Soluble lanthanide salts (LnCl3,·2 LiCl) for the improved addition of organomagnesium reagents to carbonyl compounds

Article abstract of DOI:10.1002/anie.200502485

(Chemical Equation Presented) Easy-to-prepare solutions of LnCl ₃·2 LiCl (Ln = La, Ce, Nd) (0.3-0.5 M in THF) are a unique source of soluble lanthanide salts with versatile applications in organic synthesis. These salts can serve as promoters or catalysts for the addition of organometallic compounds to sterically hindered, enolizable or α,β-unsaturated ketones or imines.

Full text of DOI:10.1002/anie.200502485

Angewandte
Chemie
Grignard Reactions
CeCl3·6H2O, or NdCl3·6H2Owith LiCl (2 equiv) in water
led to a slurry which was stirred 4 h at 258C under high
vacuum (0.01 mm Hg). The resulting white powder was
stirred with gradual increase of temperature (208C/4 h to
1608C) for 28 h. The solid was dissolved in THF and stirred
for one day in the presence of molecular sieves (4 Š). After
filtration, transparent, ca. 0.33m solutions of LnCl3·2LiCl
(1a–c) were obtained, which can be stored indefinitely at
258C under argon. The amount of remaining protic impurities
was less than 5% as shown by titration.[7] Solutions of
LnCl3·2LiCl promote the addition of Grignard reagents 2 to
various types of hindered and easily enolizable ketones 3
leading to tertiary alcohols of type 4. The side products
usually obtained in these reactions arise from the enolization
of the ketone leading to the corresponding magnesium
enolate 5 and the b-hydride reduction leading to the alcohol
6. The addition of lanthanide salts minimizes considerably
these side reactions. Thus, the reaction of the secondary
alkylmagnesium chloride 2a with cyclopentanone (3a) leads
in the absence of lanthanide salts to enolization and formation
of aldol products, and only 3–5% of the addition product is
obtained (entry 1, Table 1). By adding CeCl3 (1.5 equiv)
according to the procedure of Imamoto et al.,[2] we obtained
the desired alcohol 4a in 72% yield, whereas the procedure of
Dimitrov et al.[3] (CeCl3, 1 equiv) provided alcohol 4a in 80%
yield. By adding LnCl3·2LiCl (Ln = La, Ce, Nd) in THF
(1 equiv) to cyclopentanone (3a) and stirring the mixture for
1 h and then adding iPrMgCl (2a) at 08C (10 min), we
obtained alcohol 4a in 92–94% yield. The same reactivity
trend was observed with cyclohexanone (3b). The addition of
iPrMgCl to this ketone again proceeded quantitatively in the
presence of LnCl3·2LiCl (Ln = La, Ce) and in better yield
than with Imamotoꢀs method (80%)[2] or with Dimitrovꢀs
method (93%; entry 2).[3]
DOI: 10.1002/anie.200502485
Soluble Lanthanide Salts (LnCl3·2LiCl) for the
Improved Addition of Organomagnesium
Reagents to Carbonyl Compounds**
Arkady Krasovskiy, Felix Kopp, and Paul Knochel*
Lanthanide(iii) salts have been used extensively to activate
carbonyl compounds and imine derivatives for the 1,2-
addition of organometallic reagents.[1] Owing to the oxophilic
nature of lanthanide salts, the 1,2-addition reaction is favored
over competitive reactions such as enolization and reduction
(by b-hydride transfer).[2] The activity of the catalyst strongly
depends on the drying procedure[3] and especially on its
solubility.[4] Only few lanthanide salts are soluble to an
appreciable degree in organic solvents.[5] The addition of LiCl
has proven to have a beneficial effect and has been used for
the synthesis of various organometallic complexes.[6]
Herein, we describe the preparation of THF-soluble
lanthanide halides LnCl3·2LiCl (Ln = La (1a), Ce(1b), Nd-
(1c)), which can be easily prepared as 0.3–0.5m solutions in
THF (Scheme 1). These convenient reagents were found to be
superior promoters for the addition of various Grignard
reagents to hindered and enolizable ketones. Thus, the
treatment
of
commercially
available
LaCl3·6H2O,
a-Tetralone (3c) also reacted quantitatively with iPrMgCl
(2a) leading to the alcohol 4c in 95% yield. In the absence of
lanthanide salt, only 30% yield was obtained, whereas
Imamotoꢀs method provided product 3c in 73% yield
(entry 3). Readily enolizable ketones such as diphenylacetone
(3d) reacted with the sterically hindered Grignard reagent
iPrMgCl (2a) only under formation of the corresponding
magnesium enolate (only 3% of the addition product was
produced), whereas in the presence of LnCl3·2LiCl a yield of
95–97% of the tertiary alcohol 4d was obtained (entry 4).
