Synthesis of Polyfunctionalized Triaryllanthanum Reagents by Using Ph3La and Related Species as Exchange Reagents

Article abstract of DOI:10.1002/chem.201801527

Ph₃La?5 LiCl and the related (m-xylyl)₃La?5 LiCl were used as Hal/La exchange reagents (Hal=Br, I) for the preparation of various triaryl- and triheteroaryl-lanthanum derivatives. These new exchange reagents are compatible with isoquinolines and some functional groups such as a nitrile or an ester. The reactivity of the resulting lanthanum compounds towards electrophiles, such as ketones, aldehydes, N,N-dimethylamides, and primary alkyl halides was investigated. Additionally, a Pd-catalyzed cross-coupling procedure with aryl bromides was developed.

Full text of DOI:10.1002/chem.201801527

A Journal of
Accepted Article
Title: Synthesis of Polyfunctionalized Triaryllanthanum Reagents Using
Ph3La and Related Species as Exchange Reagents
Authors: Andreas Dominik Benischke, Lucile Anthore-Dalion, Fabien
Kohl, and Paul Knochel
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To be cited as: Chem. Eur. J. 10.1002/chem.201801527
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Synthesis of Polyfunctionalized Triaryllanthanum Reagents Using
Ph3La and Related Species as Exchange Reagents
Andreas D. Benischke,+ Lucile Anthore-Dalion,+ Fabien Kohl, and Paul Knochel*
Abstract: Ph3La·5LiCl and the related (m-Xylyl)3La·5LiCl were used
as Hal/La-exchange reagents (Hal = Br, I) for the preparation of
various triaryl- and triheteroaryl-lanthanum derivatives. These new
exchange reagents are compatible with isoquinolines and some
functional groups such as a nitrile or an ester. The reactivity of the
resulting lanthanum compounds towards electrophiles, such as
It exchanges only its two butyl residues, whereas the methyl
substituent plays the role of a dummy group. Additionally, this
reagent gave unsatisfactory results with more sensitive
substrates bearing for example an ester substituent or
heterocycles such as isoquinoline.
ketones, aldehydes, N,N-dimethylamides and primary alkyl halides Results and Discussion
was investigated. Additionally, Pd-catalyzed cross-coupling
a
procedure with aryl bromides was developed.
In the search for a more general and convenient exchange
reagent avoiding the presence of a dummy residue, we wish now
to report the use of Ph3La·5LiCl (2) as a more stable exchange
reagent. The triaryllanthanum derivative 2 can be stored for at
least two weeks at 0 °C.9 Ph3La·5LiCl (2) was best prepared by
transmetalation3a-c of PhLi (3.0 equiv) with LaCl3·2LiCl in THF at
−30 °C for 0.5 h leading to a brownish-black solution of 2 (ca.
0.15 M, 79% yield; Scheme 1).10
Introduction
Organometallic reagents derived from lithium, magnesium or zinc
have found numerous applications in organic synthesis.1
Nevertheless there is
a need for other chemoselective
organometallic reagents, which could, for instance, combine the
high reactivity of organolithium reagents with a larger functional
group tolerance. The preparation and reactivity of
organolanthanides, such as La, Ce or Sm, have recently attracted
much interest.2 Whereas they are especially used in coordination
and inorganic chemistry,3 their applications in organic synthesis
have been less reported.4,5 Organolanthanides are good
candidates for fine-tuning the character of the carbon-metal bond,
but convenient methods for their preparation are still scarce.6
They show useful properties, such as a high reactivity towards
carbonyl compounds, resulting from the high oxophilicity and
Lewis acidity of lanthanides(III).7
Scheme 1. Preparation of Ph3La·5LiCl (2).
We found that several aryl or heteroaryl halides, which
decomposed
under
our
previous
conditions
using
nBu2LaMe·5LiCl (2), can now be converted to the desired
triaryllanthanum derivatives. Whereas performing an exchange
on 1-iodoisoquinoline (3) with nBu2LaMe·5LiCl (1) resulted in
degradation, using Ph3La·5LiCl (2) led to a fast reaction at −50 °C
within 5 min providing the triheteroaryllanthanum species 4.
Subsequent trapping with aldehyde 5a led to the desired alcohol
6 in 60% yield (Scheme 2, equation 1). Remarkably, an ester
group can be tolerated under those new conditions. Hence, ethyl
5-bromothiophene-2-carboxylate (7) was converted into the
corresponding triheteroaryllanthanum derivative 8 which added to
aldehyde 5b giving the secondary alcohol 9 in 76% yield
(equation 2).
