added at ꢀ788C. The reaction mixture was stirred for
40 min at ꢀ788C, and then Et3N (30 mL, 216.42 mmol) was added. The
solution was allowed to warm to RT. After 1 h of stirring, the mixture
was quenched by the addition of water and extracted with CH2Cl2 (3ꢁ
100 mL). The combined organic phase was washed with brine, dried over
Na2SO4, and evaporated. Purification of the residue by column chroma-
tography (n-hexane/AcOEt=6:1 to 3:1) gave compound 34 (5563.6 mg,
83%, endo/exo=2:1) as a yellow oil. 1H NMR (CDCl3): 9.73 (d, J=
1.40 Hz, 0.67H; -CHO of endo isomer), 9.65 (d, J=1.80 Hz, 0.33H;
-CHO of exo isomer), 7.26 (d, J=8.64 Hz, 2H), 6.87 (d, J=8.72 Hz, 2H;
-Ph), 4.62–4.59 (m, 1H; bridgehead), 4.54–4.53 (s, 2H; -O-CH2-Ph), 4.05–
3.96 (m, 2H; -CH2-OCH2Ph), 3.81 (s, 3H; -Ph-OCH3), 3.09–3.04 (m,
0.67H; H-C(2) of endo isomer), 2.53–2.49 (m, 0.33H; H-C(2) of exo
isomer), 2.14–2.10 (m, 1H), 1.92–1.64 (m, 4H), 1.53–1.45 (m, 1H; CH2 ꢁ
1
compound 30 (6.421 g, 97%) as a yellow oil. H NMR (CDCl3): 4.97–4.96
(m, 1H), 4.80 (s, 1H; C=CH2), 4.54 (d, J=4.64 Hz, 1H; bridgehead), 3.81
(s, 3H; COOCH3), 2.84 (m, 1H), 2.42–2.38 (m, 1H), 2.23–2.20 (m, 1H),
2.11–2.03 (m, 1H), 1.82–1.75 (m, 1H), 1.60–1.54 (m, 1H; CH2 ꢁ3),
1.40 ppm (s, 9H; -C
Synthesis of 31: CaCl2 (5542.5 mg, 49.941 mmol) and NaBH4 (3879.3 mg,
102.55 mmol) at 08C were added to solution of 30 (6.421 g,
ACHTUNGTRENNUNG(CH3)3).
a
24.02 mmol) in EtOH (100 mL)/THF (70 mL). The reaction mixture was
stirred for 3 h at RT and quenched by the addition of a 10% aqueous so-
lution of citric acid. Then, the inorganic salts were isolated by filtration
through a Celite pad and the residue was washed with AcOEt (70 mL).
The filtrate was extracted with AcOEt (3ꢁ100 mL). The organic phases
were combined, washed with brine, dried over Na2SO4, and evaporated.
Column chromatography (n-hexane/AcOEt=3:1) of the residue gave
compound 31 (5249.1 mg, 91%) as a colorless oil. 1H NMR (CDCl3):
4.94–4.92 (m, 1H; C=CH2), 4.88 (brs, 1H; -OH), 4.75 (s, 1H; C=CH2),
4.48 (d, J=4.08 Hz, 1H; bridgehead), 3.96–3.87 (m, 2H; -CH2OH), 2.62–
2.57 (m, 1H), 2.07–2.02 (m, 1H), 1.94–1.85 (m, 2H), 1.65–1.53 (m, 1H),
3), 1.44 (s, 6.03H; -C
AHCTUNGTRENNG(UN CH3)3 of exo isomer).
ACHTUGNERTN(NUNG CH3)3 of endo isomer), 1.36 ppm (s, 2.97H; -C-
Synthesis of 35endo/exo: 2-Methyl-2-butene (30 mL) and a solution of
NaClO2 (12.05 g, 133.26 mmol) and NaH2PO4·2H2O (16.18 g,
103.72 mmol) in H2O (125 mL) at RT were added to a solution of 34
(5563.6 mg, 14.82 mmol) in tBuOH (125 mL), and the reaction mixture
was stirred for 3 h at RT. tBuOH was evaporated, then the aqueous resi-
due was poured into a 0.5n aqueous solution of HCl and the whole was
extracted with CHCl3 (3ꢁ100 mL). The combined organic phase was
washed with brine, dried over Na2SO4, and evaporated to give the crude
carboxylic acid as a colorless oil. TMSCHN2 (15 mL, 2.0m Et2O solution,
30.0 mmol) at 08C was added to a solution of the resultant carboxylic
acid derivative in toluene/MeOH (200 mL/50 mL). The reaction mixture
was stirred for 1 h at RT and evaporated. Purification of the residue by
column chromatography (n-hexane/AcOEt=12:1 to 3:1) gave com-
pound 35-exo (1799.3 mg, 36% yield) as a colorless oil and 35-endo
(2982.9 mg, 60% yield) as a colorless oil (5207.0 mg, quantitative yield
1.50–1.42 (m, 1H; CH2 ꢁ3), 1.44 ppm (s, 9H; -CACHTNUGTRNEUNG(CH3)3).
Synthesis of 32: NaH (1898.9 mg, 47.47 mmol, about 60%) at 08C was
added to a solution of 31 (5249.1 mg, 21.93 mmol) in DMF (170 mL).
