LETTER
Grignard Formation of Aryl Chlorides
1599
Mg (turnings)
THF, I2, MW
100 °C, 60 min
MgBr
Br
4
1n
1) 4 mol% Pd(dba)2
8 mol% t-Bu3PHBF4
MW, 80 °C, 30 min
O
O
S
N
N
Br
O
O
S
N
N
4
2) 2.2 M HCl/Et2O
r.t., 45 min
O
O
HO OH
5
6
67 %
Scheme 3
Procedure for Kumada Coupling Using Aryl Chlorides
In conclusion, this study demonstrates the possibility of
performing the Grignard reaction with reluctant aryl chlo-
rides using a microwave heating protocol in a reliable
manner. The transformations can be conducted without
the necessity of entrainment carriers23 or sophisticated re-
agents like Rieke’s magnesium.24,25 The benefits of the
methodology have been illustrated in the rapid synthesis
of a novel HIV-1 protease inhibitor.
2-Chloronaphthalene (0.25 mmol, 41 mg), Pd(dba)2 (5 mmol, 3 mg),
t-Bu3PHBF4 (10 mmol, 3 mg) were placed in a 5 mL process vial.
Grignard reagent prepared from o-chloroanisole (1 mmol, 143 mg)
following the procedure outlined in Table 1, was added via syringe
and the reaction mixture was heated in the microwave at 160 °C for
20 min. After addition of 0.1 M HCl (30 mL), the reaction mixture
was extracted with CH2Cl2. Subsequent evaporation of the organic
solvent under reduced pressure and flash column chromatography
using 9:1 isohexane–CH2Cl2 as the eluent, yielded the pure product
3 in 87% yield as a white solid (>95% purity by 1H NMR and GC-
MS). Spectral data were consistent with that within the literature.32
The microwave reactions were performed in a SmithSynthesizer
producing controlled radiation at 2450 MHz with a power of 0–300
W. The reaction temperature and pressure were determined using
the built-in on-line sensors. 1H NMR and 13C NMR spectra were re-
corded at 399.8 and 100.6 MHz, respectively. Chemical shifts are
reported as d values (ppm) and indirectly referenced to TMS via the
solvent residual signal. Analytical HPLC/MS was performed using
a Chromolith SpeedROD RP-18e column, 50 × 4.6 mm (4 mL/min,
20–100% MeCN in H2O, 3 min gradient) employing UV detection
(214 and 254 nm) and a mass selective detector (ESI). GC-MS was
performed with an instrument equipped with a mass selective detec-
tor (EI, 70 eV) and a CP-SIL 5 CB Low bleed column (30 m × 0.25
mm) to analyze conversion and reaction mixture composition. THF
was freshly distilled over Na/benzophenone. All other chemicals
were commercially available and used as received. Compounds
2a,26 2b,27 2c,28 2d,29 2e,26 2f,26 2g,30 2h,31 2i,31 2j,27 and 332 were
previously described. Compound 5 was prepared following a litera-
ture procedure.33 Spectral data were in agreement with the proposed
structures.
3,4,5,6-Tetrahydro-(4S,5S)-2-[2-(4-benzylphenyl)benzyl]-7-
benzyl-4,5-dihydroxy-1,2,7-thiadiazepine 1,1-dioxide (6)
Compound 5 (0.041 mmol, 20 mg), Pd(dba)2 (1.7 mmol, 1 mg) and
t-Bu3PHBF4 (3.4 mmol, 1 mg) were transferred to a 5 mL process
vial and capped with a Teflon coated septum. Grignard reagent 4,
prepared using the General Method starting from (4-bromophe-
nyl)phenylmethane (0.33 mmol, 82 mg), was added via syringe and
the reaction mixture was microwave heated at 80 °C for 30 min. Af-
ter cooling, the reaction mixture was filtered through Celite and
concentrated under reduced pressure, followed by flash column
chromatography using 1:4 iso-hexane–CH2Cl2 as the eluent. The
protective group was removed using 2.2 M HCl/Et2O (1 mL) and
MeOH (2 mL) at r.t. for 45 min. Concentration and flash column
chromatography using 1% MeOH in CH2Cl2 furnished the pure
product in 67% yield over two steps as a white solid; mp 65–68 °C.
LC-MS: tR = 2.18 min, m/z = 529 [M + H+]. 1H NMR (acetone-d6):
d = 7.68 (ddd, J = 0.69, 1.42, 7.72 Hz, 1 H), 7.45–7.18 (m, 17 H),
4.69 (d, J = 16.4 Hz, 1 H), 4.65 (d, J = 15.8 Hz, 1 H), 4.49 (d,
J = 16.4 Hz, 1 H), 4.48 (d, J = 15.8 Hz, 1 H), 4.17 (d, J = 4.5 Hz, 1
H), 4.10 (d, J = 4.3 Hz, 1 H), 4.05 (s, 2 H), 3.52 (m, 1 H), 3.38 (m,
1 H), 3.25 (ddd, J = 1.2, 9.9, 14.9 Hz, 1 H), 3.21 (ddd, J = 1.2, 9.7,
15.1 Hz, 1 H), 3.06 (dd, J = 3.5, 15.1 Hz, 1 H), 2.97 (dd, J = 3.1,
14.9 Hz, 1 H). 13C NMR (acetone-d6): d = 142.6, 142.2, 141.5,
139.3, 138.5, 135.6, 130.9, 130.1, 129.8, 129.7, 129.4, 129.3, 128.9,
128.8, 128.6, 128.4, 128.1, 126.9, 73.1, 72.9, 53.1, 50.9, 49.0, 48.6,
42.1. Anal. Calcd for C31H32N2O4S (%): C, 70.43; H, 6.10; N, 5.30.
Found: C, 70.21; H, 6.29; N, 5.19.
General Method for Synthesis of Grignard Reagents from Aryl
Halides and Subsequent Addition of Benzaldehyde
Aryl halide, 1 (1.0 mmol), Mg turnings (4.0 mmol, 97 mg), I2 (one
crystal) were mixed in a process vial under air and immediately
capped with a Teflon coated septum. The vial was set under vacuum
and back filled with nitrogen gas, in order to remove humid air. THF
(2.5 mL) was added via a syringe. The microwave synthesizer was
set to the required temperature for 60 min (see Table 1). After Grig-
nard formation, the benzaldehyde was added (0.5 mmol, 53 mg,
condition A; or 1.0 mmol, 106 mg, condition B) directly to the re-
action mixture with a syringe and additionally heated for 30 min at
100 °C. After cooling, the reaction mixture was acidified with 0.1
M HCl (30 mL) and extracted with CH2Cl2. The organic solvent was
evaporated under reduced pressure. The residue was purified by
flash column chromatography, using 4:1 to 1:4 iso-hexane–CH2Cl2
as the eluent, providing the diarylmethanol products 2 (>95% purity
by 1H NMR and GC-MS).
Acknowledgment
We acknowledge the financial support from the Swedish Research
Council and from Knut and Alice Wallenberg’s Foundation. We
thank Peter Fritzon for laboratory assistance, Shane Peterson for
linguistic advice and Biotage AB for providing the SmithSynthesi-
zer. We would like also to thank Lotta Vrang and Bertil Samuelsson
and Medivir AB for the biological evaluation.
Synlett 2005, No. 10, 1596–1600 © Thieme Stuttgart · New York