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S. L. Clarke et al. / Tetrahedron: Asymmetry 25 (2014) 356–361
1.81 (4H, m, 2ꢁ CH2), 1.91–2.25 (4H, m, 2ꢁ CH2), 2.54–2.67 (4H, m,
2ꢁ CH2), 2.80 (1H, dd, J = 8.8, 12.2 Hz, CH2), 3.00 (1H, dd, J = 5.1,
12.2 Hz, CH2), 3.52–3.75 (2H, m, CH2), 4.59–4.67 (1H, m, CH). dC
(CDCl3, 75.5 MHz) 20.7 (CH2), 23.5 (2ꢁ CH2), 28.7, 45.6 (2ꢁ CH2),
54.7 (2ꢁ CH2), 59.5 (CH2), 60.3 (CH). Since nitrosamines are poten-
tially carcinogenic, no further data was obtained and the crude
reaction mixture was used without purification in the next step.
10 min. On completion, water (10 mL) was added, followed by
extraction with diethyl ether (3ꢁ 25 mL). The organic layers were
combined and washed with water (2ꢁ 10 mL), dried over MgSO4
and concentrated in vacuo to yield the ketone, which was purified
by silica column chromatography.
4.4. Procedure for PPL hydrolysis
To a solution of PPL (100 mg) in water (10 mL) was added a
solution of alkylated hydrazone (1.05 mmol) in acetone (6 mL).
The reaction was allowed to stir at room temperature for 23 h, di-
luted with diethyl ether (20 mL), washed with brine (3ꢁ 15 mL),
dried over MgSO4 and concentrated in vacuo. Purification was
achieved using silica column chromatography to yield 9 as a yellow
oil (19.3 mg, 10% yield over two steps).
4.1.4. (S)-2-(Pyrrolidin-1-ylmethyl)pyrrolidin-1-amine 5
To a solution of LiAlH4 (2.61 g, 69 mmol) in dry THF (120 mL)
was added dropwise a solution of 4 (6.30 g, 34 mmol) in dry THF
(60 mL) under a nitrogen atmosphere at 0 °C. The reaction mixture
was allowed to stir at 0 °C for 1 h, then at room temperature for 1 h
before being heated at reflux for 4.5 h and stirred at room temper-
ature overnight. The reaction progress was monitored by 1H NMR
spectroscopy. On completion, the reaction vessel was transferred
to an ice bath and quenched by the dropwise addition of H2O
(2.6 mL), 3 M aq NaOH (2.6 mL) and H2O (7.2 mL). The reaction
mixture was filtered through a pad of CeliteÒ using ether to elute
the product. The mother liquor was concentrated in vacuo to yield
4.5. General procedure for oxalic acid hydrolysis
At first, satd aq oxalic acid (1.5 vol with respect to mmol hydra-
zone) was added to a vigorously stirred solution of alkylated
hydrazone in diethyl ether (4 vol with respect to mmol hydrazone).
The reaction progress was monitored by TLC analysis and on com-
pletion were added water (5 mL) and diethyl ether (3ꢁ 20 mL). Or-
ganic extracts were combined, dried over MgSO4 and concentrated
in vacuo to yield the ketone which was purified by silica column
chromatography.
5 as a yellow oil (4.98 g, 86%). ½a D20
ꢂ
¼ ꢀ11:4 (c 1, EtOH).
m
max/cmꢀ1
(KBr): 3306 (N–H stretch, m), 1591 (N–H bending, m), 1137 (C–N
stretch, m). dH (CDCl3, 300 MHz) 1.41–1.54 (1H, m, CH2), 1.68–
1.85 (6H, m, 3ꢁ CH2), 1.93–2.07 (1H, m, CH2), 2.26–2.41 (3H, m,
2ꢁ CH2), 2.45–2.53 (2H, m, CH2), 2.54–2.62 (2H, m, CH2), 2.69–
2.72 (3H, m/br s, CH2/NH2), 2.85–2.91 (1H, m, CH2), 3.22–3.29
(1H, m, CH). dC (CDCl3, 75.5 MHz) 20.6 (CH2), 23.5 (2ꢁ CH2), 28.7
(CH2), 54.8 (2ꢁ CH2), 59.6 (CH2), 61.5 (CH2), 67.8 (CH). Exact mass
calcd for C8H11IO2 [(M+H)+], 170.1657. Found 170.1674.
