10.1002/adsc.201800855
Advanced Synthesis & Catalysis
vacuum. Aqueous residue was washed twice with diethyl
ether. Diethyl ether extracts were discarded. Aqueous layer
was made basic with NaOH solution and extracted with
diethyl ether. Combined organic layers were dried over
K2CO3 and treated with 2M HCl in diethyl ether.
Precipitated product was filtered, washed with diethyl
2H), 2.05–1.07 (m, 21H), 13C NMR δ 174.52, 66.93, 63.97,
53.37, 53.37, 28.95, 27.94, 25.77, 25.70, 25.04, 24.72,
24.02, 23.98, 23.17, 22.84; MS (EI) m/z 253 (M+), 209,
166, 110, 83; HRMS (EI) calc. for C15H27NO2: 253.20363,
found 253.20346; αD22= -35.2 (c 1.01, CHCl3).
1
ether and dried affording 18∙HCl in 65% (1.98 g) yield. H
(2S)-Pyrrolo[1,2-c][1,4]azaoxacyclohexadecanone-3 30.
According to general procedure E, the reaction of (2S)-
pyrrolo[1,2-c][1,4]azaoxacyclohexadecen-6-dione-3,16 25
(1.47 g, 5 mmol) and triethyloxonium tetrafluoroborate
(1.15 g, 6 mmol), following by hydrogenation over 5%
Pt/C (390 mg) and K2CO3 (345 mg) in 10 ml of EtOH,
after work up and silica gel chromatography using
EA/hexane (1:5) as eluent afforded 26 (Rf 0.29) as
NMR (CDCl3) δ 12.12 (s, 1H), δ 3.68 (td, J = 10.5, 5.4 Hz,
2H), 2.90 – 2.85 (m, 2H), 2.84 (d, J = 5.0 Hz, 3H), 2.19 –
2.03 (m, 4H). 13C δ 55.22, 40.79, 23.67. Hydrochloride
was treated with 25% sodium hydroxide solution,
separated organic layer was distilled over K2CO3,
obtaining 18. Spectroscopic properties of 18 matched those
previously described.[38]
1
colorless syrup in 59% (0.83 g) yield. H NMR (CDCl3) δ
N-Methylazepane 20. According to general procedure C,
the reaction of N-methylcaprolactam 19 (3.18 g, 25 mmol)
and dimethyl sulfate (2.6 mL, 27 mmol), following by
hydrogenation with 5% Pd/C (1.06 g, 2 mol%) and 12.5 ml
of 2 M methanolic solution of MeONa in 25 ml of MeOH,
work up and distillation (bp 86-87°C/190 mbar) afforded
20 in 55% (1.56 g) yield. Spectroscopic properties of 20
matched those previously described.[3g]
4.22 (ddd, J = 10.9, J = 7.1, J = 4.9, 1H), 4.00 (ddd, J =
10.8, J = 6.1, J = 4.7, 1H), 3.13 (dd, J = 8.5, J = 5.4, 1H),
3.09 (td, J = 8.3, J = 3.5, 1H), 2.61 (ddd, J = 11.6, J = 10.0,
J = 6.0, 1H), 2.37 (ddd, J = 11.5, J = 9.8, J = 5.3, 1H), 2.32
(q, J = 8.0, 1H), 1.98-2.05 (m, 1H), 1.84-1.91 (m, 2H),
1.71-1.77 (m, 1H), 1.57-1.62 (m, 2H), 1.18-1.48 (m, 18H);
13C δ 174.72, 66.06, 64.40, 54.92, 53.55, 29.28, 28.58,
27.22, 26.75, 26.64, 26.55, 26.12, 25.79, 25.64, 25.53,
25.05, 23.18; MS (EI) m/z 281 (M+), 237, 194, 110, 83;
MS ESI-TOF C17H32NO2 (M+H)+ calc. 282.24276 found
282.24266. αD23= -39.0 (c 1.04, CHCl3).
