Journal of Medicinal Chemistry
Article
8.3 ppm. HRMS (ESI): m/z [M + H]+ calcd for C20H31ClN, 320.2140;
found, 320.2137. HPLC: tR = 7.57 min.
(Z)-N-Ethyl-N-(4-phenylbut-2-en-1-yl)heptan-1-amine (79). Prop-
argylic amine 21 (136 mg, 0.5 mmol), quinoline (10 μL, 0.08 mmol),
and Lindlar’s catalyst (20% w/w Pd, 49 mg, 2.5 mg Pd) were dissolved in
EtOAc (140 mL). The flask was flushed with N2 before being saturated
with H2. After 72 h, the mixture was concentrated in vacuo. The residuet
was purified by 2× preparative TLC (30% EtOAc−petroleum ether and
General Procedure for the Synthesis of Compounds 20−26, 34−
39, 46−47, and 52−55. To a solution of alkyne (16−19, 31−33, 45,
50−51) (1 mmol) in 1,4-dioxane (1 mL) were added paraformaldehyde
(32 mg, 1.05 mmol), copper(II) acetate hydrate (21 mg, 0.105 mmol), and
amine (1.05 mmol). The mixture was stirred at 90 °Cfor12handfiltered, and
the filtrate was purified by flash chromatography on silica gel (20% EtOAc−
petroleum ether) to afford 20−26, 34−39, 46−47, and 52−55 as oils.
N-Butyl-4-(4-chlorophenyl)-N-ethylbut-2-yn-1-amine (22). Yield
288 mg (55%). 1H NMR (400 MHz, CDCl3) δ 7.27 (s, 4H), 3.58 (t, J =
2.0 Hz, 2H), 3.44 (t, J = 2.0 Hz, 2H), 2.54 (q, J = 7.2 Hz, 2H), 2.48−2.44 (m,
2H), 1.48−1.41 (m, 2H), 1.36−1.27 (m, 2H), 1.06 (t, J = 7.2 Hz, 3H), 0.91
(t, J = 7.2 Hz, 3H) ppm. 13C NMR (101 MHz, CDCl3) δ 135.8, 132.4, 129.3,
128.6, 81.8, 77.6, 53.3, 47.7, 41.8, 29.8, 24.7, 20.9, 14.2, 12.7 ppm, HRMS
(ESI): m/z [M + H]+ calcd for C16H23ClN, 264.1514; found, 264.1515.
HPLC: tR = 14.2 min.
General Procedure for the Oxidative Coupling of Phenyl-
acetylenes and Propargylamines. Alkyne 41 (446 mg, 3.2 mmol),
4-substituted phenylacetylene (0.64 mmol), and Cu(OAc)2.H2O
(13 mg, 0.064 mmol) were dissolved in CH2Cl2 (5 mL). Piperidine
(0.2 mL, 1.9 mmol) was added, and a balloon filled with air was put on
the flask. After 48 h at 25 °C, the mixture was concentrated in vacuo and
purified by preparative TLC (20% EtOAc−petroleum ether), yielding
dyine 42, 43.
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5% MeOH−CH2Cl2), yielding 79 (53 mg, 25%) as an oil. H NMR
(400 MHz, CDCl3) δ 7.28 (d, J = 6.8 Hz, 2H), 7.18 (d, J = 7.2 Hz, 2H),
5.75−5.69 (m, 1H), 5.66−5.60 (m, 1H), 3.44 (d, J = 6.8 Hz, 2H), 3.23
(d, 6.4 Hz, 2H), 2.57 (q, J = 14.0, 6.8 Hz, 2H), 2.45 (t, J = 7.6 Hz, 2H),
1.47 (m, 2H), 1.27−1.26 (m, 8H), 1.05 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 5.6
Hz, 3H) ppm. 13C NMR (101 MHz, CDCl3) δ 140.8, 130.7, 128.6,
128.4, 128.1, 126.1, 53.4, 50.2, 47.5, 33.9, 32.0, 29.8, 29.4, 27.8, 27.0,
22.8, 14.3, 11.9 ppm. HRMS (ESI): m/z [M + H]+ calcd for C19H32N,
274.2528; found, 274.2529. HPLC: tR = 14.2 min.
