Zincation of N-Phenylpyrrole
FULL PAPER
This compound could result from the release of LiTMP
toluene were distilled after drying over P
pared by using a described procedure.
4
33]
O
10. ZnCl
Nuclear magnetic resonance
spectra were acquired on a Bruker ARX 200 spectrometer (200 MHz and
2
·TMEDA was pre-
[
from the expected lithium–zinc mixed intermediate A (see
1
13
Scheme 1). H and C NMR analysis seem to show that the
complex 5 is also the main species in solution.
1
13
5
0 MHz for H and C, respectively). Chemical shifts are given in ppm
as d values relative to tetramethylsilane. The ratios were determined
1
The reaction was finally conducted by using in situ pre-
pared bis(2,2,6,6-tetramethylpiperidino)zinc (0.5 equiv), and
.10, 0.25, 0.40, or 0.60 equivalents of LiTMP (Table 6). The
from the H NMR integration values. High-resolution mass spectral
measurements were performed at the CRMPO in Rennes (Centre RØ-
gional de Mesures Physiques de l’Ouest) by using a Micromass MS/MS
ZABSpec TOF instrument in EI mode.
0
Metalation procedure by using the in situ prepared mixture of
ZnCl ·TMEDA and LiTMP: To a stirred, cooled (08C) solution of
2
2,2,6,6-tetramethylpiperidine (0.53 mL, 3.0 mmol) in hexane (5 mL) were
successively added BuLi (1.6m solution in hexanes, 3.0 mmol), TMEDA
Table 6. Metalation of 1 by using in situ prepared bis(2,2,6,6-tetramethyl-
piperidino)zinc (0.5 equiv) in the presence of substoichiometric amounts
of LiTMP.
(
1.5 mL, 10 mmol), and ZnCl
2
·TMEDA (0.25 g, 1.0 mmol). The mixture
was stirred for 15 min at 08C before introduction of N-phenylpyrrole (1,
0
3
.29 g, 2.0 mmol). After 2 h at room temperature, a solution of I
.0 mmol) in THF (5 mL) was added. The mixture was stirred overnight
(2 mL) and
extraction with EtOAc (315 mL). The combined organic layers were
dried over MgSO , filtered, and concentrated under reduced pressure.
-Iodo-N-phenylpyrrole (2): Compound 2 was obtained according to the
metalation procedure and was isolated after purification by flash chroma-
tography on silica gel (heptane/CH Cl : 80/20) as a colorless oil (0.41 g,
5%) which rapidly turned brown (decomposition by loss of iodine).
2
(0.76 g,
[
a]
[b]
2 2 3
before addition of an aqueous saturated solution of Na S O
Entry
x equiv LiTMP
1/2 ratio
1
2
3
4
0.10
0.25
0.40
0.60
84/16
50/50
20/80
5/95
4
2
2
2
[
[
a] Very small amounts of the iodides 3 and 4 were detected (<5%).
b] Ratios determined from the integration values of the H NMR spectra
7
1
1
3
H NMR (CDCl ): d=6.32 (dd, J=3.0 and 3.6 Hz, 1H), 6.53 (dd, J=1.8
of the crude reaction mixtures.
and 3.6 Hz, 1H), 7.02 (dd, J=1.8 and 3.0 Hz, 1H), 7.41 ppm (m, 5H);
1
3
C NMR (CDCl
2C), 140.9 ppm; HRMS: 1 and I
unstable. Data for 1: m/z: calcd: 143.0735 [M ]; found: 143.0721.
3
): d=69.1, 111.9, 120.5, 125.9, 127.0 (2C), 128.0, 128.9
were detected instead of 2, which is
(
2
+
results show that the zinc diamide cannot be satisfactorily
used in the presence of substoichiometric amounts of
2-Iodo-N-(2-iodophenyl)pyrrole (3): Compound 3 was identified in crude
1
[29]
mixtures. H NMR (CDCl ): d=6.28 (dd, J=3.2 and 3.4 Hz, 1H), 6.53
LiTMP.
3
(
(
dd, J=1.4 and 3.4 Hz, 1H), 7.02 (dd, J=1.4 and 3.2 Hz, 1H), 7.08–7.43
m, 3H), 7.89 ppm (d, J=8.0 Hz, 1H).
