Stereoselective preparation of functionalized acyclic alkenylmagnesium reagents using i-PrMgCl-LiCl

Article abstract of DOI:10.1021/ol048363h

(Chemical Equation Presented) Acyclic functionalized alkenyl iodides are converted with high stereoselectivity to the corresponding functionalized alkenylmagnesium derivatives by the reaction with i-PrMgCl-LiCl between -40 and -20°C. Functional groups such as a nitrile, chloride, iodide, and ester are readily tolerated. The conversion of an alkenyl iodide bearing a keto group to the corresponding silylated cyanohydrin allows preparation of the corresponding Grignard reagent affording, after acylation and deprotection, unsaturated 1,4-diketones.

Full text of DOI:10.1021/ol048363h

ORGANIC
LETTERS
2004
Vol. 6, No. 23
4215-4217
Stereoselective Preparation of
Functionalized Acyclic
Alkenylmagnesium Reagents Using
i-PrMgCl‚LiCl
Hongjun Ren, Arkady Krasovskiy, and Paul Knochel*
Department Chemie, Ludwig-Maximilians-UniVersita¨t, Butenandtstrasse 5-13,
81377, Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received August 17, 2004
ABSTRACT
Acyclic functionalized alkenyl iodides are converted with high stereoselectivity to the corresponding functionalized alkenylmagnesium derivatives
by the reaction with i-PrMgCl LiCl between 40 and 20 C. Functional groups such as a nitrile, chloride, iodide, and ester are readily tolerated.
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−
−
°
The conversion of an alkenyl iodide bearing a keto group to the corresponding silylated cyanohydrin allows preparation of the corresponding
Grignard reagent affording, after acylation and deprotection, unsaturated 1,4-diketones.
Organomagnesium reagents are key organometallic inter-
mediates for organic synthesis.1,2 Whereas a standard prepa-
ration of these reagents is the direct insertion of magnesium
to an organic halide,1,3 this method is not suitable for the
preparation of functionalized organomagnesium compounds
because of the competitive reduction of several important
functional groups.4 Furthermore, the Mg-insertion to alkenyl
iodides or bromides is not stereoselective and provides an
E/Z-mixture of alkenylmagnesium reagents.5 Recently, we
have shown that an I/Mg exchange using i-Pr2Mg leads
stereoselectively to alkenylmagnesium reagents.6 Unfortu-
nately, the relatively high temperature for performing the
exchange reaction (25 °C) precludes the presence of func-
tional groups and only substrates bearing a chelating oxygen
atom at the appropriate position undergo the I/Mg-exchange
at lower temperature. Recently, we have found that the
complex i-PrMgCl‚LiCl7 (1) has a dramatically increased
reactivity for performing halogen-magnesium exchange
reactions compared to i-PrMgCl or i-Pr2Mg.8 This may be
(1) (a) Handbook of Grignard Reagents; Silverman, G. S., Rakita, P.
E., Eds.; Marcel Dekker: New York, 1996. (b) Grignard Reagents: New
DeVelopments; Richey, H. G., Jr., Ed.; Wiley: New York: 1999. (c)
Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn,
T.; Sapountzis, I.; Vu, V. A. Angew. Chem. 2003, 115, 4438; Angew. Chem.,
Int. Ed. 2003, 42, 4302.
(2) For recent applications see: (a) Klos, A.; Heintzelman, G. R.;
Weinreb, S. M. J. Org. Chem. 1997, 62, 3758. (b) Taber, D. F.; Green, J.
H.; Geremia, J. M. J. Org. Chem. 1997, 62, 9342. (c) Hayashi, Y.;
Shinokubo, H.; Oshima, K. Tetrahedron Lett. 1998, 39, 63. (d) Inoue, A.;
Kitagawa, K.; Shinokubo, H.; Oshima, K. J. Org. Chem. 2001, 66, 4333.
(e) Heron, N. M.; Adams, J. A.; Hoveyda; A. H. J. Am. Chem. Soc. 1997,
119, 6205. (f) Houri, A. F.; Xa, Z.; Cogan, D. A.; Hoveyda; A. H. J. Am.
Chem. Soc. 1995, 117, 2943. (g) Fleming, F. F.; Gudipati, V.; Steward, O.
W. Org. Lett. 2002, 4, 659. (h) Fleming, F. F.; Zhang, Z.; Wang, Q.;
Steward, O. W. Org. Lett. 2002, 4, 2493.
(4) (a) Burns, T. P.; Rieke, R. D. J. Org. Chem. 1987, 52, 3674. (b)
Sapountzis, I.; Knochel, P. Angew. Chem., Int. Ed. 2002, 41, 1610.
(5) Knochel, P.; Normant, J. F. Tetrahedron Lett. 1986, 27, 4431.
(6) Rottla¨nder, M.; Boymond, L.; Cahiez, G.; Knochel, P. J. Org. Chem.
1999, 64, 1080.
(7) Preparation of Reagent i-PrMgCl‚LiCl. Magnesium turnings (110
mmol) and anhydrous LiCl (100 mmol) were placed in an Ar-flushed flask,
and THF (25 mL) was added. A solution of i-PrCl (100 mmol) in THF (25
mL) was slowly added at room temperature. The reaction starts within a
few minutes. After addition, the reaction mixture was stirred for 12 h at
room temperature. The gray solution of i-PrMgCl‚LiCl was cannulated to
an other flask under Ar and removed in this way from excess of magnesium.
A yield of ca. 95-98% of i-PrMgCl‚LiCl is obtained.
(3) The use of activated magnesium (Rieke-magnesium) has an especially
broad reaction scope: (a) Rieke, R. D.; Xiong, H. J. Org. Chem. 1991, 56,
3109. (b) Rieke, R. D. Science 1989, 246, 1260.
(8) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 3333.
10.1021/ol048363h CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/15/2004

