Journal of Agricultural and Food Chemistry
Article
bath; a white solid appeared, and it was filtered and washed with
cool acetone.
crude was purified using FCC (DCM/2-propanol = 9.5:0.5) and
after that was recrystallized in DCM/hexane.
Data for Compound 9. Yield: 65%, crystalline white solid, mp
Data for Compound 5. Yield: 70%, white solid. Spectral data
matched with previous reports;19 the H NMR data is provided here
1
130−133 °C, [α]23.5 = −65.2 (c 1, MeOH). H NMR (500 MHz,
1
for convenience. 1H NMR (500 MHz, CDCl3) δ: 7.51−7.36 (m,
5H), 4.31 (d, J = 12.8 Hz, 1H), 4.08 (d, J = 12.8 Hz, 1H), 3.87 (t, J
= 7.8 Hz, 1H), 3.32−3.24 (m, 1H), 2.97 (q, J = 8.8 Hz, 1H), 2.35−
2.22 (m, 1H), 2.00−1.89 (m, 2H), 1.85−1.71 (m, 1H).
DMSO-d6, 60 °C) δ: 8.70 (b, 1H), 7.80 (s, 2H), 7.37−7.21 (m,
5H), 4.00 (d, J = 13.3 Hz, 1H), 3.41−3.30 (m, 2H), 3.27−3.22 (m,
1H), 2.87−2.77 (m, 2H), 2.23 (td, J = 9.2, 7.2 Hz, 1H), 1.91 (dt, J
= 12.2, 8.2 Hz, 1H), 1.72−1.52 (m, 3H). 13C NMR (125 MHz,
DMSO-d6, 60 °C) δ: 160.5, 139.8, 129.0, 128.5, 127.2, 62.1, 58.4,
Preparation of Compound 6. The solution of 6.4 g (31.18
mmol) N-benzyl-S-proline in 64 mL of THF was treated with 1.77 g
(37.95 mmol) of LiAlH4 at 0 °C. The mixture was stirred at room
temperature for 12 h, and KOH (10% in water) was added until a
white precipitate appeared. The mixture was filtered and the residue
was washed with THF, then the filtrate was dried over Na2SO4 and
evaporated. The crude was used without further purification.
Data for compound 6. Yield: 83%, slightly yellow oil. Spectral
+
54.0, 43.8, 28.4, 23.0. HRMS (ESI): calculated for C13H20N5O2 [M
+ H]+, 278.1612; found, 278.1617 (−2.9).
Preparation of Compound 10. A 4.1 mL sample of Et3N (2.97
g, 29.35 mmol) was added in a single portion to a stirred solution of
7 (4.33 g (22.63 mmol) in 57 mL DCM); afterward, the mixture
was cooled at 0 °C and 2.27 mL (3.37 g, 29.41 mmol) of
methanesulfonyl chloride was slowly added, and the mixture was
stirred for 2 h at 0 °C. Afterward, 15 mL of water was added, and
the organic phase was separated; the aqueous phase was extracted
with 30 mL of DCM, the organic extracts were washed with brine,
dried over Na2SO4, filtered, and evaporated in a rotatory evaporator
to obtain the crude mesylate. This was dissolved in 33 mL of
DMSO, 4 Å molecular sieve (1.85 g), KI 0.75 g (11.43 mmol), and
KCN 3.38g (51.9 mmol) were successively added, and the reaction
was stirred during 4 h at 60 °C. The reaction was diluted with water
and extracted with AcOEt; the organic phase was washed with
aqueous saturated solution of NaHCO3 and brine, dried over
Na2SO4, filtered, and evaporated with a rotatory evaporator. The
residue was purified by FCC (hexane/AcOEt = 9:1).
1
1
data matched with previous reports; the H NMR data is provided
1
here for convenience. H NMR (500 MHz, CDCl3) δ: 7.35−7.23
(m, 5H), 3.97 (d, J = 13.0 Hz, 1H), 3.66 (dd, J = 10.7, 3.4 Hz, 1H),
3.43 (dd, J = 10.8, 2.1 Hz, 1H), 3.35 (d, J = 13.0 Hz, 1H), 2.97
(ddd, J = 9.4, 6.2, 3.1 Hz, 1H), 2.79 (s, 1H), 2.77−2.70 (m, 1H),
2.29 (td, J = 9.4, 7.6 Hz, 1H), 1.94 (dq, J = 12.7, 8.8 Hz, 1H),
1.88−1.80 (m, 1H), 1.75−1.63 (m, 2H).
