Atom-economical preparation of aryl- And heteroaryl-lanthanum reagents by directed ortho metalation by using tmp3[La]

Article abstract of DOI:10.1002/chem.200903157

Chemical Equation Presentation Chemoselectivity and reactivity : The directed ortho-lanthanation by using tmp₃La·3MgCl ₂·5LiCl provides triarylor heteroaryl-La^III species in high yields (tmp = 2,2,6,6-tetramethylpiperidyl). A range of functionalities and sensitive heterocycles are tolerated in this metalation procedure. The resulting organometallic species can directly undergo Pd-catalyzed cross-coupling reactions (see scheme)

Full text of DOI:10.1002/chem.200903157

DOI: 10.1002/chem.200903157
Atom-Economical Preparation of Aryl– and Heteroaryl–Lanthanum
Reagents by Directed ortho-Metalation by Using tmp3[La]**
Stefan H. Wunderlich and Paul Knochel*[a]
The ortho-metalation of aromatics and heteroaromatics is
a powerful method for the functionalization of these ring
systems.[1] Although lithium bases[2] and several ate-bases[3]
allow the preparation of various ortho-metalated products,
there is still a need for more chemoselective bases. Recently,
we reported that the reaction of tmpMgCl·LiCl (1; tmp=
2,2,6,6-tetramethylpiperidyl)[4,5] or tmpLi[6] with metallic
brown solution (0.33m in THF; 95% yield as determined by
titration)[7a] is stable under argon for at least 2 months with-
out decomposition (Scheme 1).
chlorides, such as ZnCl2,[7] AlCl3,[8] MnCl2·2LiCl,[9]
[10]
FeCl2·2LiCl, or FeCl3
provides highly chemoselective
bases that tolerate a range of functional groups. The pres-
ence of MgCl2 and LiCl in these bases ensures good solubili-
ty in THF and
a
high kinetic basicity (compare
tmp2Zn·2MgCl2·2LiCl with tmpZnCl·LiCl).[7d]
Organolanthanum derivatives are relatively inexpensive
organometallic intermediates of low toxicity.[11] They are
usually prepared by transmetalation reactions starting from
lithium or magnesium reagents as has been pioneered by
Imamoto.[11,12] Several lanthanum amides have been report-
ed, mainly for the performance of hydroamination reac-
tions[11,13] or for structural studies.[11,14] Herein, we wish to
report a new base, that is, tmp3La·3MgCl2·5LiCl (2, abbrevi-
ated, for the sake of clarity, to tmp3[La]). The reaction of
tmp3[La] (2) with functionalized arenes and heteroarenes of
type 3 allows an expedient access to functionalized aryl and
heteroaryl derivatives of type 4 under mild conditions.
These unsaturated lanthanum derivatives display a unique
reactivity pattern and react with various electrophiles (5)
producing a range of polyfunctional products of type 6.
The new base 2 is readily prepared by the reaction of
tmpMgCl·LiCl[4] (1; 3.0 equiv) with the THF soluble com-
plex LaCl3·2LiCl[15] in THF for 12 h. The resulting dark
Scheme 1. Preparation of 2 and its reactivity with unsaturated substrates
of type 3 leading to triorganolanthanum reagents of type 4. E=electro-
phile, DG=directing group, FG=functional group, X=CH or hetero-
AHCTUNGTERGaNNUN tom.
The new base 2 is highly chemoselective and tolerates
methyl esters without special precautions. It also displays
good atom economy[16] since all three tmp groups can be
used for a directed metalation. Thus, the reaction of methyl
3-fluorobenzoate (3a) with 2 (0.35 equiv) in THF at À58C
(45 min) affords the triaryllanthanum species 4a.[17] This lan-
thanum organometallic reacts smoothly with hindered car-
bonyl derivatives, such as 2,6-dibenzylidenecyclohexanone
(5a, 1.0 equiv, À58C, 1 h) giving the spirolactone 6a in 87%
yield. Similarly, the reaction of 4a with 2-furoyl chloride
(5b, 1.1 equiv, À58C, 1 h) smoothly leads to the ketone 6b
in 85% yield. Remarkably, no further addition of 4a to 6b
was observed (Scheme 2).[18]
Furthermore, the metalation of ethyl 3-chlorobenzoate
(3b) proceeds within 3.5 h at 08C, and the reaction with di-
cyclopropyl ketone (5c; activated with LaCl3·2LiCl
(0.25 equiv)) leads to the lactone 6c in 69% yield (Table 1,
entry 1). Additionally, ethyl 3-bromobenzoate (3c) can be
converted into the lanthanated species within 2.5 h at 258C
and subsequent treatment with ethyl oxalyl chloride (5d)
gives the ketone 6d in 67% yield (Table 1, entry 2). Inter-
[a] S. H. Wunderlich, Prof. Dr. P. Knochel
Department Chemie und Biochemie
Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5–13, Haus F, 81377 Mꢁnchen (Germany)
Fax : (+49)89-2180-77680
E-mail: paul.knochel@cup.uni-muenchen.de
[**] tmp=2,2,6,6-tetramethylpiperidyl; tmp3[La]=tmp3La·3MgCl2·5LiCl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903157.
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Chem. Eur. J. 2010, 16, 3304 – 3307

COMMUNICATION
Table 1. Lanthanation of aromatic substrates by using 2 and subsequent
reactions with electrophiles.
Substrate
T [8C],
t [h]
Electrophile
Product/Yield [%][a]
1
2
3b
3c
0, 3.5
5c
5d
6c: 69[b]
Scheme 2. Typical metalation conditions of a functionalized arene, such
as 3a with 2 and its reaction with a hindered ketone (5a) or an acid chlo-
ride (5b).
25, 2.5
6d: 67
estingly, the triaryllanthanum species undergo Pd-catalyzed
cross-coupling reactions without the need of any additional
transmetalation. Thus, the lanthanum species 4d, obtained
by the metalation of ethyl 3-fluorobenzoate (3d) within
30 min at 08C, reacts directly with the aryl iodide 5e in the
3
4
3d
3e
0, 0.5
5e
6e: 79[c]
0, 1.25 5 f
6 f: 74[b]
presence of [PdACHTUNGTRENNUNG(PPh3)4] (2.5 mol%) giving the biphenyl 6e
in 79% yield (Table 1, entry 3). Moreover, ethyl 3-cyano-
benzoate (3e) is regioselectively metalated at the 2-position
within 1.25 h at 08C. After the reaction with cyclooctanone
(5 f; activated with LaCl3·2LiCl (0.25 equiv)), the spirolac-
tone 6 f is isolated in 74% yield (Table 1, entry 4). Addition-
ally, the lanthanation of ethyl 4-cyanobenzoate (3 f) pro-
ceeds within 3 h at À258C and the reaction with 3-chloro-
benzoyl chloride provides the ketone 6g in 68% yield
(Table 1, entry 5). Furthermore, 2-bromo-5-fluoro-benzoni-
trile (3g) is converted into the lanthanum species 4g within
30 min at À358C. Treatment of 4g with dicyclohexyl ketone
provides the alcohol 6h in 66% yield (Table 1, entry 6). 3-
Methoxybenzonitrile (3h) is readily lanthanated at the 2-po-
sition within 1.5 h at 258C and subsequent treatment with
cyclohexane carbaldehyde (5i) gives the product 6i in 74%
yield (Table 1, entry 7). Additionally, the metalation of 4-flu-
orobenzonitrile (3i) is accomplished within 1 h at 08C giving
the triaryllanthanum species 4i. The alcohol 6j is obtained
in 77% yield after the addition of 4i to dicyclopropyl
ketone (5c), whereas the cross-coupling product 6k is isolat-
5
3 f
À25, 3
5g
6g: 68
6
7
3g
3h
À35, 0.5
5h
5i
6h: 66
6i: 74
25, 1.5
8
9
3i
3i
0, 1
0, 1
0, 2
5c
5j
6j: 77
ed in 73% yield by using [PdACHTNUGTRNEUNG(PPh3)4] (2.5 mol%) and ethyl
4-iodobenzoate (5j) (Table 1, entries 8 and 9). Finally, the
lanthanation of 4-chloro-N,N-diethylbenzamide (3j) pro-
ceeds smoothly within 2 h at 08C and the subsequent Pd-cat-
alyzed cross-coupling with 4-iodobenzonitrile (5l) afforded
the biphenyl 6l in 80% yield (Table 1, entry 10).
Heterocyclic systems are also readily metalated by using
2. Thus, the treatment of 2-phenyl-1,3,4-oxadiazole (3k)
with 2 (0.35 equiv) in THF (À458C, 30 min) gives the de-
sired metalated species 4k. In contrast to the corresponding
magnesiated or lithiated heterocycle,[7a] no fragmentation of
this sensitive heterocycle resulting in the formation of ben-
zonitrile is observed. Quenching the reaction with 4-phenyl-
cyclohexanone (5l, 1.0 equiv, À458C, 1 h) leads to the de-
sired tertiary alcohol 6m in 80% yield. Alternatively, the re-
action of 4k with 3,3-dimethyl acryloyl chloride (5m,
6k: 73[c]
10 3j
5k
6l: 80[c]
[a] Yield of the analytically pure isolated product. [b] LaCl3·2LiCl
(0.25 equiv) was used. [c] [Pd(PPh3)4] (2.5 mol%) was used.
AHCTUNGTRENNUNG
1.1 equiv, À458C, 1 h) provides the ketone 6n in 75% yield
(Scheme 3).
The metalation of both electron-rich and -poor heterocy-
cles can be performed as summarized in Table 2. Thus, the
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3305

S. Wunderlich and P. Knochel
(3n) undergoes a smooth metalation at À308C within
45 min and subsequent treatment with cycloheptanone (5r)
gives the tertiary alcohol 6s in 71% yield (Table 2, entry 5).
In summary, we have reported a new convenient proce-
dure for preparing polyfunctional aryl and heteroaryl lan-
thanum derivatives tolerating important functional groups,
such as a methyl ester, a cyano group, and halogen atoms.
These triaryl- and triheteroaryllanthanum species react with
various electrophiles. Especially interesting is the direct Pd-
catalyzed cross-coupling reaction with aryl iodides. Remark-
ably, addition reactions to aldehydes or ketones afford steri-
cally hindered alcohols or lactones and the acylation reac-
tions with acid chlorides and an anhydride provide the ex-
pected ketones in satisfactory yields. The excellent atom
economy of the reaction is worth mentioning, since only
0.33 equivalent of La is required for this metalation proce-
dure. Further investigations of these lanthanation reactions
applied to more complex unsaturated substrates are current-
ly underway in our laboratories.
Scheme 3. Metalation of 2-phenyl-[1,3,4]-oxadiazole (3k) with 2 and its
reaction with a ketone (5l) and an acid chloride (5m).
Table 2. Lanthanation of heteroaromatics of type 3 by using 2 and subse-
quent reactions with electrophiles.
Substrate
T [8C],
t [h]
Electrophile
Product/Yield [%][a]
1
2
3l
0, 0.5
0, 0.5
5n
6o: 83 (d.r. 9:1)
Experimental Section
Preparation of reagent 2: In a dry and argon-flushed 250 mL Schlenk
flask, freshly titrated tmpMgCl·LiCl (100 mmol, 1.18m, 85 mL) was
purged and cooled to 08C. Then, LaCl3·2LiCl (0.5m in THF, 66 mL,
33 mmol) was added over 5 min. The resulting mixture was stirred for
30 min at 08C, warmed to 258C and stirred for another 12 h. The result-
ing solution of 2 was concentrated in vacuo and was titrated prior to use
at 08C with benzoic acid (0.5m in THF) by using 4-(phenylazo)diphenyl-
3l
5o
6p: 77
AHCTUNGTRENNUNG
A
equipped with a magnetic stirring bar was charged with a solution of 3a
(308 mg, 2 mmol) in dry THF (2 mL) and cooled to À58C. A solution of
2 (0.33m in THF, 2.2 mL, 0.73 mmol) was added dropwise and the reac-
tion mixture was stirred at À58C for 45 min. The metalation progress was
monitored by GC analysis of reaction aliquots that were quenched with
allyl bromide. Then, compound 5a (550 mg, 2.0 mmol) was added, and
the resulting mixture was stirred for 1 h at À58C. After standard workup,
the solvent was evaporated in vacuo. The crude product was purified by
column chromatography (pentane/ether=8:1) to give 6a (690 mg, 87%
yield) as a colorless solid.
3
4
3m
3m
À20, 0.75
À20, 0.75
5p
5q
6q: 74
6r: 85
5
3n
À30, 0.75
5r
6s: 71
Acknowledgements
[a] Yield of the analytically pure isolated product.
We thank the Fonds der Chemischen Industrie, the European Research
Council (ERC) and the Deutsche Forschungsgemeinschaft (DFG) for fi-
nancial support. We also thank Evonik AG (Hanau), BASF AG (Ludwig-
shafen), W. C. Heraeus GmbH (Hanau), and Chemetall GmbH (Frank-
furt) for the generous gift of chemicals.
metalation of benzothiazole (3l) proceeds smoothly within
30 min at 08C. The subsequent reactions with camphor (5n)
or the acid chloride 5o give the products 6o and 6p in 83
and 77% yield, respectively (Table 2, entries 1 and 2). More-
over, the reaction of ethyl 2-chloronicotinate (3m) with 2
gives the fully metalated species 4m within 45 min at
À208C.[19] The lactone 6q is obtained in 74% yield after
quenching with a-tetralone (5p, Table 2, entry 3). Surpris-
ingly, the addition of 4m to the sterically hindered anhy-
dride 5q leads to the tert-butyl ketone 6r in 85% yield
(Table 2, entry 4). Additionally, 2-chloro-3-cyanopyridine
Keywords: acylation · cross-coupling · directed metalation ·
lanthanum · metal amides
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Preparation of Aryl and Heteroaryl-Lanthanum Reagents
COMMUNICATION
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Received: November 17, 2009
Published online: February 24, 2010
Chem. Eur. J. 2010, 16, 3304 – 3307
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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