We have reported
a straightforward method to prepare
functionalized diaryl- and diheteroaryl-lanthanum derivatives via
a novel halogen-lanthanum exchange.8 The mixed species
nBu2LaMe·5LiCl (1) allows a fast halogen-lanthanum exchange
on aryl and heteroaryl bromides and iodides leading to Ar2LaMe
species which undergo selective trapping reactions with a range
of carbonyl compounds and amides.8 This exchange proceeds
with a higher functional group tolerance compared to the well-
known halogen-lithium exchange1a,b,e and with enhanced reaction
rates compared to the halogen-magnesium exchange.1c,d
Nevertheless, nBu2LaMe·5LiCl (1) needs to be freshly prepared
at −30 °C, starting from the corresponding alkyllithium reagents
and LaCl3·2LiCl for optimum results.4a In fact, the reagent 1 is not
long-term stable and decomposes within less than 2 h at −30 °C.
[*]
[+]
M. Sc. A. D. Benischke,[+] Dr. Ing. Lucile Anthore-Dalion,[+] F. Kohl,
Prof. Dr. P. Knochel
Department Chemie, Ludwig-Maximilians-Universität München
Butenandtstrasse 5–13, Haus F, 81377 München (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
Scheme 2. Comparison of nBu2LaMe·5LiCl (1) and Ph3La·5LiCl (2) as
exchange reagents. (Yields are calculated based on the electrophile amounts)
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Next, we have examined the scope of Ph3La·5LiCl (2) as I/La-
exchange reagent. We found that 4-iodobenzotrifluoride (10a,
1.0 equiv) underwent a fast exchange using Ph3La·5LiCl (2,
0.40 equiv) leading to the 4-CF3 substituted triaryllanthanum
reagent 11a. Further reaction with 3,4,5-trimethoxybenzaldehyde
led to the secondary alcohol 12a in 97% yield. Similarly, two 3,5-
dihalogenated aryl iodides 10b and 10c were used for the same
transformation and subsequent trappings with benzophenone
derivatives resulted in the desired tertiary alcohols 12b and 12c
in 61-73% yield. Additionally, aryl iodides bearing a nitrile group
such as 10d and 10e were also compatible with these reaction
conditions leading to the corresponding triaryllanthanum species
11d and 11e. Further addition of ketones gave alcohols 12d and
12e in 60-73% yield. An electron-rich aryl iodide 10f was
converted into the expected triaryllanthanum reagent 11f by using
Ph3La·5LiCl (2, 0.40 equiv) and was trapped with 2,4-dichloro-
benzaldehyde to produce alcohol 12f in 73% yield. In this special
case, the exchange can be explained by the possible coordination
of lanthanum to the ortho-methoxy group, which leads to a more
stable Ar3La 11f. Finally, 2-iodothiophene (10g) and a 3-
iodoindole derivative 10h underwent similar exchanges, and the
related lanthanum species 11g and 11h added to carbonyl
compounds resulting in the alcohols 12g and 12h in 86-94%
yields (Scheme 3).
electrophile. This behavior was not observed using the new
exchange reagent Ph3La·5LiCl (2).
Additionally, functionalized aryl bromides of type 13 underwent an
exchange reaction using Ph3La·5LiCl (2, 0.40 equiv) at −50 °C
within 5 min. 4-Bromobenzotrifluoride (13a) gave the same result
as the corresponding iodide 10a, and the expected secondary
alcohol 12a was obtained in 95% yield. Furthermore, the two
fluoro-substituted aryl bromides 13b and 13c reacted under the
same conditions leading to the derived triaryllanthanum reagents.
Subsequent trapping with ketones resulted in the tertiary alcohols
12i and 12j in 82-88% yield. Cyano-substituted aryl bromides
such as 13d-f were converted into the corresponding
triaryllanthanum reagents, and further reactions with ketones or
an aldehyde furnished the alcohols 12k-m in 63-83% yield.
Interestingly, the exchange on heteroaryl bromides 13g and 13h
provided the corresponding lanthanum reagents, which further
added to an aldehyde or an Ellman tert-butyl sulfinyl imine
resulting in the alcohol 12n and the amine 12o in 85-90% yield.
Finally, a keto-steroid reacted with a triaryllanthanum reagent,
leading to the desired tertiary alcohol 12p in 79% yield. (Scheme
4).
Scheme 4. Exchange on aryl bromides of type 13 using Ph3La·5LiCl (2). (Yields
are calculated based on the electrophile amounts)
Scheme 3. Exchange on aryl iodides of type 10 using Ph3La·5LiCl (2). (Yields
are calculated based on the electrophile amounts)
Interestingly, this halogen-lanthanum exchange proceeded well
with N-heterocycles such as iodo- or bromo-pyridines and
isoquinolines of type 14, using Ph3La·5LiCl (2, 0.40 equiv) at
−50 °C within 5 min. The corresponding triheteroaryllanthanum
reagents 15 underwent efficient trapping reactions with a range of
carbonyl compounds of type 5 and furnished alcohols of type 16
in 50-81% yield (Scheme 5).
