Magnesiation of functionalized iodobenzenes at room temperature: Clarification of the stability of ethoxycarbonylphenylmagnesium iodides

Article abstract of DOI:10.1016/j.tetlet.2003.12.136

Magnesiation of functionalized aromatic halide, ethyl 3- or 4-iodobenzoate, was accomplished using active magnesium. The resulting phenylmagnesium iodides decomposed little by little in proportion to extension of the reaction time at room temperature. The

Full text of DOI:10.1016/j.tetlet.2003.12.136

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1915–1917
Magnesiation of functionalized iodobenzenes at room temperature:
clarification of the stability of ethoxycarbonylphenylmagnesium
iodides
Osamu Sugimoto,* Keiji Aoki and Ken-ichi Tanji*
Laboratory of Organic Chemistry, School of Food and Nutritional Sciences, University of Shizuoka, 52-1 Yada,
Shizuoka 422-8526, Japan
Received 5 November 2003; revised 20 December 2003; accepted 25 December 2003
Abstract—Magnesiation of functionalized aromatic halide, ethyl 3- or 4-iodobenzoate, was accomplished using active magnesium.
The resulting phenylmagnesium iodides decomposed little by little in proportion to extension of the reaction time at room tem-
perature. The magnesiation followed by addition of carbonyl compounds gave the corresponding adducts in good to moderate
yields.
Ó 2004 Elsevier Ltd. All rights reserved.
Metalation of an aromatic compound is a useful tech-
nique to introduce an electrophilic substituent into an
aromatic moiety. Especially, since arylmagnesium halide
is stable and has mild reactivity compared to aryl-
lithium, preparation of functionalized arylmagnesium
compounds has been developed by many chemists.1–7
The halogen–magnesium exchange, reaction of the cor-
responding aryl halide with other Grignard reagent
(RMgX)1–5 or trialkylmagnesates (R3MgLi),6;7 is a
popular method to generate functionalized arylmagne-
sium compounds. However, the halogen–magnesium
exchange reaction requires low temperature (between
)20 and )78 °C) because the Grignard reagent is reac-
tive with functional groups such as an ester group.
Another magnesiating method, oxidative addition of
magnesium into functionalized bromobenzene deriva-
tives was reported by Lee et al.8 In the paper the
magnesiation of tert-butyl bromobenzoates using active
magnesium (MgÃ) was accomplished at )78 °C, but the
magnesiation of ethyl or methyl bromobenzoates failed
at the temperature. They speculated that a possible
explanation might be the coordination of the ester group
to the magnesium surface, blocking the active sites of
the metal and thus preventing the oxidative addition
step. So we performed the magnesiation of ethyl 4-iodo-
benzoate (1), ethyl 3-iodobenzoate (2), and ethyl
2-iodobenzoate (3), which are more reactive than the
bromo compounds toward metalation. As shown in
Scheme 1, magnesiation9 of 1, 2, and 3 using MgÃ10
between )70 and )60 °C was accomplished followed by
quenching with water to afford ethyl benzoate in 71%,
76%, 72%, respectively.
Lee et al.8 also described that raising the temperature to
)50 °C permitted the magnesiation of bromobenzoic
acid esters, but at the higher temperatures, more
byproducts were formed, which limited the scope of the
reaction. In order to clarify the reaction temperature–
yield relationship, magnesiation of 1, 2, and 3 was car-
ried out under various temperatures. To our surprise,
the magnesiation of 1 and 2 proceeded at several tem-
peratures ()70, )40, )10, and 25 °C) and it was found
that the resulting Grignard reagents are stable for 10–
30 min even at room temperature. On the contrary,
Keywords: Magnesiation; Grignard reagent; Active magnesium.
* Corresponding authors. Tel.: +81-54-264-5545; fax: +81-54-264-5099
(O.S.); tel./fax: +81-54-264-5542 (K.T.); e-mail addresses: osamu@
smail.u-shizuoka-ken.ac.jp; tanji@smail.u-shizuoka-ken.ac.jp
Scheme 1. Magnesiation of ethyl iodobenzoates using MgÃ.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.136

