Selective metallation of thiophene and thiazole rings with magnesium amide base

Article abstract of DOI:10.1039/b007376h

The chemoselective magnesiation of thiophene and thiazole derivatives were reported using magnesium chloride. Organomagnesium compounds were used at relatively higher temperatures. The results showed that hydrogen-magnesium exchange reaction of thiophene derivatives with ⁱPr₂NMgCl proceeded selectively.

Full text of DOI:10.1039/b007376h

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Selective metallation of thiophene and thiazole rings with
magnesium amide base
Manabu Shilai, Yoshinori Kondo* and Takao Sakamoto*
1
Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai,
980-8578, Japan
Received (in Cambridge, UK) 12th September 2000, Accepted 21st December 2000
First published as an Advance Article on the web 22nd January 2001
Selective hydrogen–metal exchange reaction of thiophene and thiazole proceeded smoothly with magnesium amide
base (iPr2NMgCl) under mild conditions.
Hydrogen–metal exchange reaction of aromatic and hetero-
aromatic rings such as directed ortho metallation or direct metal-
lation has been developed as one of the major tools of organic
synthesis.1 Various strong bases such as alkyllithiums or lithium
Scheme 1 Reagents and conditions: i, iPr2NMgCl, THF, rt; ii, Electro-
dialkylamides have been used for hydrogen–metal exchange of
aromatics. However, organolithium compounds show high
reactivity toward electrophilic groups and the use of organo-
lithium compounds as metallating reagents has unavoidable
limitations. For example, electrophilic directing groups often
react with the nucleophilic bases or with the aryllithium inter-
mediates. Directed ortho lithiation, therefore, usually requires
low temperatures such as Ϫ78 ЊC or lower. Besides, directed
ortho lithiations of aromatics bearing an ester functionality have
only proceeded in bulky esters such as neopentyl or isopropyl
esters with less nucleophilic metallating reagents.2
On the other hand, organomagnesium compounds have been
used at relatively higher temperatures such as 0 ЊC or room
temperature. Magnesium amide bases such as Hauser bases
(R2NMgX) and magnesium diamides are known, but their uses
in directed ortho magnesiation have barely been explored. In
1989, Eaton reported directed ortho magnesiation of both
methyl benzoate and N,N-diethylbenzamide with Hauser bases
(iPr2NMgBr or TMPMgBr, TMP = 2,2,6,6-tetramethylpiper-
idino) or magnesium diamides ((iPr2N)2Mg or TMP2Mg).3 In
1995, Schlecker extended this methodology and reported regio-
selective magnesiation of pyridine derivatives.4 In a study of
the scope and limitations of this methodology we reported
the regioselective magnesiation of 1-substituted indoles using
magnesium amide bases.5 Now we report the chemoselective
magnesiation of thiophene and thiazole derivatives using
(diisopropylamino)magnesium chloride (iPr2NMgCl).
phile, THF, rt.
Table 1 Magnesiation of ethyl thiophene-2-carboxylate 1
iPr2NMgCl
(mol equiv.)
Reaction
time
Yield
(%)a
Electrophile
E
1.0
1.0
2.0
2.0
2.0
2.0
2.0
2.0
1 h
24 h
10 min
30 min
1 h
24 h
10 min
10 min
I2
I2
I2
I2
I2
I2
I
I
I
21 (73)
0 (90)
77
I
I
60
52
I
0
52
NFPb
PhCHO
CHO
CH(OH)Ph
60
a Values in parentheses are recovery yields of 1. b NFP = N-formyl-
piperidine.
Scheme 2 Reagents and conditions: i, iPr2NMgCl, THF, rt; ii, Electro-
phile, THF, rt.