This behavior was also observed for less reactive Grignard
reagents such as functionalized arylmagnesium chlorides 2b–
e prepared by a halogen–magnesium exchange reaction. Due
to the low reactivity of these reagents the use of iPrMgCl·LiCl
for the exchange reaction is essential to convert the arylmag-
nesium chlorides into reagents of the more reactive type
ArMgCl·LiCl.[8] Thus, the reaction of these relatively unreac-
tive magnesium reagents with various ketones proceeded in
only moderate yields in the absence of lanthanide salts,
whereas excellent yields were obtained in the presence of
LnCl3·2LiCl (73–95% yield; entries 5–11).
Scheme 1. Preparation of soluble lanthanide salts 1 and products of
the reaction of organomagnesium reagents 2 with ketones 3.
[*] Dr. A. Krasovskiy, Dipl.-Chem. F. Kopp, Prof. Dr. P. Knochel
Ludwig-Maximilians-Universität München
Department Chemie
Butenandtstrasse 5–13, Haus F, 81377 München (Germany)
Fax: (+49)89-2180-77680
E-mail: paul.knochel@cup.uni-muenchen.de
[**] We thank the Fonds der Chemischen Industrie and Merck Research
Laboratories (MSD) for financial support. We also thank Chemetall,
BASF, and Bayer Chemicals for generous gifts of chemicals. Ln=La,
Ce, Nd.
Even Grignard reagent 2e bearing a sensitive nitro
function reacted cleanly with the ketone 3g in the presence
of LaCl3·2LiCl. In contrast, in the absence of lanthanide salts
as well when Imamotoꢀs procedure was employed, no product
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Reactions of ketones 2 with Grignard reagents 1 without additives, and in the presence of CeCl3 or LnCl3·2 LiCl (Ln=La, Ce, Nd).
Entry Grignard reagent 2 Ketone of type 3 Product of type 4 Yield [%]
without with
with
additives[a] CeCl3 LnCl3·2LiCl
[b]
92[d]
72
1
2
iPrMgCl
iPrMgCl
2a
2a
3a
4a
4b
3–5
30
94[e]
92[f]
(80)[c]
80
97[d]
98[e]
3b
3c
3d
(93)[c]
95[d]
95[e]
3
4
iPrMgCl
iPrMgCl
2a
2a
4c
4d
30
3
73
–
96[d]
95[e]
97[f]
92[d]
91[e]
5
6
7
2b
2c
2c
3d
3d
3c
4e
4 f
4g
39
37
48
11
86[d]
89[e]
88[f]
8
16
87[d]
8
2c
2c
2d
2e
3e
3a
3 f
3g
4h
4i
50
27
35
0
–
–
–
0
86[d]
95[d]
94[e]
9
10
11
4j
81[d]
4k
73[d]
61[d]
65[e]
12
13
MeMgCl
2 f
3h
3i
4l
4l
1
47
57
69[d,g]
71[e,g]
2g
22
498
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Chemie
Table 1: (Continued)
Entry Grignard reagent 2
Ketone of type 3
Product of type 4
Yield [%]
without with
with
additives[a] CeCl3 LnCl3·2LiCl
[b]
92[d]
14
15
tBuMgCl·LiCl 2h
3b
4m
4n
4
–
–
93[e]
93[d]
PhMgCl
2i
2j
2k
2l
3j
3j
3j
3j
21
92[d]
16
17
18
PhMgBr·LiCl
PhMgI·LiCl
4n
4n
4o
–
–
–
–
(65)[h]
89[d]
17
53
92[d]
[a] Yield of isolated product obtained by the direct reaction of the ketone with the Grignard reagent. [b] Yield of isolated product obtained in the
presence of CeCl3 (1.5 equiv) according to the method of Imamoto. [c] Yield of isolated product obtained in the presence of CeCl3 (1.0 equiv)
according to the method of Dimitrov. [d] Reaction performed with LaCl3·2LiCl (1.0 equiv). [e] Reaction performed with CeCl3·2LiCl (1.0 equiv).
