10.1002/ejoc.201801134
European Journal of Organic Chemistry
FULL PAPER
Compound 28: (RS)-2-[2-Aminoethyl]butandioic acid, hydrochloride
Viscous, colourless oil, 272 mg (71%). 1H NMR (400 MHz, CD3OD): δ
2.97-3.09 (m, 2H), 2.83-2.91 (m, 1H), 2.71 (A of ABX, J = 17.2, 7.8 Hz,
1H), 2.56 (B of ABX, J = 16.8, 5.8 Hz, 1H), 1.99-2.08 (m, 1H), 1.84-1.93
(m, 1H); 13C NMR (101 MHz, CD3OD): δ 175.6, 173.6, 38.4, 37.6, 35.2 &
28.8; MS-MS 162.02 (30%, free base MH+); HRMS (ESI-TOF) m/z MH+
Calcd for C6H11NO4 162.0761, found 162.0758.
MS 166.06 (100%, free base MH+); HRMS (ESI-TOF) m/z MH+ Calcd for
C6H7D4NO4 166.1012, found 166.1015.
Compound 52: (RS)- 6-(trifluoromethyl)tetrahydropyrimidin-4(1H)-
one
White solid, 372 mg (91%). 1H NMR (400 MHz, CD3OD): δ 4.23 & 4.18
(ABq, J = 12.4 Hz, 2H), 3.70-3.79 (m, 1H), 2.50 (A of ABX, J = 17.2, 5.5
Hz, 1H), 2.39 (B of ABX, J = 17.2, 10.5 Hz, 1H); 19F NMR (377 MHz,
CD3OD): δ -79.06 (d, JHF = 7.9 Hz, 3F); 13C NMR (101 MHz, CD3OD): δ
169.5, 125.3 (q, JCF = 279.1 Hz), 55.9, 53.3 (q, JCF = 30.7 Hz) & 30.1;
HRMS (ESI-TOF) m/z MH+ Calcd for C5H7F3N2O 169.0595, found
169.0583.
Compound 32: (RS)-5-Methoxypiperidin-2-one
Viscous, colourless oil, 252 mg (98%). 1H NMR (400 MHz, CD3OD): δ
3.64-3.68 (m, 1H), 3.37 (s, 3H), 3.34-3.40 (m, 2H), 2.41 (ddd, J = 17.6,
10.5, 6.6 Hz, 1H), 2.25 (ddd, J = 17.9, 6.2, 4.3 Hz, 1H), 1.99-2.05 (m, 1H),
1.90-1.96 (m, 1H); 13C NMR (101 MHz, CD3OD): δ 173.2, 71.3, 54.9, 44.8,
26.3 & 24.0; MS-MS 130.07 (100%, MH+); HRMS (ESI-TOF) m/z MH+
Calcd for C6H11NO2 130.0863, found 130.0867.
Compound
57:
3-[(2R,4S)-4-Isopropyl-2-methyloxazolidin-2-
yl]propanoic acid, hydrochloride
Pale yellow crystals, for a total yield of 422 mg (65%). 1H NMR (400 MHz,
D2O + CH3CN reference): δ 3.86 (A of ABX, J = 12.5, 3.9 Hz, 1H), 3.66 (B
of ABX, J = 12.5, 7.8 Hz, 1H), 3.08-3.14 (m, 1H), 2.85 (t, J = 6.5 Hz, 2H),
2.58 (t, J = 6.1 Hz, 2H), 2.21 (s, 3H), 1.90-2.02 (m, 1H), 1.01 (d, J = 6.6
Hz, 3H), 0.98 (d, J = 7.1 Hz, 3H); 13C NMR (101 MHz, D2O + CH3CN
reference): δ 175.0, 119.5, 60.0, 59.0, 28.2, 28.1, 27.8, 18.3 & 18.2; MS-
MS 202.06 (100%, free base MH+); HRMS (ESI-TOF) m/z MH+ Calcd for
C10H19NO3 202.1436, found 202.1438.