Table 2 Magnesiation of thiophene derivatives
Substituent
X
Reaction
time
Yield
(%)
Results and discussion
Electrophile
E
Initially, the metallation of ethyl thiophene-2-carboxylate
i
i
1 with Pr2NMgCl, which was prepared from Pr2NH and
BuMgCl, was investigated. The results are summarized in
Scheme 1 and Table 1. When two mole equivalents of iPr2NMg-
Cl for 1 were used, the metallation proceeded smoothly at room
temperature within 10 min and the arylmagnesium inter-
mediates thus prepared were treated with electrophiles to give
CO2Et
CO2Et
CO2Et
H
H
H
10 min
10 min
10 min
24 h
24 h
24 h
I2
I
94
0
79
52
84
93
NFP
PhCHO
I2
NFP
PhCHO
CHO
CH(OH)Ph
I
CHO
CH(OH)Ph
i
2a–c without nucleophilic attack of Pr2NMgCl or the aryl-
magnesium intermediate at the ethoxycarbonyl group.
Hydrogen–magnesium exchange reaction of ethyl thiophene-2-
4c–e (Scheme 2, Table 2). Though two mole equivalents of
iPr2NMgCl for 3b were used, a disubstituted thiophene was not
detected. These results show that hydrogen–magnesium
exchange reaction of thiophene derivatives with Pr2NMgCl
proceeds selectively.
We turned our attention to the metallation of azoles and then
that of thiazole 5 was investigated (Scheme 3, Table 3). Though
thiazole 5 has three different hydrogens, the regioselective
i
carboxylate with Pr2NMgCl is considered to proceed at the
5-position of the thiophene ring.6 Similarly, the metallation
of ethyl thiophene-3-carboxylate 3a proceeded to give 2,3-
disubstituted thiophenes 4a,b with metallation at the 2-position
selectively (Scheme 2, Table 2). Reaction of unsubstituted
thiophene 3b proceeded to give monosubstituted thiophenes
i
442
J. Chem. Soc., Perkin Trans. 1, 2001, 442–444
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b007376h

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(0.30 cm3, 2.14 mmol) and dry THF (10 cm3) and the mixture
was stirred at rt for 10 min. I2 (638 mg, 2.51 mmol) in dry THF
(5 cm3) was added and the mixture was stirred at rt for 1 h
before being purified by silica gel column chromatography,
using n-hexane–AcOEt (5:1) as solvent. The solvent was
removed to give 2a (231 mg, 77%) as a colorless oil (Found: C,
29.89; H, 2.50; I, 44.62; S, 11.53. C7H7IO2S requires C, 29.80;
H, 2.50; I, 44.99; S, 11.36%); δH 1.36 (3H, t, J 7.2 Hz), 4.33 (2H,
q, J 7.2 Hz), 7.25 (1H, d, J 3.9 Hz), 7.43 (1H, d, J 3.9 Hz); m/z
(EI) 282 (Mϩ).
Scheme 3 Reagents and conditions: i, iPr2NMgCl, THF, rt, 24 h;
ii, Electrophile, THF, rt.
Table 3 Magnesiation of thiazole
Electrophile
E
Yield (%)
Ethyl 5-formylthiophene-2-carboxylate 2b
I2
I
88
51
52
NFP
PhCHO
CHO
CH(OH)Ph
According to general procedure B, ethyl thiophene-2-carboxyl-
ate (159 mg, 1.02 mmol) was added to a mixture of BuMgCl in
THF (0.60 mol dmϪ3; 3.30 cm3, 1.98 mmol), iPr2NH (0.30 cm3,
2.14 mmol) and dry THF (10 cm3) and the mixture was stirred
at rt for 10 min. 1-Formylpiperidine (NFP) (288 mg, 2.54
mmol) was added and the mixture was stirred at rt for 30 h
before being purified by silica gel column chromatography,
using n-hexane–AcOEt (5:1) as solvent. The solvent was
removed to give 2b (99.8 mg, 52%) as colorless prisms, mp 57–
58 ЊC (Found: C, 52.24; H, 4.30; S, 17.53. C8H8O3S requires C,
52.16; H, 4.38; S, 17.40%); δH 1.40 (3H, t, J 7.2 Hz), 4.40 (2H, q,
J 7.2 Hz), 7.75 (1H, d, J 4.2 Hz), 7.84 (1H, d, J 3.9 Hz), 9.98
(1H, s); m/z (EI) 184 (Mϩ).
metallation proceeded at the 2-position at room temperature to
give 2-substituted thiazoles 6a–c.