(E)-N-(4-(4-Chlorophenyl)but-2-en-1-yl)-N,N-diethylheptan-1-
aminium Iodide (80). Allylamine 78 (100 mg, 0.32 mmol) was
dissolved in acetone (1.1 mL). Ethyl iodide (40 μL, 0.48 mmol) was
added. After 24 h of stirring, an additional amount of ethyliodide (40 μL,
0.48 mmol) was added and after another 24 h the reaction mixture was
heated to 55 °C. After 4 days in total, the mixture was concentrated in
vacuo. The residue was dissolved in CH3CN and then precipitated by
adding Et2O. After filtration and removal of the solvents, ammonium 80
(89 mg, 60%) was obtained as a dark-brown oil. 1H NMR (400 MHz,
CDCl3) δ 7.27 (d, J = 6.8 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 6.39−6.32
(m, 1H), 5.72−5.64 (m, 1H), 4.04 (d, J = 7.6 Hz, 2H), 3.55−3.40 (m,
6H), 3.21 (t, J = 8.4 Hz, 2H), 1.71−1.69 (m, 2H), 1.39 (t, J = 7.2 Hz,
7H), 1.30−1.19 (m, 9H), 0.88 (t, J = 6.8 Hz, 3H) ppm. 13C NMR
(101 MHz, CDCl3) δ 144.3, 136.7, 130.2, 128.9, 116.9, 60.2, 58.0, 54.0,
38.3, 31.6, 28.8, 26.4, 22.5, 22.3, 14.1, 8.5 ppm. HRMS (ESI): m/z [M]+
calcd for C21H35Cl, 336.2453; found, 336.2453. HPLC: tR = 14.3 min.
N-Ethyl-N-(4-phenylbutyl)heptan-1-amine (81). Allylamine 78
(180 mg, 0.6 mmol) and Pd/C (10% w/w Pd, 55 mg, 30 wt %) were
dissolved in MeOH (10 mL). The flask was flushed with N2 before being
saturated with H2. After 4.5 h stirring at rt, the mixture was filtered on
Celite, the volatiles were removed in vacuo, and the residue was purified
by flash chromatography on silica gel (100% EtOAc then 20% MeOH−
N-Butyl-5-(4-chlorophenyl)-N-ethylpenta-2,4-diyn-1-amine (42).
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Yield 25 mg (14%). H NMR (400 MHz, CDCl3) δ 7.42 (d, J =
8.8 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 3.59 (s, 2H), 2.58 (q, J = 7.2 Hz,
2H), 2.51 (t, J = 7.2 Hz, 2H), 1.48−1.44 (m, 2H), 1.37−1.32 (m, 2H),
1.09 (t, J = 7.2 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H) ppm. 13C NMR
(101 MHz, CDCl3) δ 135.3, 133.9, 128.9, 120.4, 80.1, 75.0, 74.8, 69.4,
53.5, 47.9, 42.2, 29.9, 20.8, 14.2, 12.9 ppm. HRMS (ESI): m/z [M + H]+
calcd for C17H21ClN, 274.1359; found, 274.1357. HPLC: tR = 14.0 min.
General Procedure for the Allylic Amination of Acetate (59). In a
test tube were added PdCl2 (9 mg, 0.05 mmol), TBAB (322 mg, 1
mmol), and K2CO3 (276 mg, 2 mmol), followed by toluene (3 mL), 59
(210 mg, 1 mmol), and N-alkyl-N-ethylamine (1 mmol). The tube was
sealed, and the mixture was heated at 85 °C for 12 h, upon which it was
filtered and the filter was rinsed with EtOAc (10 mL). The filtrate was
washed with water (5 mL) and brine (5 mL) and dried over MgSO4. The
volatiles were removed in vacuo, and the residue was purified by flash
chromatography on silica gel (20% EtOAc−petroleum ether) to afford
allylic amine 60/61 as an oil.
(E)-N-(3-(4-Chlorophenyl)allyl)-N-ethylbutan-1-amine (60). Yield
204 mg (81%). 1H NMR (400 MHz, CDCl3) δ 7.30−7.25 (m, 4H), 6.46
(d, J = 16 Hz, 1H), 6.26 (dt, J = 16, 6.8 Hz, 1H), 3.23 (dd, J = 6.8, 1.2 Hz,
2H), 2.56 (q, J = 7.2 Hz, 2H), 2.48−2.44 (m, 2H), 1.50−1.43 (m, 2H),
1.36−1.26 (m, 2H), 1.05 (t, J = 7.2 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H)
ppm. 13C NMR (101 MHz, CDCl3) δ 135.9, 133.0, 130.9, 128.8, 127.6,
56.2, 53.1, 47.5, 29.2, 20.9, 14.2, 11.8 ppm. HRMS (ESI): m/z [M + H]+
calcd for C15H23ClN, 252.1514; found, 252.1513. HPLC: tR = 13.4 min.
General Procedure for the Allylic Amination of Allylic Acetates
70−72. Allylic acetates 70−72 (1 mmol) were put in a microwave tube,
together with K2CO3 (276 mg, 2 mmol), PPh3 (40 mg, 0.15 mmol), and
Pd(OAc)2 (12 mg, 0.05 mmol) dissolved in THF (4 mL). The
corresponding amine (2 mmol) was added, and the mixture was stirred
at 65 °C until TLC showed completion (2−18 h). When completed, the
mixture was filtered on paper filter and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel (20−100%
EtOAc−petroleum ether) to afford pure allylamines 73−78.