N-(2-Iodophenyl)pyrrole (4): Compound 4 was identified in crude mix-
Conclusion
1
tures. H NMR (CDCl
3
): d=6.34 (t, J=2.1 Hz, 2H), 6.81 (t, J=2.1 Hz,
2
H), 7.10 (ddd, J=1.8, 7.8, and 7.8 Hz, 1H), 7.30 (dd, J=1.8 and 7.8 Hz,
Metalation of N-phenylpyrrole by using an in situ mixture
1H), 7.41 (ddd, J=1.3, 7.8, and 7.8 Hz, 1H), 7.94 ppm (dd, J=1.3 and
1
3
7
.8 Hz, 1H); C NMR (CDCl
3
): d=96.0, 109.3 (2C), 122.3 (2C), 128.2,
of ZnCl ·TMEDA (0.5 equiv) and LiTMP (1.5 equiv) has
2
1
ture.
29.1, 129.5, 140.1, 144.1 ppm. These values are consistent with the litera-
been optimized. Hexane containing a (hemi)labile lithium
ligand proved to be a better solvent than bulk ethers for this
lithium-mediated zincation. To save 2,2,6,6-tetramethylpi-
[
34]
Bis(2,2,6,6-tetramethylpiperidino)zinc: To a stirred, cooled (08C) solution
of 2,2,6,6-tetramethylpiperidine (1.0 mL, 6.0 mmol) were successively
added BuLi (2.0m solution in cyclohexane, 6.0 mmol) and
peridine, an in situ prepared mixture of ZnCl ·TMEDA
2
(
0.5 equiv), LiTMP (1.0 equiv), and BuLi (0.5 equiv) was
ZnCl ·TMEDA (0.76 g, 3.0 mmol). After addition of THF (10 mL), the
2
1
3
tested with success. When used in hexane containing five
equivalents of TMEDA at room temperature, the in situ
mixture of ZnCl ·TMEDA (0.5 equiv) and LiTMP
mixture was stirred for 15 min at 08C. C NMR (C
6.7 (8C), 39.5 (4C), 53.0 ppm (4C).
6 6
D ): d=19.5 (2C),
3
Metalation procedure by using LiTMP: To a stirred, cooled (08C) solu-
tion of 2,2,6,6-tetramethylpiperidine (0.35 mL, 2.0 mmol) in hexane
2
(
1.5 equiv) gave better results (92% conversion after two
(
5 mL) were successively added BuLi (1.6m hexanes solution, 2.0 mmol)
and TMEDA (1.5 mL, 10 mmol). The mixture was stirred for 15 min at
8C before introduction of N-phenylpyrrole (1, 0.29 g, 2.0 mmol). After
2 h at room temperature, a solution of I2 (0.51 g, 2.0 mmol) in THF
5 mL) was added. The mixture was stirred overnight before addition of
an aqueous saturated solution of Na (2 mL) and extraction with
EtOAc (315 mL). The combined organic layers were dried over
MgSO , filtered, and concentrated under reduced pressure. A 1/2 ratio of
0:20 was estimated from the integration values of the crude reaction
hours) than LiTMP (1 equiv, 20% conversion after two
hours) and its corresponding zinc diamide (no conversion).
In addition to the synergic chemistry it exhibits, the 1:3 in
situ mixture of ZnCl ·TMEDA and LiTMP could be useful
in synthetic applications in the metalation of sensitive and/
or functionalized substrates such as bare diazines,
which reaction with classical lithium amides,
lithium–magnesium amides can hardly be performed due
to competitive nucleophilic addition reactions.
0
(
2
2 2 3
S O
[30]
for
4
[31]
or mixed
8
[32]
1
mixture H NMR spectrum.
Crystallography: Crystals of 5 were obtained according to the metalation
procedure, but by using cyclohexane instead of hexane, and with an addi-
tional amount of THF (10 mL). Single crystals suitable for X-ray diffrac-
1
tion were grown after storage for several days at 48C. H NMR (C
6
D
6
):
Experimental Section
d=1.90 (brs, 16H), 6.36 (m, 2H), 6.50 (t, J=2.8 Hz, 2H), 7.10 (m, 8H),
1
3
7
6 6
.74 ppm (d, J=7.8 Hz, 4H); C NMR (C D ): d=111.0 (2C), 120.4
All reactions were performed in Schlenk tubes under argon atmosphere.
THF and DEE were distilled over sodium/benzophenone. Hexane and
(2C), 121.3 (2C), 124.0 (4C), 124.5 (2C), 129.5 (4C), 140.6 (2C),
147.0 ppm (2C).
Chem. Eur. J. 2007, 13, 9982 – 9989
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9987