A R T I C L E S
Mure et al.
-OH), 10.229 (2H, br s, exchangeable); 13C NMR (CD3CN) δ 12.8,
br m, -N(CH3)CH2(CH2)2CH3], 6.869 (1H, s, ring proton at C3), 7.071
(1H, s, ring proton at C6), ∼8.5 (br s, -OH), 10.10 (br s, -OH); 13C
NMR (CD3CN) δ 12.8, 15.3, 19.2, 23.2, 29.8, 47.3, 59.5, 108.2, 117.0,
128.9, 129.2, 131.7, 144.8, 146.4; MS (EI) m/z 223 (M+, 34%), 180
(M+ - C3H7+, 100%); HRMS (EI) C13H21NO2 (M+) calcd 223.15723,
obsd 223.15703.
15.3, 19.2, 23.2, 26.8, 47.3, 59.5, 108.2, 117.0, 128.9, 129.2, 144.8,
146.4; MS (EI) m/z 209 (M+ - HCl, 56%), 166 (M+ - HCl - C3H7
,
+
100%); HRMS (EI) C12H19NO2 (M+ - HCl) calcd 209.14158, obsd
209.14132.
(E) Synthesis of 4-n-Butylamino-5-ethyl-1,2-benzoquinone (1ox).
1red (22.5 mg, 0.09 mmol) was dissolved in a CH3CN-H2O solution
(1:4, 10 mL), and a 10 µL aliquot of NaOH (1 M) was added to the
mixture to facilitate the autoxidation. The reaction was monitored by
UV-vis spectroscopy (formation of a species absorbing at 504 nm),
and when the oxidation was complete, the reaction mixture was frozen
in liquid N2. The solvent was removed by lyophilization to yield 1ox as
a dark purple solid (quantitative yield): 1H NMR (CD3CN) δ 0.947
[3H, t, J ) 7.4 Hz, -NH(CH2)3CH3], 1.167 (3H, t, J ) 7.3 Hz,
-CH2CH3), 1.395 [2H, m, -NH(CH2)2CH2CH3], 1.640 (2H, m,
-NHCH2CH2CH2CH3), 2.485 (2H, dq, J ) 1.5, 7.3 Hz, -CH2CH3),
3.270 (2H, m, -NHCH2CH2CH2CH3), 5.410 (1H, s, 3-H), 6.154 (1H,
t, J ) 1.5 Hz, 6-H), 6.226 (1H, br s, -NH); MS (EI) m/z 207 (M+,
73%), 150 (M+ - C4H9+, 100%); HRMS (EI) C12H17NO2 (M+) calcd
207.12593, obsd 207.12559.
4-(N-n-butyl-N-methylamino)-5-ethyl-1,2-benzoquinone (3ox) was
generated in situ by autoxidation of N-n-butyl-N-methylamino-5-ethyl-
1,2-dihydroxybenzene as described in the synthesis of the quinone (1ox).
3ox was stable in a dilute aqueous solution but decomposed upon either
solvent removal by lyophilization or when concentrated, thereby
preventing full characterization. Attempts to extract 3ox with organic
solvents were unsuccessful due to the instability of the quinone.
(H) Synthesis of 2-N-n-Butylamino-5-tert-butyl-1,4-benzoquinone
(8) and 2-(N-n-Butyl-N-methylamino)-5-tert-butyl-1,4-benzoquinone
(9). 8 and 9 were formed from the reactions of 2-tert-butyl-1,4-
benzoquinone and n-butylamine and N-methyl-n-butylamine, respec-
tively, and then purified by silica gel chromatography. The reaction
conditions were same as described for the reaction of 2-tert-butyl-1,4-
benzoquinone and benzylamine.37 8: 1H NMR (CDCl3) δ 0.946 [3H,
t, J ) 7.3 Hz, -NH(CH2)3CH3], 1.296 [9H, s, -(CH3)3], 1.396 [2H,
m, -N-(CH2)2CH2CH3], 1.611 (2H, m, -NHCH2CH2CH2CH3), 3.062
[2H, 2t, -NHCH2(CH2)CH3], 5.382 (1H, s, ring proton at C3 + 1H, br
s, NH), 6.425 (1H, s, ring proton at C6); 13C NMR (CDCl3) δ 13.6,
20.0, 29.6, 30.1, 35.6, 41.9, 100.1, 127.2, 134.8, 145.3, 184.7, 185.6.