In summary, selective metallation of thiophene and thiazole
derivatives including those bearing an ester functionality was
i
realized with Pr2NMgCl as a base. In the hydrogen–metal
exchange, magnesium amide bases which can be used near
ambient temperature may have great potential to replace the
corresponding lithium bases for heterocyclic systems.
Experimental
THF was distilled from sodium–benzophenone ketyl before
use. Pr2NH was distilled from CaH2 before use. BuMgCl was
Ethyl 5-[hydroxy(phenyl)methyl]thiophene-2-carboxylate 2c
i
According to general procedure B, ethyl thiophene-2-carboxyl-
ate (228 mg, 1.46 mmol) was added to a mixture of BuMgCl in
THF (0.83 mol dmϪ3; 3.60 cm3, 2.99 mmol), iPr2NH (0.46 cm3,
3.28 mmol) and dry THF (10 cm3) and the mixture was stirred
at rt for 10 min. Benzaldehyde (241 mg, 2.27 mmol) was added
and the mixture was stirred at rt for 23 h before being purified
by silica gel column chromatography, using n-hexane–AcOEt
(2:1) as solvent. The solvent was removed to give 2c (228 mg,
60%) as a yellow, viscous oil, δH 1.34 (3H, t, J 7.1 Hz), 4.30
(2H, q, J 7.1 Hz), 6.00 (1H, s), 6.86 (1H, d, J 3.8 Hz), 7.32–7.44
(6H, m), 7.83 (1H, d, J 3.8 Hz); m/z (EI) 262 (Mϩ) (Found:
Mϩ, 262.0665. C14H14O3S requires M, 262.0663).
titrated using Ph2Te2 before use. Mps were determined on a
Yazawa micro melting-point apparatus and are uncorrected.
1H NMR spectra were recorded on a Varian Gemini-2000
(300 MHz) spectrometer for samples in CDCl3 solution and
chemical shifts are reported in δ (ppm)-values relative to
SiMe4 (TMS) as internal standard. Mass spectra and high-
resolution mass spectra were recorded on a JMX-DX303 and
a JMX-AX500 mass spectrometer. Elemental analyses were
carried out on a Yanaco CHN CORDER MT-5 apparatus.
General procedure A
Under an argon atmosphere, commercial BuMgCl in THF was
added to the mixture of Pr2NH and dry THF at rt and the
Ethyl 2-iodothiophene-3-carboxylate 4a
i
According to general procedure A, ethyl thiophene-3-carboxyl-
ate (158 mg, 1.01 mmol) was added to a mixture of BuMgCl
mixture was stirred at rt for 24 h. A heteroaromatic compound
was added to the mixture at rt and the mixture was stirred at rt.
I2 in dry THF was added at rt and the mixture was stirred at
rt for 1 h, diluted with saturated aq. Na2S2O3 (20 cm3) and
saturated aq. NH4Cl (30 cm3), and extracted with CHCl3 (50
cm3 × 3). The organic layer was dried over dry MgSO4. The
solvent was removed, and the residue was purified by silica gel
column chromatography. The solvent was removed to give a
pure product.
i
in THF (0.90 mol dmϪ3; 2.22 cm3, 1.98 mmol), Pr2NH (0.30
cm3, 2.14 mmol) and dry THF (10 cm3) and the mixture was
stirred at rt for 10 min. I2 (666 mg, 2.62 mmol) in dry THF
(5 cm3) was added and the mixture was stirred at rt for 1 h
before being purified by silica gel column chromatography,
using n-hexane–AcOEt (5:1) as solvent. The solvent was
removed to give 4a (270 mg, 94%) as a colorless oil (Found:
C, 30.15; H, 2.45; I, 44.63; S, 11.84. C7H7IO2S requires C,
29.80; H, 2.50; I, 44.99; S, 11.36%); δH 1.39 (3H, t, J 7.2 Hz),
4.34 (2H, q, J 7.2 Hz), 7.34 (1H, d, J 5.9 Hz), 7.41 (1H, d, J
5.9 Hz); m/z (EI) 282 (Mϩ).
General procedure B
Under an argon atmosphere, commercial BuMgCl in THF was
added to a mixture of iPr2NH and dry THF at rt and the mix-
ture was stirred at rt for 24 h. A heteroaromatic compound was
added to the mixture at rt and the mixture was stirred at rt. An
electrophile was added at rt and the mixture was stirred at rt,
diluted with saturated aq. NH4Cl (50 cm3), and extracted with
CHCl3 (50 cm3 × 3). The organic layer was dried over dry
MgSO4. The solvent was removed, and the residue was purified
by silica gel column chromatography. The solvent was removed
to give a pure product.