Remarkably, the I/La-exchange with aryl iodides using
Ph3La·5LiCl (2) instead of nBu2LaMe·5LiCl (1) proved to be much
more efficient. In the case of nBu2LaMe·5LiCl (1), in situ
generated butyl iodide showed a detrimental effect on the
exchange. Indeed, butyl iodide underwent a reverse exchange
with the formed diaryllanthanum reagents leading to an
equilibrium, and therefore to an incomplete I/La-exchange. The
highest yields were achieved by using 0.65 equivalents of
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Scheme 6. Acylation reactions of triaryllanthanum reagents using N,N-dimethyl
amides 17. (Yields are calculated based on the electrophile amounts)
Scheme 5. Halogen-lanthanum exchanges on N-heterocycles of type 14 using
Ph3La·5LiCl (2). (Yields are calculated based on the electrophile amounts)
Remarkably, the triaryllanthanum species prepared from 13i
reacted with alkyl halides at −30 °C without the need of any
transition-metal catalyst. This nucleophilic substitution with the
alkyl bromide 19a proceeded within 1 h at −30 °C, resulting in the
alkylated arene 20a in 60% yield. Furthermore, alkyl iodide 19b
provided the substitution product 20b in 66% yield. Unfortunately,
the scope of such nucleophilic substitutions proved to be quite
limited (Scheme 7).
Besides additions to ketones, organolanthanum compounds
underwent acylation reactions with N,N-dimethylamides.8,11 The
formation of a stable tetrahedral intermediate at −50 °C hampers
a subsequent addition reaction, and only traces of overaddition
alcohols are observed. Thus, 1-iodoisoquinoline (3) reacted with
Ph3La·5LiCl (2, 0.40 equiv) leading to the corresponding
triheteroaryllanthanum derivative 4 which was acylated with N,N-
dimethylamide 17a (0.80 equiv) affording cyclopropyl ketone 18a
in 78% yield. Also, 2,5-dimethoxy bromobenzene 13j was
converted into the desired triaryllanthanum species and was
trapped with amide 17b, resulting in the ketone 18b in 69% yield.
In this case, the same phenomenon as for 10f was observed. The
coordination of the lanthanum to the ortho-methoxy substituent is
the driving force of the reaction, making the Br/La-exchange
complete, although 13j is more electron-rich than the phenyl
residue. Similarly, electron-poor arenes such as 13k underwent
this exchange sequence. The triaryllanthanum species underwent
a subsequent acylation with amide 17c leading to ketone 18c in
64% yield (Scheme 6).
Scheme 7. Alkylation reactions of an organolanthanum compound. (Yields are
calculated based on the electrophile amounts)
Preliminary experiments, using 4-iodoanisole (10i) and
Ph3La·5LiCl (2) resulted in a 1:1 mixture of iodobenzene and 10i.
This equilibrium, already described with lithium compounds,12
could neither be shifted by an excess of exchange reagent, nor
by increasing the temperature up to 0 °C.9
We envisioned that the use of the electron-rich and sterically
hindered meta-xylyl residue may allow to shift the
equilibrium in I/La-exchanges. Thus, tri(meta-xylyl)lanthanum
((m-Xylyl)3La·5LiCl, 21) was prepared by transmetalation of
m-xylyllithium with LaCl3·2LiCl at −30 °C (ca. 0.11 M, 80% yield).13
To our delight, 4-iodoanisole (10i) underwent now a full exchange
at −50 °C within 5 min using (m-Xylyl)3La·5LiCl (21, 0.40 equiv).
The resulting triaryllanthanum reagent 11i was further trapped
with 3-methoxybenzaldehyde (5b), and the secondary alcohol
12q was obtained in 67% yield. In the case of related
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4-bromoanisole (13l), however, no exchange took place at −50 °C
even after elongated reaction time, probably because of the steric
hindrance of the m-Xylyl group. However, this exchange could be
performed at 0 °C within 5 min, and the corresponding lanthanum
reagent subsequently added to 5b producing 12q in 64% yield.
Interestingly, Ph3La·LiCl did not react at 0 °C with m-xylyl-2-
bromide, even after extended reaction times. In contrast,
(m-Xylyl)3La·5LiCl led to full conversion of bromobenzene.9
Similarly, aryl bromides 13m and 13n reacted with
(m-Xylyl)3La·5LiCl (21) at 0 °C affording, after trapping with a
ketone or an amide, the expected products 12r and 18d in 62-
85% yield. Also 1-iodonaphthalene (10j) underwent an efficient
exchange under these conditions, and the resulting lanthanum
compound added to an amide leading to 18e in 50% yield.
