PAPER
Arylglycines from Diethyl N-Boc-iminomalonate and Organomagnesium Reagents
65
formed white precipitate was filtered, washed with Et2O and dried
in vacuo (69.8 g, 92% yield); mp 148 °C (Lit.11148 °C).
Anal. Calcd for C14H19NO5: C, 59.78; H, 6.81; N, 4.98. Found: C,
59.53; H, 6.60; N, 4.76.
Diethyl N-Boc-Iminomalonate (3)
Diethyl 2-Amino-2-(3-methoxyphenyl)-malonate (8c)
Following the general procedure using 3-iodoanisole (936 mg, 4
mmol) and performing the halogen-metal exchange at r.t.
A solution of N-Boc-triphenyliminophosphorane (5, 41.5 g, 0.11
mol) and diethyl mesoxalate 98% (17.4 g, 0.1 mol) in anhyd THF
(200 mL), was refluxed at 80 ºC under N2 for 12 h. The THF was
evaporated and anhyd Et2O (150 mL) was added to precipitate the
triphenylphosphine oxide. The solid was filtered, washed with cold
Et2O, and the collected filtrate was evaporated to dryness to afford
a pale yellow oil. The crude product was purified by ball-tube dis-
tillation (140 ºC, 0.45 mbar) to give pure 3 as a colorless oil (24.3 g,
89%), which was stored at 4 °C.
Pale yellow oil (801 mg, 71%).
1H NMR (CDCl3): = 7.28 (m, 1 H, Ar-H), 7.19 (br m, 1 H, Ar-H),
7.13 (ddd, 1 H, J = 7.8, 1.7, 0.9 Hz, Ar-H), 6.88 (ddd, 1 H, J = 8.1,
2.6, 0.9 Hz, Ar-H), 4.27 (m, 4 H, OCOCH2CH3), 3.81 (s, 3 H,
OCH3), 2.29 (br s, 2 H, NH2), 1.28 (t, 6 H, J = 7.1 Hz,
OCOCH2CH3).
13C NMR (CDCl3): = 171.0, 159.4, 139.3, 129.0, 119.5, 113.7,
112.8, 69.1, 62.2, 55.1, 13.8.
1H NMR (CDCl3): = 4.39 (q, 4 H, J = 7.2 Hz, OCOCH2CH3), 1.56
[s, 9 H, C(CH3)3], 1.37 (t, 6 H, J = 7.2 Hz, OCOCH2CH3).
13C NMR (CDCl3): = 161.3, 158.2, 158.0, 151.6, 84.5, 63.1, 62.9,
27.6, 13.6.
Anal. Calcd for C14H19NO5: C, 59.78; H, 6.81; N, 4.98. Found: C,
59.88; H, 6.75; N, 4.82.
Anal. Calcd for C12H19NO6: C, 52.74; H, 7.01; N, 5.13. Found: C,
52.89; H, 6.96; N, 5.00.
Diethyl 2-Amino-2-(4-methoxyphenyl)-malonate (8d)
Following the general procedure using 4-iodoanisole (936 mg, 4
mmol) and performing the halogen-metal exchange at r.t.
Arylglycine Derivatives 8; General Procedure
Pale yellow oil (866 mg, 77%).
To a stirred solution of the aryl iodide 6 (4 mmol) in THF (20 mL)
under N2 at the indicated temperature, was added dropwise 2.0 M
i-PrMgCl in THF (2.2 mL, 4.4 mmol). After 1 h the mixture was
cooled to –78 ºC and a solution of the N-Boc-iminomalonate 3 (1.09
g, 4 mmol) in THF (2 mL) was added. Stirring was continued for 1
h at –78 ºC before quenching cold with H2O (3 mL). The reaction
mixture was allowed to warm to r.t., sat. aq NH4Cl (20 mL) was
added and the mixture was extracted with EtOAc (3 30 mL). The
combined organic layers were washed with brine (20 mL), dried
(MgSO4), filtered and concentrated to afford crude 7 as an oil.
Crude 7 was dissolved in anhyd Et2O (10 mL) under N2, 2 M HCl
in Et2O was added (6 mL, 12 mmol) and stirring at r.t. was contin-
ued for 12 h. The solvents were removed in vacuo, H2O (30 mL)
was added and the mixture washed with Et2O (3 10 mL). A sat. aq
solution of NaHCO3 was added to the water phase until reaching pH
7 and the unclear solution was extracted with Et2O (5 30 mL). The
combined organic layers were washed with brine (20 mL), dried
(MgSO4), filtered and evaporated to give the pure product 8.
1H NMR (CDCl3): = 7.50 (d, 2 H, J = 9.0 Hz, Ar-H), 6.88 (d, 2 H,
J = 9.0 Hz, Ar-H), 4.26 (m, 4 H, OCOCH2CH3), 3.80 (s, 3 H,
OCH3), 2.35 (br s, 2 H, NH2), 1.27 (t, 6 H, J = 7.1 Hz,
OCOCH2CH3).
