PRACTICAL SYNTHETIC PROCEDURES Oxidative Homocoupling of Aryl, Alkenyl, and Alkynyl Grignards
2469
TEMPO, THF
–6 h, reflux
Ethyl 4-(Ethoxycarbonylphenyl)benzoate (2m); Typical Proce-
dure
i-PrMgCl·LiCl in THF (1.95 M, 1.1 mL, 2.1 mmol, 1.05 equiv) was
added dropwise under stirring to a solution of ethyl 4-iodobenzoate
R
MgCl
R
R
4
2r–x: 65–94%
Scheme 4 Oxidative homocoupling of alkynyl Grignard reagents
(0.33 mL, 2.00 mmol, 1.0 equiv) in anhyd THF (3 mL) at –20 °C
and the stirring was continued at the same temperature for 30 min.
TEMPO (340 mg, 2.16 mmol, 1.08 equiv) was then added and the
resulting mixture was stirred at 0 °C for 2 h. The mixture was then
a
Table 3 Oxidative Homocoupling of RC≡CMgCl with TEMPO
Entry
Diyne
2r
R
Temp (°C) Time (h) Yield (%)
partitioned between MTBE (30 mL) and sat. aq NH Cl (10 mL).
4
The aqueous layer was extracted with MTBE (2 × 30 mL); the com-
bined organic phases were washed with brine (20 mL), dried
1
2
3
4
5
6
7
Ph
Ph
20
66
66
66
66
66
66
72
4
55
90
86
94
94
76
65
(MgSO ), filtered, and concentrated in vacuo. Purification by flash
4
column chromatography on silica gel using MTBE–pentane (1:4) as
2r
2s
4-MeOC H
6
6
eluent provided 2m (262 mg, 88%) as white crystalline solid. Ana-
1
lytical data were in agreement with those reported in the literature.
4
0
2t
4-CF C H
3
5
6
4
1
H NMR (300 MHz, CDCl ): d = 8.12 (d, J = 8.2 Hz, 4 H), 7.64 (d,
3
J = 8.2 Hz, 4 H), 4.41 (q, J = 7.1 Hz, 4 H), 1.42 (t, J = 7.1 Hz, 6 H).
2u
n-C H
6
5
13
1
3
C NMR (75 MHz, CDCl ): d = 165.6 (C), 143.6 (C), 129.6 (CH),
3
2v
c-C H
6
5
11
1
29.5 (C), 126.6 (CH), 60.5 (CH ), 13.8 (CH ).
2
3
2w
TMS
5
Diene 2q; Typical Procedure
i-PrMgCl·LiCl in THF (1.76 M, 0.70 mL, 1.23 mmol, 1.14 equiv)
was added to a stirred solution of 1q (256 mg, 1.08 mmol, 1.0 equiv)
in anhyd THF (0.5 mL) at –30 °C. The stirring was continued at that
temperature for 16 h. A solution of TEMPO (204 mg, 1.3 mmol, 1.2
equiv) in THF (2.5 mL) was then added. The resulting mixture was
refluxed for 25 min. The mixture was then allowed to cool to r.t. and
8
2x
66
5
72
a
Reactions were carried out with TEMPO (1.08 equiv) in THF under
different conditions.
was partitioned between MTBE (30 mL) and sat. aq NH Cl (10
4
mL). The aqueous layer was extracted with MTBE (2 × 30 mL); the
combined organic phases were washed with brine (20 mL), dried
In conclusion, we have presented a practical method for
highly efficient oxidative homocoupling of various alkyl,
alkenyl, and alkynyl Grignard reagents by using stoichio-
metric amounts of TEMPO as an organic environmentally
benign commercially available oxidant. No transition
metals were necessary to perform these C–C bond form-
ing reactions. Various functional groups were tolerated
under the applied conditions.
(MgSO ), filtered, and concentrated in vacuo. Purification by flash
4
column chromatography on silica gel using pentane as eluent pro-
vided 2q (77 mg, 64%). Analytical data were in agreement with
11
those reported in the literature.