Furthermore, aryl halides bearing more electron-donating
substituents such as 10k and 13o,p could be converted into the
corresponding lanthanum reagents and were subsequently
trapped with ketones affording tertiary alcohols 12s-u in 60-76%
yield. Finally, a competitive reaction between the meta-xylene
derived exchange reagent 21 and 5-iodo-m-xylene 10l resulted,
after trapping with a ketone, in the alcohol 12v in 74% yield and
only trace amounts of the other regioisomer were observed
(Scheme 8).
Scheme 9. Halogen-lanthanum exchanges on 13q (m-Xylyl)3La·5LiCl (21).
(Yields are calculated based on the electrophile amounts)
Although Kumada-Corriu (Mg),14 Negishi (Zn),15 Stille (Sn),16 and
Suzuki-Miyaura (B)17 couplings are well-established, cross-
couplings with organolanthanum reagents have not been reported.
Additionally, Feringa demonstrated the feasibility of a direct cross-
coupling of highly reactive organolithium compounds.18 Due to the
similar reactivity of organolanthanum compounds compared to
organolithium reagents, we have examined this cross-coupling.
In preliminary experiments, we used Ph3La·5LiCl (2) and 4-
bromoanisole (13l) as the electrophile. A range of Pd- and Ni-
catalysts were tested, toluene was used as solvent, and the
reactions were carried out at 25 °C.9 A catalytic system consisting
of Pd(OAc)2 (5.0 mol%) and XPhos19 (10 mol%) proved to
perform best, providing biphenyl 22a in 74% yield, and only trace
amounts of both homocoupling products 23a and 24a, along with
anisole (25a) were observed (Scheme 10).
Scheme 10. Pd-catalyzed cross-coupling of Ph3La·5LiCl (2) with aryl bromide
13l.
Next, we examined the compatibility of these results with our
standard exchange reactions. Therefore, the 4-CF3 substituted
aryl bromide 13a was treated under the optimized conditions with
2, leading to the in situ generation of bromobenzene (13r) and the
corresponding triaryllanthanum reagent 11a. The cross-coupling
product 22b was isolated in 81% yield (Scheme 11).
Scheme 8. Halogen-lanthanum exchanges on electron-rich substrates with
(m-Xylyl)3La·5LiCl (21). (Yields are calculated based on the electrophile
amounts)
The exchange of N,N-dimethyl-4-bromoaniline (13q) succeeded
at 0 °C within 30 min, although in only 75% GC-conversion.
Subsequent trapping with amide 17d gave the ketone 18f in 86%
yield. Remarkably, although the exchange was not completed,
product 18g resulting from xylene attack was not observed
(Scheme 9).
Scheme 11. Pd-catalyzed cross-coupling of 11a with the in situ generated
bromobenzene 13r.
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To make sure that the in situ generated bromobenzene will not Conclusion
disturb the coupling if additional aryl bromides were added, we
examined other exchange reagents such as (m-Xylyl)3La·5LiCl
(21) and nBu2LaMe·5LiCl (1). Indeed, in those cases, in situ
generated 2-bromo-m-xylene or butyl bromide are less reactive
than most aryl bromides added. The use of nBu2LaMe·5LiCl (1)
as exchange reagent gave the best results. The reactions were
carried out in toluene as solvent at 25 °C. The catalyst loading
could be lowered to 1.0 mol% of Pd(OAc)2 and 2.0 mol% of
XPhos.19
Thus, aryl bromides of type 13 were converted into the
corresponding diaryl(methyl)lanthanum reagents of type 26 using
nBu2LaMe·5LiCl (1) and underwent efficient cross-coupling
reactions with aryl bromides within 5 min at 25 °C. Hence,
halogenated lanthanum reagents 26a-d reacted with
bromoanisole derivatives leading to the expected substituted
biphenyls 22c-f in 50-64% yield. Similarly, the cross-couplings of
26e and 26f proceeded smoothly with 4-bromoveratrole or N,N-
dimethyl-4-bromoaniline to furnish products 22g and 22h in 59-
69% yield. Furthermore, the reactions of more electron-rich
lanthanum reagents 26g-k with various aryl bromides succeeded
under those conditions, resulting in the desired non-symmetric
biphenyls 22i-m within only 5 min reaction times in 50-63% yield.