4.6. Example procedure for the alkylation of chiral hydrazone
To
a stirred solution of dry diisopropylamine (0.16 mL,
1.16 mmol) in dry diethyl ether (4 mL) in an N2 filled Schlenk tube
at ꢀ78 °C was added 1.6 M n-BuLi (0.86 mL, 1.21 mmol). The solu-
tion was allowed to stir at 0 °C for 30 min to generate a solution of
LDA. Hydrazone 6 (250 mg, 1.05 mmol) was added slowly drop-
wise at ꢀ78 °C and allowed to stir at 0 °C for 16 h. A solution of
n-pentyl iodide (250 mg, 1.26 mmol) in dry diethyl ether (2 mL)
in a separate Schlenk, which was previously evacuated and filled
with N2 three times, was added dropwise to a solution of deproto-
nated hydrazone at ꢀ110 °C. The temperature of the reaction was
kept at ꢀ110 °C for 1 h, then at ꢀ70 °C for 5 h before being allowed
to warm gradually to room temperature overnight. Next, satd aq
NH4Cl solution (10 mL) was added to quench the reaction followed
by extraction with diethyl ether (3 ꢁ 20 mL). The organic layers
were combined, dried over MgSO4 and concentrated in vacuo to
yield the crude alkylated hydrazone as a yellow oil, which was
hydrolysed using HCl/diethyl ether to yield the crude product as
a yellow oil. Purification was carried out using silica column chro-
matography eluting with 95:5 hexane/diethyl ether to afford 12 as
4.1.5. (S)-N-(Pentan-3-ylidine)-2-(pyrrolidin-1-ylmethyl)pyrroli-
din-1-amine 6
3-Pentanone (9.34 mL, 88 mmol) was added dropwise to a stir-
red solution of 5 (4.98 g, 29 mmol) in cyclohexane (8 mL) under an
atmosphere of nitrogen. The reaction mixture was then allowed to
stir at room temperature overnight and reaction progress moni-
tored by 1H NMR spectroscopy. On completion, the reaction mix-
ture was poured into 6:1 DCM/H2O and the organic layer
extracted. The organic layer was dried over MgSO4 and concen-
trated in vacuo to give the crude product as a yellow oil (5.61 g,
80% yield). Purification was achieved by Kugelrohr distillation to
yield the product as
¼ þ114 (c 1, EtOH).
a
m
colourless oil (4.52 g, 65% yield).
½
a 2D0
ꢂ
max/cmꢀ1 (NaCl): 1637 (C@N stretch, s),
1342, 1138 (C–N stretch, m). dH (CDCl3, 300 MHz) 1.07 (6H, q, 2ꢁ
CH3), 1.53–1.66 (1H, m, CH2), 1.69–1.91 (6H, m, 3ꢁ CH2),
2.02–2.14 (1H, m, CH2), 2.17–2.29 (2H, m, CH2), 2.30–2.55 (9H,
m, 4ꢁ CH2, CH), 2.97–3.10 (2H, m, CH2). dC (CDCl3, 75.5 MHz)
10.9 (2ꢁ CH3), 11.8, 21.8, 23.5, 23.5, 28.6, 28.7, 54.8, 55.0, 61.4
(10ꢁ CH2), 66.1 (CH), 173.3 (CN). Exact mass calcd for C14H27N3
[(M+H)+], 238.2277. Found 238.2283.
a pale yellow oil (22 mg, 13% and 92% ee). ½a D20
¼ þ5:5 (c 0.2, Et2O).
ꢂ
m
max/cmꢀ1 (film) 2961, 2932 (alkane CH stretches), 1714 (C@O). dH
(CDCl3, 300 MHz) 0.88 (3H, t, J = 6.8 Hz, CH3), 1.04 (3H, t, J = 7.3 Hz,
CH3) 1.06 (3H, d, J = 6.9 Hz, CH3), 1.17–1.35 (8H, m, 4ꢁ CH2), 2.46
(2H, dq, J = 1.5, 7.3 Hz, CH2), 2.48–2.58 (1H, m, CH). dC (CDCl3,
125 MHz) 7.8, 14.1, 16.5 (3ꢁ CH3), 22.5, 27.0, 31.9, 33.1, 34.2 (5ꢁ
4.2. General procedure for synthesis of racemic ketones
To THF (5 mL) was added commercially available LDA (1.1 equiv)
at ꢀ78 °C. The reaction was stirred for 5 min and 3-pentanone was
added dropwise. The reaction was stirred at ꢀ78 °C for 30 min and
the electrophile (1.1 equiv) was added (in 3 mL THF if solid). The
reaction was allowed to warm to room temperature overnight. Next,
at. aq NH4Cl solution (10 mL) was added and the crude product ex-
tracted with ethyl acetate or ether (3ꢁ 15 mL), dried over MgSO4 and
concentrated in vacuo to yield the crude product, which was purified
by silica column chromatography.
CH2), 46.1 (CH), 215.7 (C@O). Exact mass calcd for C10H21O
[(M+H)+], 157.1592. Found 157.1584. Sample for GC made up at
1 mg/mL in dry dichloromethane and run on Agilent Technologies
7820A GC System using G4513A Injector and Astec Chiraldex G-TA
fused silica capillary column purchased from Sigma Aldrich Supe-
lco using conditions 105 °C hold 10 min, ramp 10 °C/min to
140 °C hold 5 min, flow 1 mL/min, inj. vol. 0.2 lL, split ratio 10:1,
front inlet 150 °C, detector 155 °C. Retention time: 3.63 min (min-
or), 3.87 min (major).
4.7. Example of the procedure for the Michael reaction
4.3. General procedure for HCl/diethyl ether hydrolysis
To a stirred solution of dry diisopropylamine (0.2 mL,
At first, 4 M HCl (0.5 mL) and water (0.5 mL) were added to a
vigorously stirred solution of alkylated hydrazone in diethyl ether
(5 mL). The reaction progress was monitored by TLC analysis every
1.39 mmol) in dry diethyl ether (4 mL) in an N2 filled Schlenk tube
at ꢀ78 °C was added 1.6 M n-BuLi (0.91 mL, 1.45 mmol). The
solution was then allowed to stir at 0 °C for 30 min to generate a