1916
O. Sugimoto et al. / Tetrahedron Letters 45 (2004) 1915–1917
Table 1. Reaction temperature–yield relationship in the magnesiation
of ethyl iodobenzoates followed by addition of water
Table 2. Reaction time–yield relationship in the magnesiation of ethyl
iodobenzoates at 25 °C followed by addition of water
Entry
Substrate
Time
Yield (%)
Entry
Substrate
Condition
Yield (%)
1
2
3
4
5
6
7
1
1
1
2
2
2
3
1 min
2 h
63
39
8
1
2
3
4
5
6
7
8
9
1
1
1
2
2
2
3
3
3
)40 °C, 10 min
)10 °C, 10 min
25 °C, 30 min
)40 °C, 10 min
)10 °C, 10 min
25 °C, 10 min
)40 °C, 10 min
)10 °C, 10 min
25 °C, 10 min
68
67
61
70
68
53
66
21a
0
18 h
1 min
2 h
59
35
9
18 h
1 min
22
a As a mixture with inseparable byproducts.
formed at )10 or 25 °C, whereas at )40 °C or lower
temperature the product was obtained in good yields
(Table 1).
Next, the magnesiation of 1, 2, and 3 at 25 °C for vari-
ous reaction times was carried out. As shown in Table 2,
magnesiation of 3 showed interesting results: Yield of
the product declined when the magnesiation was per-
Table 3. Magnesiation of ethyl iodobenzoates followed by addition of carbonyl compounds
Entry
Substrate
Electrophile
E
Yield (%)
1
1
1
1
1
1
1
2
2
3
3
3
3
EtCH@Oa
iPrCH@O
tBuCH@O
Ph2C@Oa
Et2C@O
CH(OH)Et
CH(OH)iPr
CH(OH)tBu
C(OH)Ph2
C(OH)Et2
C(OH)iPr2
CH(OH)Et
C(OH)Et2
CH(OH)Et
CH(OH)Et
C(OH)Et2
C(OH)Et2
62
71
39
65
54
29
64
42
0
2
3
4
5
6
iPr2C@Oa
EtCH@O
Et2C@O
7
8
9
EtCH@O
EtCH@O
Et2C@O
10b
11
12b
0
0
Et2C@O
0
a Five equivalents of an electrophile was used.
b Condition: )60 °C, 1 min/)60 °C to rt.