13C NMR (CDCl3): = 171.3, 159.4, 129.6, 128.3, 113.3, 68.5,
62.0, 55.0, 13.7.
Anal. Calcd for C14H19NO5: C, 59.78; H, 6.81; N, 4.98. Found: C,
59.84; H, 6.63; N, 4.91.
Diethyl 2-Amino-2-(2-thienyl)-malonate (8e)
Following the general procedure using 2-iodothiophene (840 mg, 4
mmol) and performing the halogen-metal exchange at 0 °C.
Pale yellow oil (750 mg, 73%).
1H NMR (CDCl3): = 7.29 (dd, 1 H, J = 5.1, 1.2 Hz, Ar-H), 7.21
(dd, 1 H, J = 3.7, 1.2 Hz, Ar-H), 7.28 (dd, 1 H, J = 5.1, 3.7 Hz, Ar-
H), 4.28 (m, 4 H, OCOCH2CH3), 2.55 (br s, 2 H, NH2), 1.29 (t, 6 H,
J = 7.1 Hz, OCOCH2CH3).
13C NMR (CDCl3): = 169.8, 141.5, 126.7, 126.3, 125.8, 66.7,
62.4, 13.6.
Diethyl 2-Amino-2-(4-tolyl)-malonate (8a)
Following the general procedure using 2-iodotoluene (872 mg, 4
mmol) and performing the halogen-metal exchange at r.t.
Pale yellow oil (798 mg, 75%).
Anal. Calcd for C11H15NO4S: C, 51.35; H, 5.88; N, 5.44. Found: C,
51.39; H, 5.63; N, 5.32.
1H NMR (CDCl3): = 7.46 (m, 2 H, Ar-H), 7.17 (m, 2 H, Ar-H),
4.26 (m, 4 H, OCOCH2CH3), 2.34 (s, 3 H, PhCH3), 1.27 (t, 6 H,
J = 7.1 Hz, OCOCH2CH3).
13C NMR (CDCl3): = 171.3, 138.1, 134.8, 128.8, 127.0, 68.9,
62.1, 20.9, 13.8.
Diethyl 2-Amino-2-(4-fluorophenyl)-malonate (8f)
Following the general procedure using 1-fluoro-4-iodobenzene
(888 mg, 4 mmol) and performing the halogen-metal exchange at
0 °C.
Anal. Calcd for C14H19NO4: C, 63.38; H, 7.22; N, 5.28. Found: C,
63.14; H, 6.97; N, 5.33.
Colourless oil (774 mg, 72%).
1H NMR (CDCl3): = 7.58 (m, 2 H, Ar-H), 7.05 (m, 2 H, Ar-H),
4.29 (m, 4 H, OCOCH2CH3), 2.72 (br s, 2 H, NH2), 1.28 (t, 6 H,
J = 7.1 Hz, OCOCH2CH3).
13C NMR (CDCl3): = 170.9, 162.7 (d, J = 247 Hz), 133.4, (d,
J = 3.2 Hz), 129.1 (d, J = 8.3 Hz), 114.9 (d, J = 21.6 Hz), 68.6, 62.3,
13.8.
Diethyl 2-Amino-2-(2-methoxyphenyl)-malonate (8b)
Following the general procedure using 2-iodoanisole (936 mg, 4
mmol) and performing the halogen-metal exchange at r.t.
Pale yellow oil (846 mg, 75%).
1H NMR (CDCl3): = 7.32 (ddd, 1 H, J = 8.1, 7.6, 1.7 Hz, Ar-H),
7.20 (dd, 1 H, J = 7.6, 1.7 Hz, Ar-H), 6.95 (m, 1 H, Ar-H), 6.92 (m,
1 H, Ar-H), 4.29 (m, 4 H, OCOCH2CH3), 3.81 (s, 3 H, OCH3), 2.30
(br s, 2 H, NH2), 1.27 (t, 6 H, J = 7.1 Hz, OCOCH2CH3).
13C NMR (CDCl3): = 171.1, 159.9, 129.5, 128.9, 127.4, 120.7,
111.6, 68.4, 62.0, 55.5, 13.9.
Anal. Calcd for C13H16FNO4: C, 57.99; H, 5.99; N, 5.20. Found: C,
57.71; H, 5.99; N, 4.91.
Diethyl 2-Amino-2-(4-chlorophenyl)-malonate (8g)
Following the general procedure using 1-chloro-4-iodobenzene
(954 mg, 4 mmol) and performing the halogen-metal exchange at
0 °C.
Synthesis 2002, No. 1, 63–66 ISSN 0039-7881 © Thieme Stuttgart · New York