Preparation of functionalized alkylmagnesium derivatives using an I/Mg-exchange

Article abstract of DOI:10.1021/ol8000987

Functionalized alkylmagnesium reagents bearing an acetal, a ketal, an ester, or a pyridine ring were prepared by an I/Mg-exchange using iPr ₂Mg-LiCI or CIMg(CH₂)₅MgCI-2LiCI starting from functionalized primary alkyl iodides.

Full text of DOI:10.1021/ol8000987

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1187-1189
Preparation of Functionalized
Alkylmagnesium Derivatives Using an
I/Mg-Exchange
Christian B. Rauhut,† Viet Anh Vu,‡ Fraser F. Fleming,‡ and Paul Knochel*,†
Department Chemie und Biochemie, Ludwig-Maximilians-UniVersita¨t, Butenandtstrasse
5-13, 81377, Mu¨nchen (Germany), and Department of Chemistry and Biochemistry,
Duquesne UniVersity, Pittsburgh PennsylVania 15282-1530
Paul.Knochel@cup.uni-muenchen.de
Received January 15, 2008
ABSTRACT
Functionalized alkylmagnesium reagents bearing an acetal, a ketal, an ester, or a pyridine ring were prepared by an I/Mg-exchange using
iPr2Mg LiCl or ClMg(CH2)5MgCl 2LiCl starting from functionalized primary alkyl iodides.
‚
‚
Organomagnesium reagents are important intermediates for
organic synthesis.1 Recently, I/Mg- and Br/Mg-exchange
reactions2 on Csp2-centers have allowed the synthesis of a
range of polyfunctional aryl and hetereoaryl magnesium
compounds.3 Nevertheless, the extension of this exchange
reaction to the preparation of sp3-hybridized alkylmagnesium
reagents failed due to the slow I/Mg-exchange rate of alkyl
iodides. The treatment of nOctI with iPrMgCl‚LiCl leads to
the magnesiated species only in traces and 1-octene is the
main product. An alkoxide-directed I/Mg-exchange was also
reported, but the use of two equivalents of n-BuLi excludes
most functional groups.4 Herein, we report that the presence
of an oxygen or nitrogen atom in γ-position to the carbon-
iodine bond5 considerably enhances the I/Mg-exchange rate.
This sp3-exchange reaction provides the first preparation of
various functionalized alkylmagnesium reagents such as
1a-f starting from the corresponding iodides 2a-f (Scheme
1).6 Performing the I/Mg-exchange reaction with iPrMgCl‚
LiCl leads to a slow and incomplete reaction, but using
iPr2Mg‚LiCl (3)7 (0.75 equiv) for the I/Mg-exchange
allows the formation of the magnesium reagent 1a within 5
h at 25 °C. Quenching with CO2 affords the carboxylic acid
4a with 63% yield (entry 1, Table 1). Although the ex-
change reagent 3 can also be used to prepare other alkyl-
magnesium species such as 1b, 1c, 1e, and 1f (entries 1, 2,
9-14), often an excess of iPr2Mg‚LiCl (3) (up to 1.1 equiv,
corresponding to 2.2 isopropyl units) is required to achieve
full conversion.
† Ludwig-Maximilians-Universita¨t.
‡ Duquesne University.
(1) (a) Knochel, P. In Handbook of Functionalized Organometallics;
Wiley-VCH, 2005. (b) Boudier, A.; Bromm L. O.; Lotz, M.; Knochel P.
Angew. Chem., Int. Ed. 2000, 39, 4415.
(2) (a) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43,
3333. (b) Liu, C.; Ren, H.; Knochel, P. Org. Lett. 2006, 8, 614. (c) Inoue,
A.; Kitagawa, K.; Shinokubo, H.; Oshima, K. J. Org. Chem. 2001, 66, 4333.
(3) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp,
F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003, 115,
4438.
(5) Hoffmann, R. W.; Kusche, A. Chem. Ber. 1994, 127, 1311.
(6) For the preparation of the iodides in most cases the corresponding
alcohols were used: (a) Nicolaou, K. C.; Dai, W. M. J. Am. Chem. Soc.
1992, 114, 3908. (b) Plieninger, H.; Zeltner, M. Chem. Ber. 1987, 108,
3286. (c) Riehs, G.; Urban, E. Tetrahedron 1996, 52, 1221; Rocca, P.
Tetrahedron 1998, 54, 8771. (d) Brocard, J. Annal. Chim. 1972, 7, 387. (e)
Eisch, J. J.; Csaba, A. K.; Chobe, P.; Boleslawski, M. P. J. Org. Chem.
1987, 5, 4427. For more details, see Supporting Information.
(7) Krasovskiy, A.; Straub, B.; Knochel, P. Angew. Chem., Int. Ed. 2006,
45, 159.
(4) Fleming, F. F.; Subrahmanyan, G.; Vu, V. A.; Mycka, R. J.; Knochel,
P. Org. Lett. 2007, 9, 4507.
10.1021/ol8000987 CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/15/2008