The reaction mixture was stirred for 30 min at 08C. Then para-methoxy-
benzyl chloride (PMB-Cl; 4.4 mL, 32.45 mmol) and tetrabutylammonium
iodide (TBAI; 791.2 mg, 2.14 mmol) at 08C were added. The reaction
mixture was stirred for 1.5 h at RT and then heated at 508C for 1 h. The
mixture was poured into water and extracted with Et2O (3ꢁ150 mL).
The combined organic phase was washed with brine, dried over Na2SO4,
and evaporated. Purification of the residue by column chromatography
(n-hexane/AcOEt=16:1 to 14:1) gave compound 32 (8000.9 mg, 101%)
as a colorless oil. 1H NMR (CDCl3): 7.27 (d, J=8.72 Hz, 2H), 6.87 (d, J=
8.68 Hz, 2H; -Ph-OMe), 4.91–4.90 (m, 1H), 4.72–4.4.71 (m, 1H; C=CH2),
4.54 (s, 2H; -O-CH2-Ph-OMe), 4.50 (d, J=4.80 Hz, 1H; bridgehead),
4.08 (d, J=9.60 Hz, 1H; -CH2-O-), 4.04 (d, J=9.60 Hz, 1H; -CH2-O-),
3.81 (s, 3H; -OMe), 2.42–2.30 (m, 2H), 1.91–1.72 (m, 3H), 1.52–1.1.44
1
from 34, combined yield). 35-exo: H NMR (CDCl3): 7.27 (d, J=8.48 Hz,
2H), 6.87 (d, J=8.60 Hz, 2H; -Ph), 4.57 (d, J=4.80 Hz, 1H; bridgehead),
4.54 (s, 2H; -O-CH2-Ph), 4.07 (s, 2H; -CH2-OCH2Ph), 3.80 (s, 3H; -Ph-
OCH3), 3.70 (s, 3H; -COOCH3), 2.58–2.54 (m, 1H; H-C(2)), 2.24–2.19
(m, 1H), 1.93–1.66 (m, 4H), 1.49–1.43 (m, 1H; CH2 ꢁ3), 1.40 ppm (s,
9H; -CACHTNUGRTNEUNG
(CH3)3). 35-endo: 1H NMR (CDCl3): 7.26 (d, J=8.48 Hz, 2H),
6.87 (d, J=8.56 Hz, 2H; -Ph), 4.53 (s, 2H; -O-CH2-Ph), 4.46–4.44 (m,
1H; bridgehead), 4.01 (d, J=9.60 Hz, 1H), 3.96 (d, J=9.60 Hz, 1H;
-CH2-OCH2Ph), 3.80 (s, 3H; -Ph-OCH3), 3.70 (s, 3H; -COOCH3), 3.08–
3.02 (m, 1H; H-C(2)), 2.11–2.06 (m, 1H), 2.00–1.93 (m, 1H), 1.78–1.69
(m, 1H; CH2 ꢁ3), 1.42 ppm (s, 9H; -CACTHNUGTRNEUNG(CH3)3).
(m, 3H), 1.51–1.40 (m, 1H; CH2 ꢁ3), 1.43 ppm (s, 9H; -C
ACHTUGNRTNE(NUNG CH3)3).
Synthesis of 33: BH3/THF (45 mL, 1.08m in THF) at 08C was added to
2,3-dimethyl-2-butene (50 mL, 1.0m in THF), and the reaction mixture
was stirred at 08C for 1 h. Then, a so-
Synthesis of nitrosamine 7:
lution of 32 (7905.2 mg, 21.99 mmol)
in THF (80 mL) was added at 08C,
and the reaction mixture was stirred
for 2 h at 08C. Next, 3n aqueous
NaOH (16 mL, 53.7 mmol) and 30%
H2O2 (16 mL) were added at 08C. The
reaction mixture was stirred for 3 h at
RT, then poured into water, and the
whole was extracted with CH2Cl2 (3ꢁ
100 mL). The combined organic phase
was washed with brine, dried over
Na2SO4, and evaporated. Column
chromatography (n-hexane/AcOEt=
1:1) of the residue gave compound 33
Synthesis of 36: Compound 35-exo (750.6 mg, 2.245 mmol) was hydrogen-
ated over 10% Pd/C (170.1 mg) in methanol (75 mL) at RT for 18 h. Pd/
C was removed by filtration. The residue obtained after evaporation of
the solvent was purified by column chromatography (n-hexane/AcOEt=
3:1) to afford 36 (436.9 mg, 1.531 mmol, 68% yield) as a colorless oil.
(6690.0 mg, 81%, endo/exo=95:5) as a colorless oil. 1H NMR (CDCl3):
7.25 (d, J=8.60 Hz, 2H), 6.87 (d, J=8.68 Hz, 2H; -Ph), 4.52 (s, 2H; -O-
CH2-Ph), 4.31–4.27 (m, 1H; bridgehead), 4.01–3.94 (m, 2H; -CH2-
OCH2Ph), 3.80 (s, 3H; -Ph-OCH3), 3.75–3.71 (m, 1H), 3.55–3.50 (m,
Chem. Eur. J. 2012, 18, 1127 – 1141
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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