Ethyl 2-[hydroxy(phenyl)methyl]thiophene-3-carboxylate 4b
According to general procedure B, ethyl thiophene-3-
carboxylate (161 mg, 1.03 mmol) was added to a mixture of
BuMgCl in THF (0.60 mol dmϪ3; 3.30 cm3, 1.98 mmol), iPr2NH
(0.30 cm3, 2.14 mmol) and dry THF (10 cm3) and the mixture
was stirred at rt for 10 min. Benzaldehyde (265 mg, 2.50 mmol)
was added and the mixture was stirred at rt for 24 h before
being purified by silica gel column chromatography, using n-
hexane–AcOEt (3:1) as solvent. The solvent was removed to
give 4b (213 mg, 79%) as a yellow, viscous oil, δH 1.33 (3H, t,
J 7.1 Hz), 4.31 (2H, q, J 7.1 Hz), 4.76 (1H, br s), 6.42 (1H, s),
7.10 (1H, d, J 5.4 Hz), 7.30–7.49 (6H, m); m/z (EI) 262 (Mϩ)
(Found: Mϩ, 262.0684. C14H14O3S requires M, 262.0663).
Ethyl 5-iodothiophene-2-carboxylate 2a
According to general procedure A, ethyl thiophene-2-
carboxylate (165 mg, 1.06 mmol) was added to a mixture of
BuMgCl in THF (0.60 mol dmϪ3; 3.30 cm3, 1.98 mmol), iPr2NH
J. Chem. Soc., Perkin Trans. 1, 2001, 442–444
443

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2-Iodothiophene 4c
yellow, viscous oil, δH 7.34–7.35 (1H, m), 7.61–7.62 (1H, m);
m/z (EI) 211 (Mϩ) (Found: Mϩ, 210.8995. C3H2INS requires M,
According to general procedure A, thiophene (127 mg, 1.51
mmol) was added to a mixture of BuMgCl in THF (0.61 mol
dmϪ3; 5.00 cm3, 3.05 mmol), iPr2NH (0.44 cm3, 3.14 mmol) and
dry THF (12 cm3) and the mixture was stirred at rt for 24 h. I2
(981 mg, 3.87 mmol) in dry THF (5 cm3) was added and the
mixture was stirred at rt for 1 h before being purified by silica
gel column chromatography, using n-hexane as solvent. The
solvent was removed to give 4c (165 mg, 52%) as a colorless oil
(Found: C, 22.56; H, 1.52; I, 60.36. C4H3IS requires C, 22.87; H,
1.44; I, 60.42%); δH 6.81 (1H, dd, J 3.6, 5.4 Hz), 7.25 (1H, dd,
J 1.5, 3.6 Hz), 7.34 (1H, dd, J 1.5, 5.4 Hz); m/z (EI) 210 (Mϩ).
210.8951).
Thiazole-2-carbaldehyde 6b
According to general procedure B, thiazole (127 mg, 1.49
mmol) was added to a mixture of BuMgCl in THF (0.83 mol
dmϪ3; 3.60 cm3, 2.99 mmol), iPr2NH (0.46 cm3, 3.28 mmol) and
dry THF (12 cm3) and the mixture was stirred at rt for 24 h.
NFP (255 mg, 2.25 mmol) was added and the mixture was
stirred at rt for 24 h before being purified by silica gel column
chromatography, using n-hexane–AcOEt (5:1) as solvent. The
solvent was removed to give 6b (86.4 mg, 51%) as a colorless oil,
δH 7.79 (1H, d, J 2.7 Hz), 8.15 (1H, d, J 2.7 Hz), 10.05 (1H, s);
m/z (EI) 113 (Mϩ) (Found: Mϩ, 112.9935. C4H3NOS requires
M, 112.9921).
