G. Xu, S. Mao, L. Mao, Y. Jiang, Y. Zhou, J. Shen, and W. Dong
Vol 000
+
1
thermometer, an addition funnel, and a nitrogen inlet. 4-
Nitrophenylacetonitrile (9, 24 g, 0.15 mol) was dissolved
in 200-mL ethanol under nitrogen, and 2.4 g 10% Pd/C
was added. Hydrazine (24 g, 0.48 mol) was added
dropwise, which resulted in gas formation. A cold water
bath was used to keep the temperature of the system at
293.1 [M + H] . H NMR (400 MHz, CDCl ): δ 7.77 (d,
3
J = 8.2 Hz, 2H, Ar-H), 7.36–7.27 (m, 7H, Ar-H), 4.97
(dd, J1 = 8.6 Hz, J2 = 3.3 Hz, 1H, CH), 4.15 (dd,
J1 = 10.3 Hz, J2 = 3.3 Hz, 1H, CH -H), 4.05 (dd,
J = 10.3 Hz, J = 8.6 Hz, 1H, CH -H), 2.45 (s, 3H,
CH3). C NMR (100 MHz, CDCl ): δ 144.0, 137.2,
2
1
2
2
1
3
3
2
5°C. After complete addition, the reaction mixture was
stirred for 2 h at room temperature. After the reaction
was completed as monitored by thin-layer
131.6, 128.9, 127.6, 127.4, 126.9, 125.1, 73.3, 70.8,
20.6.
(R)-2-((4-Aminophenethyl)amino)-1-phenylethan-1-ol (6).
A
chromatography (TLC) (PE: EA = 7:1), Pd/C was
removed by filtration, and the solution was concentrated.
The crude residue (10) was used in the next step without
further purification.
mixture of compound 11 (25 g, 0.184 mol), compound 13
(46 g, 0.167 mol), and acetonitrile (200 mL) was heated at
70°C for 10 h. After completion (monitored by TLC, PE:
EA = 10:1), acetonitrile was distilled off at 55°C under
reduced pressure. After cooling to ꢀ5°C, n-hexane
Preparation of 4-(2-aminoethyl)aniline (11).
To a
compound 10 solution (derived from the last step),
Raney nickel (2.4 g) was added under the nitrogen
atmosphere. Hydrazine (50 g, 1.0 mol) was added
dropwise under nitrogen. A cold water bath was used to
keep the temperature in the flask at 25°C. The reaction
mixture was stirred for 5 h at 60°C. After the reaction
was completed as monitored by TLC (PE: EA = 7:1),
the reaction mixture was filtered to remove the Raney
nickel. The ethanol was evaporated under reduced
pressure to give 16 g of compound 11 as a form of
yellow oil with 81% yield and 98.2% purity as
determined by HPLC. HPLC analysis was performed on
an Agilent LC1260 HPLC system with a UV detector
(
70 mL) was added. While stirring, massive light yellow
precipitation was formed. After filtration, the precipitate
formed was washed with cold toluene and dried to afford
3
8.5 g of compound 6 with a yield of 89.7%. LC-MS m/
+
1
z (%): 257.2 [M + H] . H NMR (400 MHz, DMSO-d ):
6
δ 7.33–7.20 (m, 5H, Ar-H), 6.84 (d, J = 12.0 Hz, 2H,
Ar-H), 6.48 (d, J = 8.0 Hz, 2H, Ar-H), 5.26 (s, 1H,
OH), 4.83 (s, 2H, NH ), 4.60 (t, 1H, J = 8.0 Hz, CH),
2
13
2
.73–2.58 (m, 4H, C H ), 2.51–2.50 (m, 2H, CH ).
C
2
4
2
NMR (100 MHz, DMSO-d ): δ 147.02, 145.12, 129.42,
6
1
28.38, 127.66, 127.20, 126.32, 114.44, 71.95, 58.11,
5
1.76, 35.68.