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CH2Cl2) to afford 81 (53 mg, 34%) as an oil. H NMR (400 MHz,
CDCl3) δ 7.29 (t, J = 8.4 Hz, 2H), 7.17 (t, J = 8.4 Hz, 2H), 3.03 (q, J =
14.8, 7.2 Hz, 2H), 2.94−2.86 (m, 4H), 2.67 (t, J = 7.6 Hz, 2H), 1.84−
1.77 (m, 2H), 1.73−1.65 (m, 4H), 1.40−1.27 (m, 11H), 0.88 (t, J =
6.8 Hz, 3H) ppm. 13C NMR (101 MHz, CDCl3) δ 141.2, 128.5, 128.3,
126.1, 51.7, 51.6, 47.0, 35.1, 31.6, 28.7, 28.6, 26.8, 23.3, 23.0, 22.5, 14.0,
8.9 ppm. HRMS (ESI): m/z [M + H]+ calcd for C19H33ClN, 276.2685;
found, 276.2686. HPLC: tR = 14.5 min.
General Procedure for the Synthesis of Amines 90−92 from Esters
88−89. Esters 88−89 (1 mmol) were dissolved in CH2Cl2 (2 mL) and
cooled to −78 °C. DiBAL-H (1.2 M in toluene, 1 mL, 1.2 mmol) was
added dropwise, and after 2 h, H2O (4 mL) and CH2Cl2 (4 mL) were
added. After an additional 30 min of stirring at rt, the mixture was
extracted with CH2Cl2 (3 × 4 mL) and washed with H2O (5 mL) and
brine (5 mL), and the organic layers were dried over MgSO4, filtered,
and concentrated in vacuo. The resulting crude aldehyde (∼1 mmol)
and NaBH(OAc)3 (318 mg, 1.5 mmol) were dissolved in 1,2-
dichloroethane (10 mL), and the corresponding amine (1.1 mmol)
was added. After overnight stirring, satd aq NaHCO3 (10 mL) was
added and the mixture was extracted with CH2Cl2 (3 × 10 mL), and the
organic layer was dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by preparative TLC (EtOAc) to afford amines
90−92 as oils.
(E)-N-(4-(4-Chlorophenyl)but-2-en-1-yl)-N-ethylheptan-1-amine
(74). Yield 654 mg (42%). 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J =
2.0 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 5.76−5.68 (m, 1H), 5.61−5.54 (m,
1H), 3.33 (d, J = 6.8 Hz, 2H), 3.06 (d, J = 6.0 Hz, 2H), 2.51 (q, J = 7.2
Hz, 2H), 2.40 (t, J = 7.6 Hz, 2H), 1.47−1.38 (m, 2H), 1.30−1.22
(m, 8H), 1.03 (t, J = 9.6 Hz, 3H) 0.88 (t, J = 6.4 Hz, 3H) ppm. 13C NMR
(101 MHz, CDCl3) δ 138.8, 131.6, 131.3, 130.7, 129.7, 129.2, 128.6,
128.3, 55.4, 53.0, 47.1, 38.1, 31.8, 29.2, 27.5, 26.7, 22.6, 14.0, 11.6 ppm.
HRMS (ESI): m/z [M + H]+ calcd for C19H31ClN, 308.2140;, found,
308.2141. HPLC: tR = 14.5 min.
N-(4-(4-Chlorophenyl)butyl)-N-ethylheptan-1-amine (90). Yield
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227 mg (73%). H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8.0 Hz,
2H), 7.09 (d, J = 8.4 Hz, 2H), 2.58 (t, J = 7.6 Hz, 2H), 2.51 (q, J = 7.2 Hz,
2H), 2.45−2.37 (m, 4H), 1.62−1.55 (m, 2H), 1.51−1.40 (m, 4H),
1.30−1.27 (m, 8H), 1.01 (t, J = 6.8 Hz, 3H), 0.88 (t, J = 6.4 Hz, 3H) ppm.
13C NMR (101 MHz, CDCl3) δ 141.0, 131.4, 129.8, 128.4, 127.2, 53.5, 53.3,
47.5, 35.2, 31.9, 29.4, 29.4, 27.7, 26.9, 26.5, 22.7, 14.2, 11.6 ppm. HRMS
(ESI): m/z [M + H]+ calcd for C19H33ClN, 310.2297; found, 310.2296.
HPLC: tR = 14.9 min.
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dx.doi.org/10.1021/jm4010434 | J. Med. Chem. 2013, 56, 9427−9440