Compound 35: (RS)-4-Methyl-5-(phenylamino)pentanoic acid,
hydrochloride
1
Viscous oil, 168 mg (87%). H NMR (400 MHz, CD3OD): δ 7.21 (dd, J =
8.6, 7.4 Hz, 2H), 6.56-6.61 (m, 3H), 2.99 (A of ABX, J = 12.5, 5.9 Hz, 1H),
2.85 (B of ABX, J = 12.5, 6.6 Hz, 1H), 2.25-2.41 (m, 2H), 1.72-1.83 (m,
2H), 1.40-1.49 (m, 1H), 0.96 (d, J = 6.7 Hz, 3H); 13C NMR (101 MHz,
CD3OD): δ 176.5, 148.9, 128.6, 116.3, 112.5, 49.7, 32.1, 31.3, 29.5 & 16.6;
MS-MS 208.01 (83%, free base MH+); UPLC (1-100%-2 min): 0.96 min;
HRMS (ESI-TOF) m/z MH+ Calcd for C12H17NO2 208.1332, found
208.1340.
Compound 58: (RS)-1-Benzyl-5-methylpiperidin-2-one
A suspension of sodium hydride (60% w/w, 120 mg, 2.99 mmol) in
anhydrous THF (4 mL), at 0 °C, under nitrogen, was treated dropwise with
Compound 36: (RS)-1-[3-hydroxyphenyl]-5-methylpiperidin-2-one
White solid, 181 mg (89%). H NMR (400 MHz, CD3OD): δ 7.21 (dd, J =
8.3, 7.8 Hz, 1H), 6.67-6.73 (m, 2H), 6.66 (dd, J = 2.4, 1.9 Hz, 1H), 3.53-
3.57 (m, 1H), 3.29-3.34 (m, 1H), 2.51 (dd, J = 8.4, 4.5 Hz, 2H), 2.09-2.18
(m, 1H), 1.92-1.97 (m, 1H), 1.56-1.67 (m, 1H), 1.06 (d, J = 6.7 Hz, 3H); 13
NMR (101 MHz, CD3OD): δ 171.1, 158.0, 144.0, 129.6, 116.9, 113.9,
113.2, 58.4, 31.3, 28.9, 28.7 & 17.1; LRMS: 206.2 (100%, MH+); MS-MS
206.03 (100%, MH+); UPLC (1-100%-5 min): 1.84 min; HRMS (ESI-TOF)
m/z MH+ Calcd for C12H15NO2 206.1176, found 206.1185.
a solution of (RS)-5-methylpiperidin-2-one (30 mg, 2.65 mmol) in
1
anhydrous THF (4 mL). The reaction was then allowed to warm to ambient
temperature and was stirred for 2 h. Benzyl bromide (0.34 mL, 2.84 mmol)
was then added, and the reaction was stirred at ambient temperature,
under argon, overnight. The reaction was quenched by addition of water
(30 mL); and the mixture was extracted with a 1:1 mixture of Et2O and
EtOAc (4 x 30 mL). Combined organic extracts were washed with
saturated aqueous NaCl solution; dried over Na2SO4; filtered and
evaporated to give the crude product. Purification by chromatography on
silica gel (eluting with 0 to 70% ethyl acetate in hexanes) gave the title
C
1
compound (362 mg 67%). H NMR (400 MHz, CDCl3): δ 7.23-7.34 (m, 5
Compound 37: (RS)-4-Methyl-5-([3-hydroxyphenyl]amino)pentanoic
H), 4.49 & 4.67 (ABq, J = 14.6 Hz, 2H), 3.16 (ddd, J = 12.1, 5.1, 2.0 Hz,
1H), 2.82 (dd, J = 12.1, 10.2 Hz, 1H), 2.54 (ddd, J = 17.9, 5.9, 3.1 Hz, 1H),
2.44 (ddd, J = 17.9, 11.5, 6.4 Hz, 1H), 1.80-1.96 (m, 2H), 1.41-1.52 (m,
1H), 0.94 (d, J = 6.6 Hz, 3H).