Piperidine 22. Piperodone-2 21 (2.5 g, 25 mmol) was
alkylated according to general procedure D with ethyl
chlorofomate (8 mL, 84 mmol) and hydrogenated in 25 ml
of EtOH over 5% Pd/C (0.98 g, 1 mol%), combined
filtrates after removing of Pt/C were treated with 1M
hydrochloric acid (25 mL) and EtOH evaporated in
vacuum. Aqueous residue was washed twice with diethyl
ether. Diethyl ether extracts were discarded. Aqueous layer
was made basic with NaOH solution and extracted with
diethyl ether. Combined organic layers were dried over
K2CO3 and treated with 2M HCl (12.5 mL) in diethyl ether.
Precipitated product was filtered, washed with diethyl
ether and dried affording 22∙HCl in 91% (2.77 g) yield.
Spectroscopic properties of 22 matched those previously
described.[39]
1-[(2S)-2-[(ethoxycarbonyl)amino]propyl]-L-proline
methyl
ester
32.
According to general procedure E, the reaction of N-Boc-
L-Ala-L-Pro-OMe 31 (3 g, 10 mmol) and triethyloxonium
tetrafluoroborate (3.80 g, 20 mmol), following by
hydrogenation over 5% Pt/C (0.78 g) and K2CO3 (0.69 g)
in 20 ml of EtOH, after work up and silica gel
chromatography using EA/hexane (1:1) as eluent afforded
1
32 (Rf 0.25) as colorless syrup in 65% (1.68 g) yield. H
NMR (CDCl3) δ 5.19 (br. s, 1H), 3.99-4.07 (m, 2H), 3.63
(s, 3H), 3.60 (q, J=6.4, 1H), 3.23 (dd, J = 8.6, J = 5.1, 1H),
3.09 (ddd, J = 8.3, J = 8.2, J = 3.9, 1H), 2.60 (dd, J = 12.4,
J = 6.0, 1H), 2.50 (dd, J = 11.7, J = 5.9, 1H), 2.47 (dt, J =
8.9, J = 7.5, 1H), 2.00-2.05 (m, 1H), 1.81-1.86 (m, 2H),
1.72-1.78 (m,1H), 1.17 (t, J = 7.1, 3H), 1.13 (d, J = 6.6,
3H); 13C δ 174.80, 156.28, 66.50, 60.38, 60.20, 54.44,
51.69, 46.41, 29.39, 23.83, 19.48, 14.64. MS (EI) m/z 258
(M+), 226, 199, 142, 114; MS ESI-TOF C12H22N2O4
Hexamethyleneimine 24. According to general procedure C,
the reaction of ε-caprolacatam 23 (2.83 g, 25 mmol) and
ethyl chlorofomate (8 mL, 84 mmol), following by
hydrogenation over 5% Pt/C (1.95 g, 2 mol%) in EtOH (25
ml), work up and distillation afforded 24 (bp 68°C/95
mbar) in 95% (2.36 g) yield. Spectroscopic properties of
24 matched those previously described.[40]
22
(M+H)+ calc. 259.16523 found 259.16499. αD -57.9 (c =
1.0, CHCl3)
1-[(2S)-2-[(ethoxycarbonyl)amino]-3-phenylpropyl]-L-
proline methyl ester 34
(2S)-Pyrrolo[1,2-c][1,4]azaoxacyclotridecanone-3
According to general procedure E, the reaction of (2S)-
pyrrolo[1,2-c][1,4]azaoxacyclotridecen-7-dione-3,13 25
26.