Table 1. I/Mg-Exchange of sp3-Hybridized Alkyliodides
Followed by Electrophilic Alkylation
Scheme 1. Grignard Reagents 1a-f Prepared by an I/
Mg-Exchange from the Corresponding Iodides 2a-f
This excess leads to side reactions with the added elec-
trophiles. We have solved this problem by using a 1,5-dimag-
nesium species such as 5 (Scheme 2). After the exchange
reaction with an alkyl iodide (RCH2I), the resulting 5-iodo-
pentylmagnesium chloride (6) undergoes immediately an
intramolecular SN2-substitution leading to cyclopentane 78
and to the desired Grignard reagent RCH2MgCl.
Using the di-Grignard reagent 5 allows the preparation of
the alkylmagnesium chlorides 1b-d in good yields. Thus,
the reaction of the alkyl iodide 2b with ClMg(CH2)5MgCl‚
2LiCl (5, 1.1 equiv, 25 °C, 2 h) provides the Grignard reagent
1b, which reacted smoothly with allyl bromide, leading to
the MOM-derivative 4c in 71% yield (entry 3). The treatment
of the alkyl iodide 2c with the exchange reagent 5 at -15
°C led to the Grignard reagent 1c after 3 h. Quenching with
methallyl bromide, benzaldehyde, or propionyl chloride gave
the desired products with 63-72% yield (entries 4-6). The
reaction of the â-iodoacetal 2d with the 1,5-dimagnesium
species 5 gave within 3 h at -20 °C the corresponding
magnesium reagent 1d. Quenching with tBuCHO or S-allyl
benzenesulfonothiate9 furnished the expected products 4g-h
(entries 7-8) with 58-72% yield. Nitrogen-containing
heterocycles such as pyridine are also compatible with our
reaction conditions. Thus, the reaction of the pyridine
derivative 2e with iPr2Mg‚LiCl (3) led after 1.5 h at 25 °C
to the Grignard reagent 1e, which was trapped with benzal-
dehyde, tBuCHO, allyl bromide, or CO2 in 56-75% yield
(entries 9-12).10 For the pyridine derivative 2f, a similar
exchange could be performed with iPr2Mg‚LiCl (25 °C, 2.5
(8) The formation of cyclopentane was proven by preparing 3-phenyl-
pentyl-1,5-dimagnesium chloride. Its reaction with the alkyl iodide 2b
provides the cyclisation product (cyclopentylbenzene), which was detected
by GC-MS as the main product. See also: Yang, X.; Knochel, P. Synlett
2004, 82.
(9) Kozikowski, A. P.; Anes, A.; Wetter, H. J. Organomet. Chem. 1978,
3, 164.
a Isolated yields. b Using as exchange reagent: iPr2Mg‚LiCl (0.65-1.1
equiv). c Using as exchange reagent: ClMg(CH2)5MgCl‚2LiCl (1.1 equiv).
d After transmetallation to copper using CuCN‚2LiCl12 (1.0 equiv).
(10) Pasquinet, E.; Rocca, P.; Godard, A.; Marsais, F.; Que´guiner, G. J.
Chem. Soc., Perkin Trans. 1 1998, 3807.
1188
Org. Lett., Vol. 10, No. 6, 2008