A related Negishi cross-coupling procedure performed via
transmetalation of compounds 26 with ZnCl2 did not give better
yields (Scheme 12).9
Various triaryl- and triheteroaryl-lanthanum derivatives were
prepared either using Ph3La·5LiCl (2) or the related reagent
(m-Xylyl)3La·5LiCl (21) within very short reaction times of 5 min.
The various properties of the exchange reagents 1, 2, and 21
have been summarized in Table 1. The resulting lanthanum
compounds underwent successful trappings with carbonyl
compounds or amides. Sensitive functional groups like nitriles
and esters were tolerated in some cases. The broad reaction
scope, combined with fast reaction rates, make these two new
exchange reagents convenient alternatives to the previously
reported nBu2LaMe·5LiCl (1). Additionally,
a
fast and
straightforward Pd-catalyzed cross-coupling procedure involving
Ar2LaMe (26) was developed. Further investigations on
organolanthanide derivatives are in progress in our laboratories.
Table 1. Comparison between the different exchange reagents 1, 2 and 21
Exchange
reagent
nBu2LaMe·5LiCl
(1)
Ph3La·5LiCl
(m-Xylyl)3La·
5LiCl (21)
(2)
Generated
Species
Ar2LaMe
Ar3La
Ar3La
Temperature
and reaction
time of the
exchange
−50 °C (ArI)
0 °C (ArBr)
5 min
−50 °C
5 min
−50 °C
5 min
Scope of aryl
halides


electron-poor
electron-rich
 electron-poor
 electron-rich

electron-poor
need to be
freshly prepared
stable for at least
2 weeks at 0 °C
Stability
stable at 0 °C
at −30 °C
Compatibility
with
functional
groups
 nitriles



nitriles
esters
isoquinolines
 esters
not determined
 isoquinolines
Experimental Section
Preparation of LaCl3·2LiCl (0.33 m in THF)4a
Commercially available LaCl3·6H2O (35.3 g, 100 mmol,) was mixed with
LiCl (8.40 g, 200 mmol) in a 500 mL Schlenk-flask, and water (100 mL)
was slowly added under vigorous stirring. The resulting slurry was stirred
under high vacuum at room temperature for 4 h. Stirring was continued for
4 h at 40 °C, 4 h at 60 °C, 4 h at 80 °C, 4 h at 100 °C, 4 h at 120 °C, 4 h at
140 °C, and finally 4 h at 160 °C. The slow increase of temperature and
efficient stirring were essential for the success of the procedure. The
resulting solid was cooled to room temperature, and freshly distilled THF
(300 mL) was added. Then, molecular sieves (50 g, 4 Å) were added, and
the resulting mixture was stirred for 24 h at room temperature. Finally, the
insoluble material (mostly crushed molecular sieves) was removed by
Schlenk-filtration under an argon atmosphere. By this procedure, a clear
and colorless solution of LaCl3·2LiCl (0.33 M in THF) was obtained, which
can be stored at room temperature under argon for several months.
Scheme 12. Cross-couplings of Ar2LaMe (26) with aryl bromides. (Yields are
calculated based on the electrophile amounts)
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To ensure the reproducibility of this procedure, the LaCl3·6H2O·2LiCl
mixture was connected to a high vacuum line, which provided at least
1·10-2 mbar. Additionally, a large stirring bar was used for continuous
stirring of the resulting slurry. The heating process was performed using a
usual hotplate, equipped with an oil bath and a sensor for temperature
control. Every 4 h the temperature was increased by 20 °C. The heating
steps were conducted in this way over 3 d. For example, the first day, the
mixture was gradually heated, namely 4 h at 20 °C, followed by 4 h at
40 °C, and then 4 h at 60 °C. The resulting mixture was then cooled to
25 °C and stored under argon overnight under vigorous stirring. The
heating was restarted on the next day, applying first a gradient of
temperature over 30 min until it reached the next stage (namely 80 °C for
the second day), and so on. For the last two heating steps, 4 h 140 °C and
4 h at 160 °C, the gradient of temperature was crucial. Afterwards, the
resulting powder was allowed to cool to 25 °C, mixed with 50 g of pre-dried
molecular sieves (4 Å), freshly distilled THF (300 mL for 100 mmol of
LaCl3) and stirred for 24 h at room temperature before being filtrated. This
procedure could also be used to prepare CeCl3·2LiCl, NdCl3·2LiCl,
ErCl3·2LiCl, PrCl3·2LiCl, YCl3·2LiCl and DyCl3·2LiCl.4a
Typical Procedure 3: Preparation of Ar2LaMe 26a from 4-
bromobenzotrifluoride (13a) with nBu2LaMe·5LiCl (1) and its Pd-
catalyzed cross-coupling with 4-bromoanisole leading to the
biphenyl 22c
A dry and argon-flushed Schlenk-tube was charged with freshly prepared
LaCl3·2LiCl (1.8 mL, 0.60 mmol, 0.60 equiv, 0.33 M in THF) and cooled to
–30 °C. Subsequently, MeLi (0.25 mL, 0.60 mmol, 0.60 equiv, 1.70 M in
Et2O) and nBuLi (0.46 mL, 1.2 mmol, 1.2 equiv, 2.61 M in hexane) were
added, and the resulting solution was stirred at –30 °C for 0.5 h.