Thiophene-2-carbaldehyde 4d
According to general procedure B, thiophene (127 mg, 1.51
mmol) was added to a mixture of BuMgCl in THF (0.60 mol
dmϪ3; 5.00 cm3, 3.00 mmol), iPr2NH (0.46 cm3, 3.28 mmol) and
dry THF (12 cm3) and the mixture was stirred at rt for 24 h.
NFP (440 mg, 3.89 mmol) was added and the mixture was
stirred at rt for 27 h before being purified by silica gel column
chromatography, using n-hexane–AcOEt (5:1) as solvent. The
solvent was removed to give 4d (143 mg, 84%) as a colorless oil,
δH 7.23 (1H, dd, J 3.9, 4.8 Hz), 7.77–7.81 (2H, m), 9.96 (1H, s);
m/z (EI) 112 (Mϩ) (Found: Mϩ, 111.9949. C5H4OS requires
M, 111.9983).
Phenyl(thiazol-2-yl)methanol 6c
According to general procedure B, thiazole (124 mg, 1.47
mmol) was added to a mixture of BuMgCl in THF (0.83 mol
dmϪ3; 3.60 cm3, 2.99 mmol), iPr2NH (0.46 cm3, 3.28 mmol) and
dry THF (12 cm3) and the mixture was stirred at rt for 24 h.
Benzaldehyde (244 mg, 2.33 mmol) was added and the mixture
was stirred at rt for 27 h before being purified by silica gel
column chromatography, using n-hexane–AcOEt (1:1) as
solvent. The solvent was removed to give 6c (146 mg, 52%) as
colorless prisms, mp 109 ЊC (Found: C, 62.98; H, 4.91; N, 7.28;
S, 16.59. C10H9NOS requires C, 62.80; H, 4.74; N, 7.32; S,
16.76%); δH 3.55 (1H, s), 6.08 (1H, s), 7.30–7.50 (6H, m), 7.34
(1H, d, J 3.3 Hz); m/z (EI) 191 (Mϩ).
Phenyl(2-thienyl)methanol 4e
According to general procedure B, thiophene (133 mg, 1.58
mmol) was added to a mixture of BuMgCl in THF (0.60 mol
dmϪ3; 5.00 cm3, 3.00 mmol), iPr2NH (0.46 cm3, 3.28 mmol) and
dry THF (12 cm3) and the mixture was stirred at rt for 24 h.
Benzaldehyde (404 mg, 3.80 mmol) was added and the mixture
was stirred at rt for 24 h before being purified by silica gel
column chromatography, using n-hexane–AcOEt (5:1) as
solvent. The solvent was removed to give 4e (279 mg, 93%) as
colorless prisms, mp 47 ЊC (Found: C, 69.19; H, 5.46; S, 16.99.
C11H10OS requires C, 69.44; H, 5.30; S, 16.85%); δH 2.40 (1H, br
s), 6.09 (1H, s), 6.82–6.96 (2H, m), 7.25–7.47 (6H, m); m/z (EI)
190 (Mϩ).
References
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2-Iodothiazole 6a
According to general procedure A, thiazole (130 mg, 1.53
mmol) was added to a mixture of BuMgCl in THF (0.83 mol
dmϪ3; 3.60 cm3, 2.99 mmol), iPr2NH (0.46 cm3, 3.28 mmol) and
dry THF (12 cm3) and the mixture was stirred at rt for 24 h. I2
(992 mg, 3.91 mmol) in dry THF (5 cm3) was added and the
mixture was stirred at rt for 1 h before being purified by silica
gel column chromatography, using n-hexane–AcOEt (5:1) as
solvent. The solvent was removed to give 6a (284 mg, 88%) as a
6 For discussions on selective lithiation of thiophenes see: (a) R. R.
Fraser, T. S. Mansour and S. Savard, Can. J. Chem., 1985, 63, 3505;
(b) D. W. Knight and A. P. Nott, J. Chem. Soc., Perkin Trans. 1, 1983,
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26, 1777.
444
J. Chem. Soc., Perkin Trans. 1, 2001, 442–444