Scheme 2. Reaction Pathway of the 1,5-Dimagnesium
Reagent 5
Table 2. I/Mg-Exchange on â-Iodalkyl Esters of Type 8
Followed by Quenching with Electrophiles
h). Reacting 1f with benzaldehyde or ethyl 2-(bromomethyl)-
acrylate11 led to the expected products (entries 13-14) in
59% yield.
Magnesium homo-enolates were also prepared by this
approach. Thus, the reaction of the â-iodoester 8a with iPr2-
Mg‚LiCl (3) at -10 °C led to the corresponding magnesium
homo-enolate, which reacted with benzaldehyde leading after
lactonization to the spirolactone 10a in 68% yield (entry 1,
Table 2).13 Its reaction with allyl bromide provided the
corresponding allylated product 10b in 78% yield (entry 2).14
The same conditions gave, with carboxylic ester 8b, the
allylated product 10c in 68% yield (entry 3).15 Cyclopropane
derived products (10d-e) were obtained after transmetalla-
tion to copper12 and trapping with PhCOCl in 71-75% yield
(entries 4-5).16
In summary, we have shown that primary alkyl iodides
bearing a γ-oxygen or γ-nitrogen substituent readily undergo
an I/Mg-exchange with iPr2Mg‚LiCl (3) or ClMg(CH2)5-
MgCl‚2LiCl (5). Quenching the resulting sp3-hybridized
Grignard reagent with a range of electrophiles allows the
preparation of various functionalized products (4a-n,
10a-e). Extension of this method to other alkylmagnesium
species is currently underway in our laboratories.
a Isolated yields. b After transmetallation to copper using CuCN‚2LiCl
(1.0 equiv).
(11) (a) Villieras, J.; Rambaud, M. Synthesis 1982, 11, 924. (b) Villieras,
J.; Rambaud, M. Org. Synth. 1988, 66, 220.
(12) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390.
(13) Treves, G. R.; Stange, H.; Olofson, R. A. J. Am. Chem. Soc. 1967,
89, 6257.
Acknowledgment. We thank the Fonds der Chemischen
Industrie for the financial support and Chemetall GmbH
(Frankfurt) and BASF AG (Ludwigshafen) for the generous
gift of chemicals.
(14) (a) Nuhrich, A.; Moulines, J. Tetrahedron 1991, 47, 3075. (b) Clive,
D. L. J.; Pham, M. P.; Subedi, R. J. Am. Chem. Soc. 2007, 129, 2713.
(15) Ashby, E. C.; Park, B.; Patil, G. S.; Gadru, K.; Gurumurthy, R. J.
Org. Chem. 1993, 58, 424; Juaristi, E.; Jimbnez-Vizquez, H. A. J. Org.
Chem. 1991, 56, 1623; Fehr, C.; Galindo, J. HelV. Chim. Acta 1986, 69,
228.
(16) These type of cyclopropane derivatives were obtained by reacting
metallic sodium, the chloro derivatives of type 8 and TMSCl: Ruehlmann,
K. Synthesis 1971, 236. See also: (a) Nakamura, E.; Kuwajima, I. J. Am.
Chem. Soc. 1983, 105, 651. (b) Nakamura E.; Shimada, J.-I.; Kuwajima, I.
Organometallics 1985, 4, 641. (c) Reissig, H.-U.; Holzinger, H.; Glomsda,
G. Tetrahedron 1989, 45, 3139.
Supporting Information Available: Experimental pro-
cedures and full characterization of all new compounds. This
material is available free of charge via Internet at http://
pubs.acs.org.
OL8000987
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