Subsequently, this solution was cooled to –50 °C, and 4-bromo-
benzotrifluoride 13a (225 mg, 1.00 mmol, 1.0 equiv) was added neat. After
5 min, the corresponding diaryl(methyl)lanthanum reagent 26a was added
dropwise within 2 min to a solution of Pd(OAc)2 (1.8 mg, 8.0 μmol,
1.0 mol%), XPhos (7.6 mg, 16 μmol, 2.0 mol%), 4-bromoanisole (150 mg,
0.80 mmol, 0.80 equiv) in freshly distilled toluene (2.4 mL) at room
temperature. The reaction mixture was further stirred for 5 min. After full
conversion of the electrophile, a saturated aqueous solution of NH4Cl was
added and extracted with EtOAc (3 × 75 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated under reduced pressure.
Purification of the crude product by flash column chromatography (SiO2,
i-hexane : EtOAc = 99 : 1, Rf = 0.58) gave the biphenyl 22c (128 mg,
0.51 mmol, 64%) as a white solid (m.p. 112 °C).
Typical Procedure 1: preparation of Ar3La 4 from 1-iodoisoquinoline
(3) with Ph3La·5LiCl (2) and subsequent trapping with aldehyde 5a
leading to alcohol 6
A pre-dried and argon flushed Schlenk-tube, equipped with a magnetic
stirring bar and a rubber septum was charged with freshly prepared
LaCl3·2LiCl (2.4 mL, 0.80 mmol, 0.40 equiv, 0.33 M in THF) and cooled to
–30 °C. Subsequently, PhLi (1.3 mL, 2.4 mmol, 1.2 equiv, 1.9 M in Bu2O)
was added, and the resulting brownish solution was stirred at –30 °C for
0.5 h, and then cooled to –50 °C. Thereupon, 1-iodoisoquinoline (3,
510 mg, 2.00 mmol, 1.0 equiv) was added dropwise, and the reaction
Acknowledgements
We thank the LMU Munich for financial support and the Humboldt
foundation for a fellowship to L.A.-D. We also thank Albemarle
and BASF for generous gifts of chemicals.
mixture was stirred for additional
5
min. As electrophile, 4-
(methylthio)benzaldehyde (5a, 244 mg, 1.60 mmol, 0.80 equiv) was used,
and the reaction was allowed to warm to room temperature. After full
conversion of the electrophile, a saturated aqueous solution of NH4Cl was
added and extracted with EtOAc (3 × 75 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated under reduced pressure.
Purification of the crude product by flash column chromatography (SiO2,
i-hexane : EtOAc = 6 : 4, Rf = 0.50) gave the secondary alcohol 6 (271 mg,
0.96 mmol, 60%) as a yellow solid (m.p. 112 °C).
Keywords: lanthanum • halogen-lanthanum exchange •
triaryllanthanum reagents • acylation • nucleophilic substitution
[1]
a) Organolithiums: selectivity for synthesis, Vol. 23., (Ed.: J. Clayden)
Elsevier, Oxford, 2002; b) F. Leroux, M. Schlosser, E. Zohar, I. Marek in
The Chemistry of Organolithium Compounds (Eds.: Z. Rappoport, I.
Marek) John Wiley & Sons, Ltd, Chichester, 2004; c) Handbook of
Functionalized Organometallics: Applications in Synthesis (Ed.: P.
Knochel), Wiley-VCH, Weinheim, 2008; d) The Chemistry of
Organomagnesium Compounds (Eds.: Z. Rappoport, I. Marek) John
Wiley & Sons, Ltd, Chichester, 2008; e) Lithium Compounds in Organic
Synthesis−From Fundamentals to Applications (Eds.: R. Luisi, V.
Capriati), Wiley-VCH, Weinheim, 2014.