(251 mg, 1 mmol) and triethyloxonium tetrafluoroborate
(0.21 g, 1.1 mmol), following by hydrogenation over 5%
Pt/C (78 mg) and K2CO3 (138 mg) in 5 ml of EtOH, after
work up and silica gel chromatography using EA/hexane
(1:5) as eluent afforded 26 (Rf 0.36) as colorless syrup in
According to general procedure E, the reaction of N-Boc-
L-Phe-L-Pro-OMe 33 (3.87 g, 10 mmol) and
triethyloxonium tetrafluoroborate (3.80 g, 20 mmol),
following by hydrogenation over 5% Pt/C (0.78 g) and
K2CO3 (0.69 g) in 20 ml of EtOH, after work up and silica
gel chromatography using EA/hexane (1:1) as eluent
1
75% (182 mg) yield. H NMR (CDCl3) δ 4.17 (ddd, J =
10.7, 7.1, 3.4 Hz, 1H), 4.07 (ddd, J = 10.9, 7.6, 3.3 Hz, 1H), afforded 34 (Rf 0.40) as colorless syrup in 1.84 g (55%)
3.24 – 3.18 (m, 1H), 3.15 (t, J = 6.9 Hz, 1H), 2.86 (dt, J =
12.0, 7.4 Hz, 1H), 2.37 (dt, J = 11.7, 5.7 Hz, 1H), 2.24 (dd,
J = 16.3, 8.4 Hz, 1H), 1.98–1.83 (m, 3H), 1.77–1.11 (m,
15H). 13C NMR δ 174.94, 66.86, 64.32, 54.57, 54.26,
28.96, 27.04, 26.85, 25.35, 25.05, 25.02, 24.10, 23.79,
23.29; MS (EI) m/z 239 (M+), 195, 152, 110, 83; HRMS
(EI) calc. for C14H25NO2: 239.18798, found 239.18790;
αD22= -27.2 (c 0.86, CHCl3).
yield. 1H NMR (CDCl3) δ 7.20 (t, J = 7.6, 2H), 7.12 (t, J =
7.8, 3H), 5.46 (br. s, 1H), 4.07 (dq, J = 10.6, J = 7.2, 1H),
4.02 (dq, J = 10.6, J = 7.1, 1H), 3.75 (br. m, 1H), 3.61 (s,
3H), 3.18 (br. m, 1H), 3.07 (br. m, 1H), 3.03 (td, J = 7.9, J
= 3.4, 1H),2.58 (dd, J = 13.5, J = 7.8, 1H), 2.52 (t, J = 11.3,
1H), 2.40 (dd, J = 12.1, J = 3.85, 1H), 2.21 (br. m, 1H),
1.98-2.04 (m, 1H), 1.98-2.04 (m, 1H), 1.66-1.72 (m, 2H),
1.18 (t, J = 7.2, 3H); 13C δ 174.71, 156.84, 138.20, 129.48,
128.29, 126.25, 65.51, 60.54, 56.79, 53.04, 51.81, 51.44,
39.48 , 29.21, 23.43, 14.69; MS (EI) m/z 334 (M+), 302,
275, 142, 114; MS ESI-TOF C18H26N2O4 (M+H)+ calc.
335.19653 found 335.19616; αD22 -53.7 (c = 1.0, CHCl3).
(2S)-Pyrrolo[1,2-c][1,4]azaoxacyclotetradecanone-3 28.
According to general procedure E, the reaction of (2S)-
pyrrolo[1,2-c][1,4]azaoxacyclotetradecen-8-dione-3,14 27
(1.33 g, 5 mmol) and triethyloxonium tetrafluoroborate
(1.14 g, 6 mmol), following by hydrogenation over 5%
Pt/C (390 mg) and K2CO3 (345 mg) in 10 ml of EtOH,
after work up and silica gel chromatography using
EA/hexane (1:5) as eluent afforded 28 (Rf 0.31) as
Acknowledgements
1
Author gratefully acknowledge Dr. Konrad Möbus for helpful
discussions. Author also thank Ralf Jantke and Stephan Weidlich
for assistance with hydrogenation experiments.
colorless syrup in 80% (1.02 g) yield. H NMR (CDCl3) δ
4.20–4.08 (m, 2H), 3.15 (td, J = 8.4, 2.9 Hz, 1H), 3.06 (dd,
J = 8.2, 6.6 Hz, 1H), 2.83–2.73 (m, 1H), 2.22–2.11 (m,
5
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