explained by the structure 2 of this reagent, which displays
an extra negative charge at the magnesium center enhancing
the nucleophilic properties of the i-Pr group (Scheme 1).
Table 1. Products of Type 5 Obtained by the Reaction of
Polyfunctional Alkenylmagnesium Reagents with i-PrMgCl‚LiCl
Scheme 1. Synthesis of Functionalized Alkenylmagnesium
Reagents Using i-PrMgCl‚LiCl
With the reagent 1, the I/Mg exchange now proceeds at
-25 °C or lower. This enhances considerably the functional
group compatibility and allows conversion of a variety of
functionalized alkenyl iodides of type 3 to the corresponding
Grignard species 4 with retention of the double bond
configuration. The reaction with various electrophiles pro-
vides polyfunctional alkenes of type 5 with good yields and
excellent stereoselectivity (Scheme 1 and Table 1).
Thus, the reaction of (E)-1-iodo-oct-1-ene (3a; E:Z )
99:1) with i-PrMgCl‚LiCl (1.1 equiv) at -40 °C gives the
corresponding alkenylmagnesium reagent (4a), which reacts
with various electrophiles (aldehyde, DMF, or PhSSPh) to
provide the expected products 5a-c with an excellent
stereoselectivity (E:Z ) 99:1, entries 1-3 of Table 1).
Similarly, (Z)-1-iodo-oct-1-ene (3b; E:Z ) 2:98) furnishes
the corresponding Z-alkenylmagnesium chloride (4b), which
after reaction with an aldehyde or a disulfide leads to the
cis-products 5d and 5e in 69-70% (entries 4 and 5).
The mild reaction conditions required for the I/Mg ex-
change now allows the preparation of functionalized alken-
ylmagnesium compounds bearing a chloride (4c and 4d;
entries 6 and 7), an iodide (4e, entry 8), a cyanide (entries
9, 13, and 14), or an ester (entries 10-12). The expected
products (5f-5n) all were obtained in satisfactory to good
yields.
Although a ketone group is usually9 not compatible with
the presence of a carbon-magnesium bond, we have found
that the corresponding silylated cyanohydrin derivative 7 of
1-iodo-oct-1-en-3-one10 can be readily converted into the
corresponding magnesium species 8 and reacted after trans-
metalation with CuCN‚2LiCl with 3-iodocyclohexane or
benzoyl chloride, leading to the unsaturated diketones 9a and
9b in 77% and 74% yield after deprotection of the interme-
diate cyanohydrin derivatives with Bu4NF and HCl (2 M in
H2O). In summary, we have developed a stereoselective
synthesis of polyfunctional alkenylmagnesium compounds
bearing various functional groups using the new reagent
a X ) Cl‚LiCl. b Isolated yield of analytically pure product. c The
exchange was performed at -40 °C for 7 h. d The exchange was performed
at -40 °C for 20 h. e The exchange was performed at -40 °C for 12 h.
f The exchange was performed at -40 °C for 5 h.
(9) For exceptions, see: Kneisel, F. F., Knochel, P. Synlett 2002, 1799.
(10) The silylated cyanohydrin 7 was prepared in situ from 1-iodo-oct-
1-en-3-one 6 by addition TMSCN in the presence of catalytical amounts
of CsF in dry CH3CN. Kim, S. S.; Rajagopal, G.; Song, D. H. J. Organomet.
Chem. 2004, 689, 1734.
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Org. Lett., Vol. 6, No. 23, 2004

Acknowledgment. We thank the Fonds der Chemischen
Industrie for financial support. We thank Boehringer-
Ingelheim (Vienna) and Chemetall (Frankfurt), for the
generous gift of chemicals.
Scheme 2. Synthesis of Unsaturated Diketones 9a and 9b
Supporting Information Available: Experimental pro-
cedures and full characterization of all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL048363H
(11) Typical Procedure. Preparation of 5k. A dry and argon-flushed
10 mL flask, equipped with a magnetic stirrer and a septum, was charged
with a solution of (E)-alkenyl iodide (3g, 155 mg, 0.5 mmol, E:Z ) 99:1)
in dry THF (0.2 mL). i-PrMgCl‚LiCl (2.0 M/THF, 0.55 mmol, 1.1 equiv)
was added slowly at -40 °C, and the resulting mixture was stirred at
this temperature for 12 h to complete the iodine-magnesium exchange
(checked by GC-MS analysis of reaction aliquots). Propionaldehyde (0.55
mmol, 1.1 equiv) was added. The mixture was warmed to room temperature
and was quenched with saturated aqueous NH4Cl solution. The aqueous
phase was extracted with ether (3 × 20 mL). The organic fractions were
dried (MgSO4) and concentrated in vacuo. Purification by flash chroma-
tography (hexane/diethyl ether ) 2: 1) yielded 99 mg (82% yield) 5k as
a colorless oil.
i-PrMgCl‚LiCl. Extensions of this work to cyclic polyun-
saturated systems is currently under way in our laboratories.11
Org. Lett., Vol. 6, No. 23, 2004
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