[f] Reaction performed with NdCl3·2LiCl (1.0 equiv). [g] The Grignard reagent was first transmetalated by addition of LnCl3·2LiCl (1.0 equiv) and
stirred for 4 h at room temperature before the ketone was added at 08C. [h] The reaction was performed in the presence of 10 mol% LaCl3·2LiCl.
4k could be obtained. The reactions of sterically very
hindered ketones such as the mesityl methyl ketone 3h and
hindered Grignard reagents such as mesitylmagnesium bro-
mide 2g and tert-butylmagnesium chloride 2h gave moderate
yields. A significant improvement was achieved when these
reactions were performed in the presence of LaCl3·2LiCl
(entries 12–14).
In a further example, the addition of PhMgCl (3i) to
camphor (3j) was highly diastereoselective and led to the
alcohol 4n in 93% yield (entry 15). The Grignard reagentꢀs
Scheme 2. 1,2-Addition of a Grignard reagent to cyclohexenone pro-
moted by LaCl3·2LiCl.
halide ion shows only little influence on the addition reaction.
Thus, the magnesium reagents obtained by insertion from
phenyl bromide and iodide, respectively, also led to the clean
formation of the desired product 4n in good yields (92 and
89%, entries 16 and 17, respectively). Even a catalytic
amount of LaCl3·2LiCl promoted this addition reaction, and
the desired product was still obtained as one diastereoisomer
in 65% yield when only 10 mol% LaCl3·2LiCl was used
(entry 16, value in brackets).
the desired alcohols were achieved, whereas other methods
gave worse results. Thus, the addition of nBuLi to cyclo-
pentanone at 08C led to the desired alcohol 9 in 96–98%
yield, whereas Imamotoꢀs procedure required low temper-
atures (À788C) and longer reaction times (Scheme 3).
Similarly, the addition of 2-pyridylmagnesium chloride
(2l) to camphor (3j) produced the pyridineisoborneol
derivative 4o as one isomer (92%, entry 18). In the case of
a,b-unsaturated ketones such as cyclohex-2-enone, the addi-
tion of secondary alkylmagnesium compounds like cyclo-
pentylmagnesium chloride proceeded exclusively in the
presence of LaCl3·2LiCl leading to the desired tertiary allylic
alcohol 7 in 93% yield. In the absence of this salt, the only
product observed was the allylic alcohol 8, which was isolated
in 77% yield (Scheme 2).
Scheme 3. Addition of nBuLi to cyclopentanone promoted by
LnCl3·2LiCl. Imamoto’s procedure: À788C, 3 h, 77%.