Ethyl 2-(2-aminothiazol-4-yl)acetate (15). To a solution
(
(
λ) at 25°C, using Waters Xbridge C18 column
250 mm × 4.6 mm, 5 μm) which was eluted with a
of ethyl 4-chloroacetoacetate (compound 2) (25 g,
0.15 mol) in cyclohexane (100 mL), pyrrolidine (13.2 mL,
solution of methanol: water (1:1) at a speed of 0.5 mL/
0
.158 mol) and TsOH·H O (1.43 g, 7.53 mmol) were
2
+
1
min. LC-MS m/z (%): 137.2 [M + H] . H NMR
400 MHz, CDCl3): 6.98 (dt, J1 8.4 Hz,
J2 = 2.0 Hz, 2H, Ar-H), 6.63 (dt, J1 = 8.4 Hz,
J = 2.0 Hz, 2H, Ar-H), 3.57 (brs, 2H, NH ), 2.89 (t,
added. The reaction mixture was refluxed for 3 h with
Dean-Stark. After cooling to room temperature, the
mixture was filtered, and the filtrate was evaporated [19].
The residue was dissolved in dry methanol (130 mL),
(
δ
=
2
2
J = 6.8 Hz, 2H, CH ), 2.63 (t, J = 6.8 Hz, 2H, CH ),
then S (4.8 g, 0.151 mol) was added in one portion,
followed by the addition of cyanamide (6.34 g,
2
1
2
8
3
1
.15(bra, 2H, NH2). C NMR (100 MHz, CDCl ): δ
3
1
44.6, 129.8, 129.6, 115.3, 43.8, 39.3.
0
.151 mol) in dry methanol (20 mL) dropwise at 0°C.
(
R)-1-Phenyl-2-tosylethan-1-ol (13).
(R)-(ꢀ)-1-Phenyl-
The reaction mixture was stirred for 2 h at room
temperature. After concentration, the residue was
purified by recrystallization to give compound 15 as a
1
,2-ethanediol (compound 12, 20 g, 0.145 mol),
dibutyltin oxide (0.75 g, 0.03 mol), and triethyl amine
15 g, 0.15 mol) were dissolved in 200-mL
1
(
pale white solid (30.5 g, 79% yield). mp 92–94°C, H
dichloromethane. The reaction mixture was then cooled
to 0°C. p-Toluenesulfonyl chloride (29 g, 0.152 mol),
dissolved in dichloromethane (DCM) (300 mL), was
added dropwise to the mixture. An ice bath was used to
keep the temperature in the flask at 0°C. After complete
addition, the reaction mixture was stirred for 3 h at room
temperature. After the reaction was completed as
monitored by TLC (PE: EA = 10:1), the mixture was
then quenched by slow addition of 0.5 M HCl, then
extracted with dichloromethane (3 × 200 mL). The
combined organic layer was dried over Na SO and
NMR (400 MHz, DMSO-d ): δ 6.91(s, 2H, NH ), 6.30(s,
6
2
1H, CH), 4.06(dd, J = 8.0 Hz, J = 8.0 Hz, 2H, CH ),
1
2
2
1
3
3.44(s, 2H, CH ), 1.17(t, J = 8.0 Hz, 3H, CH ). C NMR
2
3
(100 MHz, DMSO-d ): δ 170.10, 168.18, 144.31, 103.05,
6
60.10, 36.87, 14.05. IR (KBr): 3422, 1716, 1641,
ꢀ
1
657 cm
.
2-(2-Aminothiazol-4-yl)acetic acid (16). To a solution of
compound 15 (20 g, 110 mmol) in methanol (40 mL),
sodium hydroxide aqueous solution (30 mL, mass
fraction is 20%) was added. The reaction mixture was
refluxed for 3 h at room temperature. After completion
(monitored by TLC, PE: EA = 5:1), the mixture was
concentrated under reduced pressure and its pH was
2
4,
concentrated under reduced pressure to afford 39 g of
compound 13 in a yield of 92.2%. LC-MS m/z (%):
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet