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Soluble Lanthanide Salts (LnCl32LiCl) for the Improved Addition of Organomagnesium Reagents to Carbonyl Compounds.

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Angewandte
Chemie
Grignard Reactions
DOI: 10.1002/anie.200502485
Soluble Lanthanide Salts (LnCl3�LiCl) 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 1,2addition 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�LiCl (Ln = La (1 a), Ce(1 b), Nd(1 c)), which can be easily prepared as 0.3?0.5 m 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�H2O,
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-Universit1t M2nchen
Department Chemie
Butenandtstrasse 5?13, Haus F, 81377 M2nchen (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.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2006, 45, 497 ?500
CeCl3�H2O, or NdCl3�H2O with LiCl (2 equiv) in water
led to a slurry which was stirred 4 h at 25 8C under high
vacuum (0.01 mm Hg). The resulting white powder was
stirred with gradual increase of temperature (20 8C/4 h to
160 8C) for 28 h. The solid was dissolved in THF and stirred
for one day in the presence of molecular sieves (4 5). After
filtration, transparent, ca. 0.33 m solutions of LnCl3�LiCl
(1 a?c) were obtained, which can be stored indefinitely at
25 8C under argon. The amount of remaining protic impurities
was less than 5 % as shown by titration.[7] Solutions of
LnCl3�LiCl 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 2 a with cyclopentanone (3 a) 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 4 a in 72 % yield, whereas the procedure of
Dimitrov et al.[3] (CeCl3, 1 equiv) provided alcohol 4 a in 80 %
yield. By adding LnCl3�LiCl (Ln = La, Ce, Nd) in THF
(1 equiv) to cyclopentanone (3 a) and stirring the mixture for
1 h and then adding iPrMgCl (2 a) at 0 8C (10 min), we
obtained alcohol 4 a in 92?94 % yield. The same reactivity
trend was observed with cyclohexanone (3 b). The addition of
iPrMgCl to this ketone again proceeded quantitatively in the
presence of LnCl3�LiCl (Ln = La, Ce) and in better yield
than with Imamoto?s method (80 %)[2] or with Dimitrov?s
method (93 %; entry 2).[3]
a-Tetralone (3 c) also reacted quantitatively with iPrMgCl
(2 a) leading to the alcohol 4 c in 95 % yield. In the absence of
lanthanide salt, only 30 % yield was obtained, whereas
Imamoto?s method provided product 3 c in 73 % yield
(entry 3). Readily enolizable ketones such as diphenylacetone
(3 d) reacted with the sterically hindered Grignard reagent
iPrMgCl (2 a) only under formation of the corresponding
magnesium enolate (only 3 % of the addition product was
produced), whereas in the presence of LnCl3�LiCl a yield of
95?97 % of the tertiary alcohol 4 d was obtained (entry 4).
This behavior was also observed for less reactive Grignard
reagents such as functionalized arylmagnesium chlorides 2 b?
e prepared by a halogen?magnesium exchange reaction. Due
to the low reactivity of these reagents the use of iPrMgCl稬iCl
for the exchange reaction is essential to convert the arylmagnesium chlorides into reagents of the more reactive type
ArMgCl稬iCl.[8] Thus, the reaction of these relatively unreactive 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�LiCl (73?95 % yield; entries 5?11).
Even Grignard reagent 2 e bearing a sensitive nitro
function reacted cleanly with the ketone 3 g in the presence
of LaCl3�LiCl. In contrast, in the absence of lanthanide salts
as well when Imamoto?s procedure was employed, no product
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
497
Communications
Table 1: Reactions of ketones 2 with Grignard reagents 1 without additives, and in the presence of CeCl3 or LnCl3�LiCl (Ln = La, Ce, Nd).
Entry Grignard reagent 2
Product of type 4
Yield [%]
without with
with
additives[a] CeCl3[b] LnCl3�LiCl
1
iPrMgCl
2a
3a
4a
3?5
72
(80)[c]
92[d]
94[e]
92[f ]
2
iPrMgCl
2a
3b
4b
30
80
(93)[c]
97[d]
98[e]
3
iPrMgCl
2a
3c
4c
30
73
95[d]
95[e]
4
iPrMgCl
2a
3d
4d
3
?
96[d]
95[e]
97[f ]
2b
3d
4e
39
11
92[d]
91[e]
5
6
2c
3d
4f
37
8
86[d]
89[e]
88[f ]
7
2c
3c
4g
48
16
87[d]
8
2c
3e
4h
50
?
86[d]
9
2c
3a
4i
27
?
95[d]
94[e]
10
2d
3f
4j
35
?
81[d]
11
2e
3g
4k
0
0
73[d]
2f
3h
4l
1
47
61[d]
65[e]
2g
3i
4l
22
57
69[d, g]
71[e, g]
12
13
498
Ketone of type 3
MeMgCl
www.angewandte.org
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 497 ?500
Angewandte
Chemie
Table 1: (Continued)
Entry Grignard reagent 2
Ketone of type 3
Product of type 4
Yield [%]
without with
with
additives[a] CeCl3[b] LnCl3�LiCl
14
tBuMgCl稬iCl
2h
3b
4m
4
?
92[d]
93[e]
15
PhMgCl
2i
3j
4n
21
?
93[d]
16
PhMgBr稬iCl
2j
3j
4n
?
?
92[d]
(65)[h]
17
PhMgI稬iCl
2k
3j
4n
?
?
89[d]
2l
3j
4o
17
53
92[d]
18
[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�LiCl (1.0 equiv). [e] Reaction performed with CeCl3�LiCl (1.0 equiv).
[f] Reaction performed with NdCl3�LiCl (1.0 equiv). [g] The Grignard reagent was first transmetalated by addition of LnCl3�LiCl (1.0 equiv) and
stirred for 4 h at room temperature before the ketone was added at 0 8C. [h] The reaction was performed in the presence of 10 mol % LaCl3�LiCl.
4 k could be obtained. The reactions of sterically very
hindered ketones such as the mesityl methyl ketone 3 h and
hindered Grignard reagents such as mesitylmagnesium bromide 2 g and tert-butylmagnesium chloride 2 h gave moderate
yields. A significant improvement was achieved when these
reactions were performed in the presence of LaCl3�LiCl
(entries 12?14).
In a further example, the addition of PhMgCl (3 i) to
camphor (3 j) was highly diastereoselective and led to the
alcohol 4 n in 93 % yield (entry 15). The Grignard reagent?s
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 4 n in good yields (92 and
89 %, entries 16 and 17, respectively). Even a catalytic
amount of LaCl3�LiCl promoted this addition reaction, and
the desired product was still obtained as one diastereoisomer
in 65 % yield when only 10 mol % LaCl3�LiCl was used
(entry 16, value in brackets).
Similarly, the addition of 2-pyridylmagnesium chloride
(2 l) to camphor (3 j) produced the pyridineisoborneol
derivative 4 o as one isomer (92 %, entry 18). In the case of
a,b-unsaturated ketones such as cyclohex-2-enone, the addition of secondary alkylmagnesium compounds like cyclopentylmagnesium chloride proceeded exclusively in the
presence of LaCl3�LiCl 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).
Lanthanide(iii) salts also promote addition of organolithium compounds to ketones. Almost quantitative yields of
Angew. Chem. Int. Ed. 2006, 45, 497 ?500
Scheme 2. 1,2-Addition of a Grignard reagent to cyclohexenone promoted by LaCl3�LiCl.
the desired alcohols were achieved, whereas other methods
gave worse results. Thus, the addition of nBuLi to cyclopentanone at 0 8C led to the desired alcohol 9 in 96?98 %
yield, whereas Imamoto?s procedure required low temperatures ( 78 8C) and longer reaction times (Scheme 3).
Scheme 3. Addition of nBuLi to cyclopentanone promoted by
LnCl3�LiCl. Imamoto?s procedure: 78 8C, 3 h, 77 %.
Finally, catalytic amounts of LnCl3�LiCl (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�LiCl (10 mol %) the addition product 10
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
499
Communications
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]
was purified by flash column chromatography (silica; pentane/Et2O
10:1) to give 4 c as a colorless, crystalline solid (361 mg, 1.90 mmol,
95 %, m.p. 101 8C).
Received: July 16, 2005
Revised: September 29, 2005
.
Keywords: 1,2-additions � enols � Grignard reaction � imines �
lanthanides
Scheme 4. LaCl3�LiCl-catalyzed addition of Grignard reagents to
imines.
In summary, we have shown that LnCl3�LiCl (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 applications of these soluble lanthanide salts are currently under
investigation in our laboratories.
Experimental Section
Typical procedure (preparation of a solution of LaCl3�LiCl in THF):
Commercially available LaCl3�H2O (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 40 8C, 4 h at 60 8C, 4 h at 80 8C,
4 h at 100 8C, 4 h at 120 8C, 4 h at 140 8C and finally 4 h at 160 8C. 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 5) 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�LiCl was obtained which was stored until use at room
temperature under argon.
Typical procedure for the LaCl3�LiCl-mediated addition of
Grignard reagents to ketones and imines (synthesis of 4 c; 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�LiCl in THF (0.33 m ; 6.10 mL, 2.00 mmol, 1.00 equiv). aTetralone (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 0 8C, iPrMgCl (2.10 mL of a 1.00 m 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 E 10 mL), and the combined extracts
were dried (Na2SO4) and concentrated to dryness. The crude residue
500
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102, 2227; b) S. Kobayashi, K. Manabe, Acc. Chem. Res. 2002, 35,
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[2] a) T. Imamoto, Y. Sugiyura, N. Takiyama, Tetrahedron Lett.
1984, 25, 4233; b) T. Imamoto, N. Takiyama, K. Nakamura,
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Takiyama, T. Hatojima, Y. Kamiya, J. Am. Chem. Soc. 1989, 111,
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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. Schumann, Chem. Rev. 2002, 102, 1851.
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[6] a) K. Rossmanith, Monatsh. Chem. 1979, 110, 109; b) J. Zhongsheng, H. Ninghai, L. Yi, X. Xiaolong, L. Guozhi Inorg. Chim.
Acta 1988, 142, 333; c) Q. Shen, W. Chen, Y. Jin, C. Shan, Pure
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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.
[8] A. Krasovskiy, P. Knochel, Angew. Chem. 2004, 116, 3396;
Angew. Chem. Int. Ed. 2004, 43, 3333. The reagent iPrMgCl稬iCl
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�LiCl 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�LiCl.
[10] Additionally,
ErCl3�H2O,
PrCl3�H2O,
YCl3�H2O,and
DyCl3�H2O were used analogously to prepare solutions of
type LnCl3�LiCl. Whereas the reactivity of PrCl3�LiCl is
similar to that of the La, Ce, and Nd derivatives (1 a?c),
ErCl3�LiCl, YCl3�LiCl, and DyCl3�LiCl display lower catalytic activities and give mediocre results in the addition
reactions.
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 497 ?500
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