Finally, catalytic amounts of LnCl3·2LiCl (10 mol%) were
sufficient to promote the addition of Grignard reagents to
nonactivated imines such as 9. In the absence of the catalyst,
the amine 10 was isolated in 15% yield, whereas in the
presence of LaCl3·2LiCl (10 mol%) the addition product 10
Lanthanide(iii) salts also promote addition of organo-
lithium compounds to ketones. Almost quantitative yields of
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499

Communications
was purified by flash column chromatography (silica; pentane/Et2O
10:1) to give 4c as a colorless, crystalline solid (361 mg, 1.90 mmol,
95%, m.p. 1018C).
was obtained in 84% yield. Similarily, the addition of
vinylmagnesium chloride to the imine 11 provides the bis-
(allyl) amine 12 in 87% yield (Scheme 4).[9]
Received: July 16, 2005
Revised: September 29, 2005
Keywords: 1,2-additions · enols · Grignard reaction · imines ·
.
lanthanides
[1] a) S. Kobayashi, M. Sugiura, H. W. L. Lam, Chem. Rev. 2002,
102, 2227; b) S. Kobayashi, K. Manabe, Acc. Chem. Res. 2002, 35,
209.
[2] a) T. Imamoto, Y. Sugiyura, N. Takiyama, Tetrahedron Lett.
1984, 25, 4233; b) T. Imamoto, N. Takiyama, K. Nakamura,
Tetrahedron Lett. 1985, 26, 4763; c) T. Imamoto, Y. Sugiyura, N.
Takiyama, T. Hatojima, Y. Kamiya, J. Am. Chem. Soc. 1989, 111,
4392; d) H. Schumann, M. Glanz, J. Gottfriedsen, S. Dechert, D.
Wolff, Pure Appl. Chem. 2001, 73, 279.
[3] V. Dimitrov, K. Koslova, M. Genov, Tetrahedron Lett. 1996, 37,
6787.
Scheme 4. LaCl3·2LiCl-catalyzed addition of Grignard reagents to
imines.
[4] a) U. Groth, M. Jeske, Angew. Chem. 2000, 112, 586; Angew.
Chem. Int. Ed. 2000, 39, 574; b) U. Groth, M. Jeske, Synlett 2001,
129; c) S. Fischer, U. Groth, M. Jeske, T. Schutz, Synlett 2002,
1922; see also d) W.-D. Z. Li, J.-H. Yang, Org. Lett. 2004, 6, 1849;
e) D. Tsvelikhovsky, D. Gelman, G. A. Molander, J. Blum, Org.
Lett. 2004, 6, 1995; f) M. Shenglof, D. Gelman, G. A. Molander,
J. Blum, Tetrahedron Lett. 2003, 44, 8593; g) P. Eckenberg, U.
Groth, T. Köhler, Liebigs Ann. Chem. 1994, 673; h) M. Hatano,
T. Matsuma, K. Ishkihara, Org. Lett. 2005, 7, 573; i) S. Fukuzawa,
T. Fujinami, S. Yamauchi, S. Sakai, J. Chem. Soc. Perkin Trans. 1
1986, 1929; j) F. T. Edelmann, D. M. M. Freckmann, H. Schu-
mann, Chem. Rev. 2002, 102, 1851.
In summary, we have shown that LnCl3·2LiCl (Ln = La,
Ce, Nd)[10] are readily available as THF solutions. They are
superior promoters for the addition of various organometallic
reagents to ketones. They also catalyze efficiently the addition
of organomagnesium compounds to imines. Further applica-
tions of these soluble lanthanide salts are currently under
investigation in our laboratories.
[5] Y. Y. Novikov, P. Sampson, Org. Lett. 2003, 5, 2263.
[6] a) K. Rossmanith, Monatsh. Chem. 1979, 110, 109; b) J. Zhong-
sheng, H. Ninghai, L. Yi, X. Xiaolong, L. Guozhi Inorg. Chim.
Acta 1988, 142, 333; c) Q. Shen, W. Chen, Y. Jin, C. Shan, Pure
Appl. Chem. 1988, 60, 1251; d) C. P. Groen, A. Oskam, A.