Preparation of Compound 7. A 1.37 g sample of triphenyl-
phosphine (5.23 mmol) and 0.92 g (6.27 mmol) of phthalimide
were dissolved in 15 mL of anhydrous THF; then a mixture of 1.0 g
(5.23 mmol) of 6 in 4 mL of THF was added, and the reaction was
stirred for 10 min. Then a solution of diethyl azodicarboxylate (40%
wt in toluene) 2.27 mL (0.91 g, 5.23 mmol) was added dropwise,
and the mixture was refluxed for 8 h. The reaction was allowed to
cool at room temperature, and the solvents were evaporated under
reduced pressure; the residue was dissolved in diethyl ether (50 mL)
and stirred for 1 h after which a precipitate appeared. The
precipitate was filtered and discarded, and the filtrate was evaporated
under reduced pressure. The residue was passed through a short pad
of silica (hexane/AcOEt = 7:3) in order to remove the excess of
triphenylphosphine oxide; in this way, the reaction yielded 1.36 g
(85%) of the corresponding intermediate as a colorless oil. This was
dissolved in EtOH (40 mL) and 1.1 mL (0.56 g, 11.18 mmol) of
hydrazine monohydrate (64 wt %) was added, and the reaction was
refluxed for 2 h; after this time, HCl (6 mL of 1.0 M in water) was
added and the heating was continued for 30 min. The reaction was
filtered, and the filtrate was evaporated. The residue was dissolved in
NaOH (10 mL of solution 1.0 M in water) and extracted with
DCM (×3), then organic phases were combined, dried over
Na2SO4, and evaporated under reduced pressure.
Data for Compound 10. Yield: 57%, colorless oil, [α]23.5
=
1
−81.5 (c 1, MeOH). H NMR (500 MHz, CDCl3) δ: 7.36−7.29
(m, 4H), 7.28−7.23 (m, 2H), 3.90 (d, J = 13.1 Hz, 1H), 3.47 (d, J
= 13.0 Hz, 1H), 3.05−2.97 (m, 1H), 2.87−2.80 (m, 1H), 2.48−2.34
(m, 2H), 2.30 (td, J = 9.4, 7.0 Hz, 1H), 2.17−2.04 (m, 1H), 1.91−
1.80 (m, 1H), 1.78−1.70 (m, 2H). 13C NMR (125 MHz, CDCl3) δ:
139.0, 128.6, 128.3, 127.1, 118.4, 59.7, 58.7, 54.4, 30.9, 23.4, 22.5.
+
HRMS (ESI): calculated for C13H17N2 [M + H]+, 201.1391; found,
201.1394 (1.0). IR (ATR) υmax: 2953, 2797, 2246, 1453 cm−1.
Preparation of Compound 11. To a stirred solution of 10 (1.2 g
(6 mmol)) in 20 mL of anhydrous diethyl ether was slowly added a
suspension of LiAlH4 (0.68g (17.97 mmol)) in 20 mL of diethyl
ether at 0 °C. The mixture was stirred for 12 h at room temperature
before the reaction was quenched with NaOH (10% in water); the
suspension was filtered over Celite, the solid residue was washed
with DCM, and then the filtrate was dried over Na2SO4 and
evaporated under reduced pressure. The residue was obtained with a
sufficient purity thus purification was not needed.