O. Sugimoto et al. / Tetrahedron Letters 45 (2004) 1915–1917
1917
7. Inoue, A.; Kitagawa, K.; Shinokubo, H.; Oshima, K.
J. Org. Chem. 2001, 66, 4333–4339.
8. Lee, J.; Velarde-Ortiz, R.; Guijarro, A.; Wurst, J. R.;
Rieke, R. D. J. Org. Chem. 2000, 65, 5428–5430.
the yield of the product declined in proportion to
extension of the reaction time. It was found the
magnesiation of the substrate 1, 2 was completed in
1 min.
9. General procedure: To a suspension of Mgà (6.00 mmol) in
tetrahydrofuran (30 mL), the substrate (2.4 mmol) was
added at )70 °C and the mixture was stirred for an
appropriate time. The reaction mixture was quenched with
1 N hydrochloric acid, and extracted with ethyl acetate.
The organic layer was dried over sodium sulfate, and
treated with silica gel chromatography to give ethyl
benzoate.
10. Preparation of MgÃ: Under argon atmosphere, a mixture
of lithium wire (ALDRICH, Catalog No. 27,832-7;
83.3 mg, 12.0 mmol), naphthalene (1538 mg, 12.0 mmol),
magnesium chloride powder (ALDRICH, Catalog
No. 24,413-9; 571 mg, 6.00 mmol), and tetrahydrofuran
(30 mL) was stirred at room temperature until lithium was
completely consumed (2–3 h) to give a gray suspension of
Mgà (about 0.2 M). The amount of these reagents may be
used in proportion to that of the substrate.
Table 3 shows the results of the magnesiation of 1, 2,
and 3 at room temperature (25–30 °C) for 1 min fol-
lowed by addition of some carbonyl compounds to give
the products.11 Reaction of 1 and 2 afforded the corre-
sponding adducts in good to moderate yields (entries 1–
8). When a hindered carbonyl compound was used as an
electrophile, yield of the product declined. The rule was
similar to our previous report.12 Magnesiation of 3 fol-
lowed by addition of carbonyl compounds at room
temperature (entries 9 and 11) or )60 °C, and raised to
room temperature (entries 10 and 12) gave no product.
Decomposition of the Grignard reagent would proceed
faster than addition of carbonyl compounds into the
aromatic moiety.
11. Chemical properties of new products: Ethyl 4-(1-hydroxy-
propyl)benzoate: Colorless oil. Bp. 185 °C/11 mmHg.
Anal. calcd for C12H16O3: C, 69.21; H, 7.74. Found: C,
68.90; H, 7.84. Ethyl 4-(1-hydroxy-2-methylpropyl)benzo-
ate: Colorless oil. Bp. 168 °C/12 mmHg. Anal. calcd for
C13H18O3: C, 70.24; H, 8.16. Found: C, 70.00; H, 8.36.
Ethyl 4-(1-hydro-xy-2,2-dimethylpropyl)benzoate: White
solids. Mp. 112–113 °C. Anal. calcd for C14H20O3: C,
71.16; H, 8.53. Found: C, 71.10; H, 8.55. Ethyl 4-
(hydroxydiphenylmethyl)-benzoate: Pale yellow oil. Bp.
255 °C/13 mmHg. Anal. calcd for C22H20O3: C, 79.50; H,
6.06. Found: C, 79.45; H, 6.11. Ethyl 4-(1-ethyl-1-
hydroxypropyl)benzoate: Pale yellow oil. Bp. 180 °C/
11 mmHg. Anal. calcd for C14H20O3: C, 71.16; H, 8.53.
Found: C, 71.12; H, 8.56. Ethyl 4-(1-hydroxy-2-methy-l-1-
[1-methylethyl]propyl)-benzoate: White solids. Mp.
185 °C/12 mmHg. Anal. calcd for C16H24O3: C, 72.69; H,
9.15. Found: C, 72.67; H, 9.15. Ethyl 3-(1-hydroxypro-
pyl)benzoate: Slight yellow oil. Bp. 177 °C/15 mmHg.
Anal. calcd for C12H16O3: C, 69.21; H, 7.74. Found: C,
69.38; H, 7.73. Ethyl 3-(1-ethyl-1-hydroxypropyl)benzoate:
Slight yellow oil. Bp. 178 °C/14 mmHg. Anal. calcd for
C14H20O3: C, 71.16; H, 8.53. Found: C, 71.18; H, 8.48.
12. Sugimoto, O.; Yamada, S.; Tanji, K. J. Org. Chem. 2003,
68, 2054–2057.
In conclusion, we have accomplished a useful and
advantageous method to prepare ethyl ester substituted
phenylmagnesium iodides using active magnesium, at
room temperature and clarified the relationship between
stability of the resulting Grignard reagent and reaction
temperature/reaction time.
References and notes
1. Sapountzis, I.; Knochel, P. J. Am. Chem. Soc. 2002, 124,
9390–9391.
2. Jensen, A. E.; Dohle, W.; Sapountzis, I.; Lindsay, D. M.;
Vu, V. A.; Knochel, P. Synthesis 2002, 565–569.
3. Dohle, W.; Lindsay, D. M.; Knochel, P. Org. Lett. 2001,
3, 2871–2873.
4. Abarbri, M.; Thibonnet, J.; Berillon, L.; Dehmel, F.;
Rottlander, M.; Knochel, P. J. Org. Chem. 2000, 65, 4618–
4634.
5. Boymond, L.; Rottlander, M.; Cahiez, G.; Knochel, P.
Angew. Chem., Int. Ed. 1998, 37, 1701–1703.
6. Kitagawa, K.; Inoue, A.; Shinokubo, H.; Oshima, K.
Angew. Chem., Int. Ed. 2000, 39, 2481–2483.