Kovacs, Inorg. Chem. 2000, 39, 6001; e) H. J. Heeres, A. Meet-
sma, J. H. Teuben, R. D. Rogers, Organometallics 1989, 8, 2637;
f) J. Guan, S. Jin, Y. Lin, Q. Shen, Organometallics 1992, 11,
2483.
[7] The amount of the remaining protic impurities was determined
by titration with nBuLi using ortho-phenanthroline as indicator
in analogy to the method for determining the concentration of Li
and Mg reagents described by Paquette: H.-S. Lin, L. Paquette,
Synth. Commun. 1994, 24, 2503.
Experimental Section
Typical procedure (preparation of a solution of LaCl3·2LiCl in THF):
Commercially available LaCl3·6H2O(0.10 mol, 35.3 g) was mixed
with LiCl (0.20 mol, 8.40 g) in a 500-mL Schlenk flask, and water
(100 mL) was slowly added with vigorous stirring. The resulting slurry
was stirred under high vacuum (0.01 mm Hg) at room temperature for
4 h. Stirring was continued for 4 h at 408C, 4 h at 608C, 4 h at 808C,
4 h at 1008C, 4 h at 1208C, 4 h at 1408C and finally 4 h at 1608C. The
slow increase of temperature and highly efficient stirring were
essential. The resulting solid was cooled to room temperature, and
THF was added until a total volume of 300 mL was reached. Then,
molecular sieves (50 g; 4 Š) were added, and the resulting mixture
was stirred vigorously for 1 d at RT. Finally, the insoluble material
(mostly crushed molecular sieves) was removed by filtration through
a combined filter system (fresh molecular sieves/filter paper) under
an argon atmosphere. By this procedure, a clear and colorless solution
of LaCl3·2LiCl was obtained which was stored until use at room
temperature under argon.
[8] A. Krasovskiy, P. Knochel, Angew. Chem. 2004, 116, 3396;
Angew. Chem. Int. Ed. 2004, 43, 3333. The reagent iPrMgCl·LiCl
is commercially available as a solution in THF from Chemetall
GmbH (Frankfurt).
[9] Imines of aliphatic aldehydes can also be used, but equimolar
amounts of LnCl3·2LiCl are required for full conversion. The
addition of Grignard reagents to imines of a,b-unsaturated
aldehydes required at least 0.3 equiv of LnCl3·2LiCl.
[10] Additionally, ErCl3·6H2O, PrCl3·6H2O, YCl3·6H2O,and
DyCl3·6H2Owere used analogously to prepare solutions of
type LnCl3·2LiCl. Whereas the reactivity of PrCl3·2LiCl is
similar to that of the La, Ce, and Nd derivatives (1a–c),
ErCl3·2LiCl, YCl3·2LiCl, and DyCl3·2LiCl display lower cata-
lytic activities and give mediocre results in the addition
reactions.
Typical procedure for the LaCl3·2 LiCl-mediated addition of
Grignard reagents to ketones and imines (synthesis of 4c; see Table 1,
entry 3): In
a flame-dried, argon-flushed 25-mL Schlenk flask
equipped with a septum and a magnetic stirring bar was placed
LaCl3·2LiCl in THF (0.33m; 6.10 mL, 2.00 mmol, 1.00 equiv). a-
Tetralone (292 mg; 2.00 mmol) was added neat, and the resulting
mixture was stirred for 1 h at room temperature. The reaction mixture
was cooled to 08C, iPrMgCl (2.10 mL of a 1.00m solution in THF,
2.10 mmol, 1.05 equiv) was added dropwise, and the reaction mixture
was allowed to stir at the same temperature. When the conversion was
complete (GC analysis of reaction aliquots), saturated aqueous
NH4Cl (2 mL) and water (2 mL) were added. The aqueous layer was
extracted with diethyl ether (4 ” 10 mL), and the combined extracts
were dried (Na2SO4) and concentrated to dryness. The crude residue
500
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