Typical Procedure 2: preparation of Ar3La 11r from 5-bromo-1,2,3-
trimethoxybenzene (13n) with (m-Xylyl)3La·5LiCl (21) and subsequent
trapping with amide 17a leading to ketone 18d
A dry and argon-flushed Schlenk-tube was charged with 2-bromo-1,3-
dimethylbenzene (222 mg, 1.20 mmol, 1.20 equiv) and freshly distilled
THF (0.5 mL) and cooled to –78 °C. tBuLi (1.3 mL, 2.6 mmol, 2.6 equiv,
1.96 M in pentane) was then added dropwise, and the resulting yellowish
mixture was stirred for 5 min. Subsequently, LaCl3·2LiCl (1.2 mL,
0.40 mmol, 0.40 equiv, 0.33 m in THF) was added, and the mixture was
placed at –30 °C for 30 min, resulting in a clear yellow solution which was
then placed at 0 °C. Thereupon, 5-bromo-1,2,3-trimethoxybenzene (13n,
247 mg, 1.00 mmol, 1.0 equiv) was added dropwise, and the reaction
[2]
a) A. S. Dudnik, V. L. Weidner, A. Motta, M. Delferro, T. J. Marks, Nature
Chem. 2014, 6, 1100-1107; b) G. Nocton, L. Ricard, Chem. Commun.
2015, 51, 3578-3581; c) A. A. Trifonov, I. V. Basalov, A. A. Kissel, Dalton
Trans. 2016, 45, 19172-19193; d) C. E. Kefalidis, L. Castro, L. Perrin, I.
Del Rosal, L. Maron, Chem. Soc. Rev. 2016, 45, 2516-2543; e) K. C.
Boteju, A. Ellern, A. D. Sadow, Chem. Commun. 2017, 53, 716-719; f) V.
Goudy, A. Jaoud, M. Cordier, C. Clavaguéra, G. Nocton, J. Am. Chem.
Soc. 2017, 139, 10633-10636.
mixture was stirred for additional
5 min. As electrophile, N,N-
dimethylcyclopropanecarboxamide (17a, 91 mg, 0.80 mmol, 0.80 equiv)
was used, and the reaction was allowed to warm to room temperature.
After full conversion of the electrophile, a saturated aqueous solution of
NH4Cl (5 mL) was added and extracted with EtOAc (3 × 10 mL). The
combined organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure. Purification of the crude product by
flash column chromatography (SiO2, i-hexane : EtOAc = 85 : 15, Rf = 0.28)
gave the ketone 18d (161 mg, 0.68 mmol, 85%) as a colorless oil.
[3]
a) G. Campari, F. A. Hart, Inorg. Chim. Acta 1982, 65, 217-218; b) P. B.
Hitchcock, M. F. Lappert, R. G. Smith, R. A. Bartlett, P. P. Power, J.
Chem. Soc., Chem. Commun. 1988, 1007-1009; c) J. L. Atwood, M. F.
Lappert, R. G. Smith, H. Zhang, J. Chem. Soc., Chem. Commun. 1988,
1308-1309; d) C. J. Schaverien, N. Meijboom, A. G. Orpen, J. Chem.
Soc., Chem. Commun. 1992, 124-126; e) P. B. Hitchcock, Q.-G. Huang,
M. F. Lappert, X.-H. Wei, J. Mater. Chem. 2004, 14, 3266-3273; f) C. G.
J. Tazelaar, S. Bambirra, D. van Leusen, A. Meetsma, B. Hessen, J. H.
Teuben, Organometallics 2004, 23, 936-939; g) S. Bambirra, A.
Meetsam, B. Hessen, Organometallics 2006, 25, 3454-3462.
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[4]
a) A. Krasovskiy, F. Kopp, P. Knochel, Angew. Chem. Int. Ed. 2006, 45,
497-500; b) K. C. Nicolaou, A. Krasovskiy, V. E. Trépanier, D. Y.-K. Chen,
Angew. Chem. Int. Ed. 2008, 47, 4217-4220; c) A. Metzger, A.
Gavryushin, P. Knochel, Synlett 2009, 1433-1436; d) K. C. Nicolaou, A.
Krasovskiy, U. Majumder, V. E. Trépanier, D. Y.-K. Chen, J. Am. Chem.
Soc. 2009, 131, 3690-3699; e) Z. Zhou, D. D. Dixon, A. Jolit, M. A. Tius,
Chem. Eur. J. 2016, 22, 15929-15936.
[5]
[6]
[7]
For selected reviews, see: a) G. A. Molander, Chem. Rev. 1992, 92, 29-
68; b) G. A. Molander, C. R. Harris, Chem. Rev. 1996, 96, 307-338; c) A.
Krief, A.-M. Laval, Chem. Rev. 1999, 99, 745-777; d) F. T. Edelmann, D.
M. M. Freckmann, H. Schumann, Chem. Rev. 2002, 102, 1851-1896; e)
S. Kobayashi, M. Sugiura, H. Kitagawa, W. W.-L. Lam, Chem. Rev. 2002,
102, 2227-2302.
a) T. Imamoto, T. Kusumoto, Y. Tawarayama, Y. Sugiura, T. Mita, Y.