1
H NMR (300 MHz, CDCl ): d = 5.95–6.05 (m, 2 H), 5.52–5.64 (m,
3
2 H), 2.05 (q, J = 6.9 Hz, 4 H), 1.29–1.37 (m, 16 H), 0.89 (t, J = 6.6
Hz, 6 H).
1
3
C NMR (75 MHz, CDCl ): d = 132.4 (CH), 130.4 (CH), 32.6
3
(
CH ), 31.8 (CH ), 29.4 (CH ), 28.9 (CH ), 22.6 (CH ), 14.1 (CH ).
2 2 2 2 2 3
Experiments were easy to perform by using standard argon atmo-
sphere technology in flame-dried glassware using anhyd THF. Most
of the starting materials were commercially available and were used
as received. Reactions were readily monitored by GC analysis. All
compounds reported in this synthetic practical procedure article
were known and spectroscopic data of the compounds prepared
Diyne 2v; Typical Procedure
i-PrMgCl in THF (1.93 M, 1.1 mL, 2.1 mmol, 1.05 equiv) was add-
ed to cyclohexylacetylene (0.22 mL, 2.0 mmol, 1.0 equiv) in anhyd
THF (3 mL) at 0 °C. The resulting reaction mixture was stirred at
r.t. for 2 h. Then TEMPO (339 mg, 2.16 mmol, 1.08 equiv) was add-
ed and the resulting mixture was refluxed for 5 h. After cooling to
r.t., the mixture was partitioned between MTBE (30 mL) and sat. aq
8
–15
were in agreement with those reported in literature.
Biphenyl (2a); Typical Procedure
PhMgBr (2.00 mL, 1.54 mmol, 1.00 equiv) was added to a stirred
solution of TEMPO (261 mg, 1.66 mmol, 1.08 equiv) in anhyd THF
(3 mL) at r.t. The resulting reaction mixture was subsequently re-
fluxed for 5 min. After cooling to r.t., the mixture was partitioned
NH Cl (10 mL). The aqueous layer was extracted with MTBE (2 ×
4
3
mL), dried (MgSO ), filtered, and concentrated in vacuo. Purifica-
0 mL); the combined organic phases were washed with brine (20
4
tion by flash column chromatography on silica gel using pentane as
eluent provided 2v (161 mg, 76%) as a white crystalline solid. An-
alytical data were in agreement with those reported in the litera-
between methyl tert-butyl ether (MTBE, 30 mL) and sat. aq NH Cl
4
(10 mL). The aqueous layer was extracted with MTBE (2 × 30 mL);
the combined organic phases were washed with brine (20 mL),
1
5
ture.
dried (MgSO ), filtered, and concentrated in vacuo. Purification by
4
1
H NMR (300 MHz, CDCl ): d = 2.38–2.46 (m, 2 H), 1.65–1.80 (m,
3
flash column chromatography on silica gel using pentane as eluent
provided 2a (116 mg, 98%) as a white crystalline solid. Analytical
data were in agreement with those reported in the literature.
8
H), 1.22–1.54 (m, 12 H).
C NMR (75 MHz, CDCl ): d = 81.8 (C), 65.1 (C), 32.3 (CH ),
3 2
1
3
8
2
9.5 (CH), 25.7 (CH ), 24.8 (CH ).
2 2
1
H NMR (300 MHz, CDCl ): d = 7.64–7.67 (m, 4 H), 7.47–7.52 (m,
3
4
H), 7.37–7.42 (m, 2 H).
1
3
Acknowledgment
C NMR (75 MHz, CDCl ): d = 141.2 (C), 128.7 (CH), 127.2 (C),
3
1
27.1 (CH).
A.S. thanks Novartis Pharma AG for financial support (Novartis
Young Investigator Award). We thank the NRW Graduate School
of Chemistry for providing a scholarship to M.S.M.
Synthesis 2009, No. 14, 2467–2470 © Thieme Stuttgart · New York