Synthesis of Functionalized Nitroarylmagnesium Halides
SCHEME 14
SCHEME 15
CDCl3, 25 °C) δ 148.1, 142.3, 140.0, 132.7, 129.8, 91.4, 69.1,
38.1, 31.4, 25.7, 22.5, 14.0. MS (70 eV, EI), m/z (%) 349 (not
detectable), 332 (2) [M - OH]+, 278 (100), 261 (16), 229 (24),
203 (4), 76 (3). IR (KBr) ν˜ 1529, 1466, 1347, 1054, 869, 832.
HRMS for C12H16INO3 (332.0148 [M - OH]+) found 332.0169
[M - OH]+. C12H16INO3 required: C, 41.28; H, 4.62; I, 36.35;
N, 4.01. Found: C, 41.66, H, 4.32; I, 36.76; N, 4.00.
Pd(dba)2 (5 mol %) and tfp (10 mol %) furnished biphenyl
29a at ambient temperature within 2 h in 68% yield
(Scheme 14).
Mesitylmagnesium bromide did not lead to the desired
Grignard species, but to the reductive addition to the
nitro group, hampering further reactions. However, the
use of an excess of an electron-poor aryl iodide, such as
4-iodobenzonitrile (21h), led to the formation of biaryl
29b in 83% isolated yield (Scheme 15).
In summary, we have shown that the I/Mg exchange
is a very powerful tool for the preparation of functional-
ized aromatic and heteroaromatic Grignard reagents
bearing a nitro group. The reaction conditions for this
exchange are compatible with the presence of a broad
variety of other functional groups, allowing the prepara-
tion of highly functionalized arylmagnesium halides
bearing nitro groups. Moreover, the reactivity of these
Mg reagents is fine-tuned by transmetalations with
transition metal salts expanding the scope of this reaction
considerably. Further applications of this methodology
are currently underway in our laboratories.
Representative Procedure for the Performance of an
Iodine-Magnesium Exchange Reaction on Functional-
ized m- and p-Iodonitroarenes: Synthesis of Ethyl 2-Al-
lyl-5-nitrobenzoate (26b): A dry argon-flushed 25-mL flask,
equipped with a magnetic stirrer and a septum, was charged
with ethyl 2-iodo-5-nitrobenzoate (1i) (321 mg, 1.00 mmol). Dry
THF (4 mL) was added, the mixture was cooled to -78 °C,
and PhMgCl (0.66 mL, 1.1 mmol, 1.6 M in THF) was added
dropwise. On completion of the I/Mg exchange (10 min,
checked by GC analysis of reaction aliquots) CuCN‚2LiCl (1.1
mL, 1.1 mmol, 1.0 m in THF) was added dropwise. The
reaction mixture was stirred for 5 min and allyl bromide (240
mg, 2.00 mmol) was added. The reaction mixture was stirred
for 2 h at -78 °C, the cooling bath was removed, and the
reaction mixture was quenched with saturated NH3/NH4Cl(aq)
(5 mL) and poured into water. The aqueous phase was
extracted with ethyl acetate (2 × 40 mL). The collected organic
phases were washed with brine (30 mL), dried (Na2SO4),
filtered, and concentrated in vacuo. Purification by flash
chromatography (pentane/diethyl ether ) 29:1) yielded the
title compound 26b (204 mg, 87%) as a yellow oil. 1H NMR
Experimental Section
Representative Procedure for the Performance of an
Iodine-Magnesium Exchange Reaction on Functional-
ized o-Iodonitroarenes: Synthesis of 1-(4-iodo-2-nitro-
phenyl)-1-hexanol (9m): A dry and argon-flushed 25-mL
flask equipped with a magnetic stirrer and a septum was
charged with 2,5-diiodonitrobenzene (1m) (562 mg, 1.50 mmol).
Dry THF (5 mL) was added, the mixture was cooled to -40
°C, and PhMgCl (0.80 mL, 1.6 mmol, 2.0 M in THF) was added
dropwise. On completion of the I/Mg exchange (5 min, checked
by GC analysis of reaction aliquots), hexanal (10c; 201 mg,
2.00 mmol) was added dropwise. The reaction mixture was
stirred for 30 min at -40 °C, the cooling bath was removed,
and the mixture was stirred for an additional 30 min at room
temperature. The reaction mixture was quenched with satu-
rated NH4Cl(aq) (2 mL) and poured into water (25 mL) and the
aqueous phase was extracted with ethyl acetate (2 × 40 mL).
The collected organic phases were washed with brine (30 mL),
dried (Na2SO4), and concentrated in vacuo. Purification by
flash chromatography (pentane/diethyl ether ) 9:1) yielded the
title compound 9m (480 mg, 86%) as a pale yellow oil. 1H NMR
4
(300 MHz, CDCl3, 25 °C) δ 8.70 (d, J(H,H) ) 2.7 Hz, 1 H),
3
4
8.24 (dd, J(H,H) ) 8.9 Hz, J(H,H) ) 2.7 Hz, 1 H), 7.46 (d,
3J(H,H) ) 8.9 Hz, 1 H), 6.03-5.89 (m, 1 H), 5.12-5.00 (m, 2
H), 4.39 (q, 3J(H,H) ) 7.1 Hz, 2 H), 3.84 (d, 3J(H,H) ) 6.6 Hz,
2 H), 1.40 (t, 3J(H,H) ) 7.1 Hz, 3 H). 13C NMR (75 MHz, CDCl3,
25 °C) δ 165.5, 148.9, 146.2, 135.6, 132.0, 131.2, 126.1, 125.7,
117.1, 61.8, 38.2, 14.2. MS (70 eV, EI), m/z (%) 235 (23) [M+],
220 (35), 207 (34), 192 (100), 179 (11), 160 (12), 144 (8), 115
(42), 89 (5). IR (KBr) ν˜ 1727, 1525, 1479, 1445, 1350, 1252.
HRMS for C12H13NO4 (235.0845) found 235.0845.
Representative Procedure for Synthesis of Nitro-
Substituted Polyfunctional Biphenyls by Negishi Cross-
Coupling of o-Nitroarylzinc Reagents: Synthesis of
Ethyl 2′,4′-Dinitrobiphenyl-4-carboxylate (22c): A dry
argon-flushed 25-mL flask, equipped with a magnetic stirrer
and a septum, was charged with 1-iodo-2,4-dinitrobenzene (1b;
441 mg, 1.50 mmol), dry THF (6 mL) was added, the mixture
was cooled to -40 °C, and mesitylmagnesium bromide (2.5 mL,
1.7 mmol, 0.72 M in THF) was then added dropwise. On
completion of the I/Mg exchange (1 min, checked by GC
analysis of reaction aliquots) zinc bromide (1.6 mL, 1.6 mmol,
1.0 M in THF) was added dropwise and the reaction mixture
was stirred for 5 min. In the meantime, another dry two-
4
(300 MHz, CDCl3, 25 °C) δ 8.21 (d, J(H,H) ) 1.8 Hz, 1 H),
3
4
7.96 (dd, J(H,H) ) 8.4 Hz, J(H,H) ) 1.8 Hz, 1 H), 7.55 (d,
3J(H,H) ) 8.4 Hz 1 H), 5.22-5.18 (m, 1 H), 2.47 (s-br, 1 OH),
1.83-1.27 (m, 8 H), 0.92-0.88 (m, 3 H). 13C NMR (75 MHz,
J. Org. Chem, Vol. 70, No. 7, 2005 2453