acid, hydrochloride
Black solid, 102 mg (55%). H NMR (400 MHz, CD3OD): δ 7.21 (dd, J =
1
7.8, 7.8 Hz, 1H), 6.10-6.18 (m, 3H), 3.53-3.57 (m, 1H), 2.98 (A of ABX, J
= 12.7, 6.1 Hz, 1H), 2.85 (B of ABX, J = 12.7, 6.8 Hz, 1H), 2.26-2.40 (m,
2H), 1.74-1.83 (m, 2H), 1.39-1.49 (m, 1H), 0.96 (d, J = 6.6 Hz, 3H); 13C
NMR (101 MHz, CD3OD): δ 176.5, 157.8, 149.6, 129.4, 105.2, 104.2, 99.7,
50.2, 32.0, 31.2, 29.5 & 16.5; MS-MS 224.05 (6%, free base MH+); HRMS
(ESI-TOF) no molecular ion observed.
Compound 59: (RS)-5-(Benzylamino)-4-methylpentanoic acid,
hydrochloride
Ring-opening of (RS)-1-benzyl-5-methylpiperidin-2-one using the Typical
Procedure for Ring-Opening in Acidic Conditions, gave the title compound
1
Compound 40: 2,3,4,5-[2H]4-(RS)-6-oxopiperidine-2-carboxylic acid
White solid, 535 mg (quantitative). H NMR (400 MHz, CD3OD): δ 2.27-
as a white solid, which was used directly in the next step. H NMR (400
1
MHz, D2O): δ 7.31 (s, 5 H), 4.07 (s, 2H), 2.84 (A of ABX, J = 12.7, 6.1 Hz,
1H), 2.72 (B of ABX, J = 12.7, 8.0 Hz, 1H), 2.15-2.31 (m, 2H), 1.70-1.80
(m, 1H), 1.48-1.56 (m, 1H), 1.26-1.35 (m, 1H), 0.73 (d, J = 6.6 Hz, 3H).
2.32 (m, 1H), 1.86-1.91 (m, 1H), 1.74-1.81 (m, 1H); 2H NMR (400 MHz,
CH2Cl2 + CDCl3 reference): δ 4.19 (s, 1D), 2.43 (s, 1D), 2.25 (s, 1D), 1.95
(s, 1D); 13C NMR (101 MHz, CDCl3): δ 173.7, 173.4, 53.5-54.1 (m), 29.6-
30.1 (m), 24.1-24.6 (m) & 17.7-18.2 (m); MS-MS 148.10 (100%, MH+);
HRMS (ESI-TOF) m/z MH+ Calcd for C6H5D4NO3 148.0906, found
148.0914.
Compound
60:
(RS)-5-(Benzyl(tert-butoxycarbonyl)amino)-4-
methylpentanoic acid
A mixture of (RS)-5-(benzylamino)-4-methylpentanoic acid, hydrochloride
(2.27 mmol), Boc anhydride (991 mg, 4.54 mmol) and triethylamine (0.63
mL, 4.5 mmol) in 1,4-dioxane (6 mL) and water (6 mL) was stirred at
ambient temperature overnight. 1,4-Dioxane was removed under reduced
pressure, and the mixture was acidified by addition of 0.1M aq. HCl (50
mL), then extracted with EtOAc (4 x 50 mL). The combined organic
extracts were washed with sat. aq. NaCl solution, dried over Na2SO4, and
concentrated under reduced pressure to give the crude compound.
Purification by silica gel chromatography (eluting with 0-100% EtOAc in
Compound
41:
(RS)-2,3,4,5-[2H]4-2-Aminohexandioic
acid,
hydrochloride
1
Beige-coloured foam, 351 mg (87%). H NMR (400 MHz, D2O + CH3CN
reference): δ 2.44-2.47 (m, 1H), 1.89-2.00 (m, 1H), 1.66-1.76 (m, 1H); 2H
NMR (400 MHz, H2O + CD3OD reference): δ 4.10 (s, 1D), 2.48 (s, 1D),
1.58-2.14 (m, 2D); 13C NMR (101 MHz, D2O + CH3CN reference): δ 178.2,
172.6, 53.0-53.4 (m), 33.2-33.6 (m), 29.3-29.6 (m) & 20.0-20.5 (m); MS-
1
hexanes) gave the title compound (579 mg, 79% over 2 steps). H NMR
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