9: 1H NMR (CDCl3) δ 0.936 [3H, t, J ) 7.3 Hz, -NH(CH2)3CH3],
1.277 [9H, s, -(CH3)3], 1.396 [2H, m, -N-(CH2)2CH2CH3], 1.578 [2H,
m, -N(CH3)CH2CH2CH2CH3], 2.982 [3H, s, -N(CH3)(CH2)3CH3],
3.477 [2H, 2t, -N(CH3)CH2(CH2)CH3], 5.478 (1H, s, ring proton at
C3), 6.303 (1H, s, ring proton at C6); 13C NMR (CDCl3) δ 13.8, 20.0,
29.5, 29.9, 35.0, 40.1, 53.7, 106.1, 129.6, 148.9, 156.8, 185.5, 186.5.
(I) Synthesis of a Phenylhydrazine Adduct of 1ox (2). To a heated
stirred solution of phenylhydrazine hydrochloride (70.1 mg, 0.485
mmol) in glacial acetic acid (5 mL) at 100 °C was added an acetic
acid solution (2 mL) of 1ox (18.6 mg, 0.09 mmol). The reaction mixture
was stirred at 100 °C for 30 min and then cooled to room temperature.
Water (50 mL) was added, and the mixture was neutralized by NaHCO3
and extracted with diethyl ether. The combined organic layers were
washed with water and dried with MgSO4, and the solvent was removed
in vacuo. The crude product was purified by silica gel chromatography
to yield 5.7 mg (21%) of 2 as an orange-red crystalline solid: 1H NMR
(CD3CN) δ 0.950 [3H, t, J ) 7.4 Hz, -NH(CH2)3CH3], 1.220 (3H, t,
J ) 7.5 Hz, -CH2CH3), 1.412 [2H, m, -NH(CH2)2CH2CH3], 1.630
(2H, m, -NHCH2CH2CH2CH3), 2.460 (2H, dq, J ) 1.0, 7.5 Hz, -CH2-
CH3), 3.240 (2H, m, J ) 8.1 Hz, -NHCH2CH2CH2CH3), 5.231 (1H,
br s, -NH), 5.940 (1H, s, 6-H), 7.240 (1H, s, 3-H), 7.267-7.656 (5H,
m, -C6H5), 14.775 (1H, br s, -OH); 13C NMR (CD3CN) δ 13.4, 14.1,
20.9, 23.3, 31.5, 43.6, 96.9, 120.3, 123.9, 128.4, 130.3, 132.0, 132.4,
149.8, 153.4, 162.2; MS (EI) m/z 297 (M+, 100%), 192 (M+ - C6H5-
N2+, 50%); HRMS (EI) C18H23N3O (M+) calcd 297.18411, obsd
297.18467.
(F) Synthesis of N-n-Butyl-N-methyl-2-ethyl-4,5-methylenedioxy-
aniline. Aqueous formaldehyde (37%, 2 mL) was added to an ice-
cold mixture of N-n-butyl-2-ethyl-4,5-methylenedioxyaniline (108.1 mg,
0.49 mmol) and formic acid (2 mL). The reaction mixture was stirred
overnight at 90 °C and then cooled to room temperature. Concentrated
HCl (2 mL) was added, and an extraction was performed with diethyl
ether. The aqueous layer was treated with 50% NaOH to adjust the pH
to 10 and then reextracted with diethyl ether. The combined ether layers
were washed with water and dried over Na2SO4. The solvent was
removed under reduced pressure to give N-n-butyl-N-methyl-2-ethyl-
4,5-methylenedioxyaniline as a yellow oil (55% yield): 1H NMR
(CDCl3) δ 0.888 [3H, t, J ) 7.2 Hz, -N(CH3)(CH2)3CH3], 1.167 (3H,
t, J ) 7.6 Hz, -CH2CH3), 1.312 [2H, m, -N(CH3)(CH2)2CH2CH3],
1.395 [2H, m, -N(CH3)CH2CH2CH2CH3], 2.549 [3H, s, -N(CH3)(CH2)3-
CH3], 2.657 (2H, q, J ) 7.6 Hz, -CH2CH3), 2.743 [2H, t, J ) 7.5 Hz,
-N(CH3)CH2(CH2)2CH3], 5.890 (2H, s, -OCH2O-), 6.701 (1H, s,
ring proton at C6), 6.710 (1H, s, ring proton at C3).