Data for Compound 11. Yield: 82%, colorless oil, [α]23.3
=
1
Data for Compound 7. Yield: 68%, colorless oil, spectral data
−81.5 (c 1, MeOH). H NMR (500 MHz, CDCl3) δ: 7.34−7.28
(m, 4H), 7.26−7.21 (m, 1H), 4.06 (d, J = 12.7 Hz, 1H), 3.16 (d, J
= 12.7 Hz, 1H), 2.90 (ddd, J = 9.8, 7.4, 2.8 Hz, 1H), 2.84 (ddd, J =
12.2, 8.9, 5.7 Hz, 1H), 2.72 (ddd, J = 12.2, 8.7, 6.2 Hz, 1H), 2.42
(qd, J = 8.0, 3.4 Hz, 1H), 2.09 (td, J = 9.3, 8.1 Hz, 1H), 1.98−1.91
(m, 1H), 1.91−1.81 (m, 1H), 1.75−1.62 (m, 2H), 1.58−1.46 (m,
4H). 13C NMR (125 MHz, CDCl3) δ: 139.5, 129.0, 128.2, 126.8,
62.4, 58.7, 54.1, 39.5, 37.7, 30.2, 22.1. HRMS (ESI): calculated for
C13H20N2Na+ [M + H]+, 227.1524; found, 227.1525 (0.4)
Preparation of Compound 12. This compound was prepared
following the same procedure described for 8. In this case, 0.6 g
(2.93 mmol) of 11 was reacted with 0.52 g (3.52 mmol) of S,-N-
dimethylnitroisothiourea in DCM (15 mL). The crude was purified
FCC (gradient from DCM/2-propanol = 9.5:0.5 to DCM/2-
propanol = 8:2).
matched with previous reports;20 the H NMR data is provided here
1
for convenience. 1H NMR (500 MHz, CDCl3) δ: 7.34−7.28 (m,
4H), 7.25−7.21 (m, 1H), 3.97 (d, J = 13.1 Hz, 1H), 3.30 (d, J =
13.1 Hz, 1H), 2.98−2.91 (m, 1H), 2.77 (dd, J = 12.9, 5.4 Hz, 1H),
2.71 (dd, J = 12.9, 3.4 Hz, 1H), 2.59−2.52 (m, 1H), 2.24−2.16 (m,
1H), 1.94−1.81 (m, 2H), 1.74−1.63 (m, 2H), 1.60−1.51 (m, 2H).
Preparation of Compound 8. A 1.0 g (5.25 mmol) sample of 7
and 0.94 g (6.30 mmol) of S-methyl-N-methylnitroisothiourea were
dissolved in 20 mL of DCM and stirred at room temperature for 18
h. The crude was purified FCC (DCM/2-propanol = 9.5:0.5).
Data for Compound 8. Yield: 43%, colorless oil, [α]23.5= −78.4
1
(c 1, MeOH). H NMR (500 MHz, DMSO-d6, 60 °C) δ: 8.76 (b,
1H), 7.87 (b, 1H), 7.33−7.20 (m, 5H), 3.98 (d, J = 13.2 Hz, 1H),
3.36 (d, J = 13.3 Hz, 1H), 3.34−3.29 (m, 1H), 3.23 (dt, J = 13.5,
4.3 Hz, 1H), 2.88−2.80 (m, 2H), 2.75 (d, J = 4.3 Hz, 3H), 2.23 (q,
J = 8.4 Hz, 1H), 1.96−1.84 (m, 1H), 1.71−1.53 (m, 3H). 13C NMR
(125 MHz, DMSO-d6, 60 °C) δ: 158.9, 139.8, 128.9, 128.5, 127.2,
62.0, 58.3, 54.0, 44.0, 28.5, 28.4, 23.1. HRMS (ESI): calculated for
Data for Compound 12. Yield: 69%, colorless oil, [α]23.4= −60.6
(c 1, MeOH). 1H NMR (500 MHz, DMSO-d6) δ: 7.77 (s, 1H),
7.34−7.16 (m, 6H), 3.95 (d, J = 13.2 Hz, 1H), 3.36−3.17 (m, 3H),
2.87−2.71 (m, 4H), 2.55−2.49 (m, 1H), 2.20−2.06 (m, 1H), 1.98−
1.80 (m, 2H), 1.69−1.55 (m, 3H), 1.54−1.45 (m, 1H). 13C NMR
(125 MHz, DMSO-d6) δ: 158.2, 139.8, 129.2, 128.5, 127.1, 61.6,
58.2, 53.7, 38.8, 29.9, 28.6, 22.4. HRMS (ESI): calculated for
+
C14H22N5O2 [M + H]+, 292.1768; found, 292.1773 (1.4).
Preparation of Compound 9. A 1.25 g (6.56 mmol) sample of 7
and 1.06 g (7.88 mmol) of S-methylnitroisothiourea were dissolved
in 20 mL of DCM and stirred at room temperature for 18 h. The
+
C14H22N5O2 [M + H]+, 306.1925; found, 306.1930 (−1.3).
1457
J. Agric. Food Chem. 2021, 69, 1455−1465