Hatanaka, M. Yokoyama, J. Org. Chem. 1984, 49, 3904-3912; b) S.
Matsubara, T. Ikeda, K. Oshima, K. Utimoto, Chem. Lett. 2001, 1226-
1227; c) S. H. Wunderlich, P. Knochel, Chem. Eur. J. 2010, 16, 3304-
3307; d) S. H. Wunderlich, T. Bresser, C. Dunst, G. Monzon, P. Knochel,
Synthesis 2010, 2670-2678.
a) T. Kauffmann, C. Pahde, A. Tannert, D. Wingbermühle, Tetrahedron
Lett. 1985, 26, 4063-4066; b) E. Ciganek, J. Org. Chem. 1992, 57, 4521-
4527; c) Lanthanides: Chemistry and Use in Organic Synthesis (Ed.: S.
Kobayashi), Springer, Heidelberg, 1999.
[8]
[9]
A. D. Benischke, L. Anthore-Dalion, G. Berionni, P. Knochel, Angew.
Chem. Int. Ed. 2017, 56, 16390-16394.
See supporting information.
[10] Titration of 2: Ph3La·5LiCl (2) was prepared from PhLi (4.55 mL,
6.00 mmol, 3.0 equiv, 1.32 m in Bu2O) and LaCl3·2LiCl (6.00 mL,
2.00 mmol, 1.0 equiv, 0.33 m in THF) at –30 °C. N-benzylbenzamide
(57 mg, 0.27 mmol) was dissolved in THF (1 mL) at 0 °C, and the freshly
prepared Ph3La·5LiCl (2) was added dropwise until a bright pink color
appeared, giving a concentration of 0.15 M (79% yield) for Ph3La·5LiCl
(2).
[11] a) S. Collins, Y. Hong, Tetrahedron Lett. 1987, 28, 4391-4394; b) S.
Collins, Y. Hong, G. J. Hoover, J. R. Veit, J. Org. Chem. 1990, 55, 3565-
3568.
[12] J. Gorecka-Kobylinska, M. Schlosser, J. Org. Chem. 2009, 74, 222-229.
[13] Titration of 21: A dry and argon-flushed Schlenk-tube was charged with
2-bromo-1,3-dimethylbenzene (555 mg, 3.00 mmol, 3.00 equiv) and
freshly distilled THF (1.25 mL) and cooled to –78 °C. tBuLi (3.00 mL,
6.60 mmol, 6.6 equiv, 2.2 M in pentane) was then added dropwise, and
the resulting yellowish mixture was stirred for 5 min. Subsequently,
LaCl3·2LiCl (3.00 mL, 1.00 mmol, 0.30 equiv, 0.33 M in THF) was added,
and the mixture was placed at –30 °C for 30 min, resulting in a clear
yellow solution. Titration with iodine gave a concentration of 0.11 M (80%
yield) for (m-Xylyl)3La·5LiCl (21).
[14] K. Tamao, K. Sumitani, M. Kumada, J. Am. Chem. Soc. 1972, 94, 4374-
4376.
[15] E. Negishi, S. Baba, J. Am. Chem. Soc. 1976, 98, 6729-6731.
[16] J. K. Stille, Angew. Chem. Int. Ed. 1986, 25, 508-524.
[17] N. Miyaura, K. Yamada, A. Suzuki, Tetrahedron Lett. 1979, 20, 3437-
3440.
[18] M. Giannerini, M. Fananas-Mastral, B. L. Feringa, Nat. Chem. 2013, 5,
667-672.
[19] H. N. Nguyen, X. Huang, S. L. Buchwald, J. Am. Chem. Soc. 2003, 125,
11818-11819.
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Andreas D. Benischke,+ Lucile Anthore-
Dalion,+ Fabien Kohl, and Paul Knochel*
Page No. – Page No.
Synthesis of Polyfunctionalized
Triaryllanthanum Reagents Using
Ph3La and Related Species as
Exchange Reagents
Ph3La·5LiCl and the related (m-Xylyl)3La·5LiCl were used as Hal/La-exchange reagents
(Hal = Br, I) for the preparation of various triaryl- and triheteroaryl-lanthanum derivatives.
These new exchange reagents are compatible with isoquinolines and some functional
groups such as a nitrile or an ester. The reactivity of the resulting lanthanum compounds
towards electrophiles, such as ketones, aldehydes, N,N-dimethylamides and primary alkyl
halides was investigated. Additionally, a Pd-catalyzed cross-coupling procedure was
developed.
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