(G) Synthesis of N-n-Butyl-N-methylamino-5-ethyl-1,2-dihy-
droxybenzene (3red) and 4-(N-n-Butyl-N-methylamino)-5-ethyl-1,2-
benzoquinone (3ox). A solution of N-n-butyl-N-methyl-2-ethyl-4,5-
methylenedioxyaniline (63.6 mg, 0.27 mmol) in dichloromethane was
stirred at room temperature for 30 min under Ar and treated with boron
trichloride (1 M in dichloromethane, 1.4 mL). The mixture was then
stirred under Ar at room temperature for a further 3 h. The reaction
was quenched by addition of methanol (5 mL), and the resulting solution
was heated under reflux for 5 min after which time the solvent was
removed in vacuo. The hydrochloride salt of N-n-butyl-N-methylamino-
5-ethyl-1,2-dihydroxybenzene was isolated as a yellow-brown solid in
quantitative yield. The compound is pure as indicated by 13C NMR
1
and mass spectrometry. The H NMR in CD3CN indicated that 3red is
present as a mixture of two forms. The chemical shifts and integrations
of the methylene protons of the n-butyl side chain [CH3CH2CH2CH2N-
(CH3)-], the methyl protons [CH3CH2CH2CH2N(CH3)-], and the
methylene protons of the ethyl side chain suggest that there are two
inequivalent forms of each. The resonances for the remaining protons
are equivalent for the two forms. This could result from 3red existing
as a mixture of the protonated and neutral forms in CD3CN, or the R
and S forms of 3red (where the protonated amine is the chiral center)
may form hydrogen-bonded dimers in CD3CN, thereby creating the
(J) NMR Assignment of 2. 1H and 13C NMR spectra were obtained
on a Bruker AM-500 spectrophotometer fitted with an inverse 1H-13C
probe operating at a proton frequency of 500.14 MHz for protons. The
spectra were recorded for a CD3CN solution containing 11 mg (0.037
mmol) of 2 in a 5 mm NMR tube. 1H chemical shifts were relative to
residual CH3CN set to 1.940 ppm. 13C chemical shifts were relative to
the 13C signal of CD3CN set to 118.2 ppm. The NOESY spectrum was
acquired at a mixing time of 2 s at 27 °C. The details of the NMR
assignment of 2 are available in the Supporting Information.
(K) Synthesis of a 4-Nitrophenylhydrazine Adduct of 1ox (10). A
stirred solution of 4-nitrophenylhydrazine (316.8 mg, 2.1 mmol) in
acetic acid (20 mL) was heated to 100 °C, and then 1ox (82.8 mg, 0.4
mmol) was added as an acetic acid solution. The reaction mixture was
stirred at 100 °C for 1 h and cooled to room temperature. Water (50
mL) was added, and the mixture was neutralized by addition of NaHCO3
1
diastereomers. In contrast to H NMR, the 13C NMR in this solvent
can be assigned to a single species, 3red
:
1H NMR (CD3CN) δ 0.763
[3H, t, J ) 7.2 Hz, -N(CH3)(CH2)3CH3], 1.122 (3H, t, J ) 7.6 Hz,
-CH2CH3), 1.20-1.23 [3H, m, -N(CH3)CH2CH2CH2CH3], 1.563 [1H,
m, -N(CH3)CH2CH2CH2CH3], 2.710 (1H, 2q, J ) 7.6 Hz, -CH2-
CH3), 2.821 (1H, 2q, J ) 7.6 Hz, -CH2CH3), 3.090 [1.5H, s,
-N(CH3)(CH2)3CH3], 3.102 [1.5H, s, -N(CH3)(CH2)3CH3], 3.423 [2H,
9
6116 J. AM. CHEM. SOC. VOL. 125, NO. 20, 2003