Preparation of Functionalized Diaryl- and Diheteroaryllanthanum Reagents by Fast Halogen–Lanthanum Exchange

Article abstract of DOI:10.1002/anie.201709553

Aryl and heteroaryl halides (X=Br, I) undergo a fast and convenient halogen–lanthanum exchange with nBu₂LaMe, which leads to functionalized diaryl- and diheteroaryllanthanum derivatives. Subsequent trapping reactions with selected electrophiles, such as ketones, aldehydes, or amides, proceeded smoothly at ?50 °C in THF, affording polyfunctionalized alcohols and carbonyl derivatives. Kinetic competition experiments revealed a similar reactivity trend as for Br/Mg exchange, but 10⁶-times higher rates, making it comparable to Br/Li exchange.

Full text of DOI:10.1002/anie.201709553

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Accepted Article
Title: Preparation of Functionalized Diaryl- and Diheteroaryl-
Lanthanum Reagents via a Fast Halogen-Lanthanum Exchange
Authors: Andreas Dominik Benischke, Lucile Anthore-Dalion,
Guillaume Berionni, and Paul Knochel
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201709553
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10.1002/anie.201709553
Angewandte Chemie International Edition
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Preparation of Functionalized Diaryl- and Diheteroaryl- Lanthanum
Reagents via a Fast Halogen-Lanthanum Exchange
Andreas D. Benischke+, Lucile Anthore-Dalion+, Guillaume Berionni, and Paul Knochel*
Dedicated to Professor Martin F. Semmelhack in recognition of his pioneer contributions in organometallic chemistry.
Abstract: nBu2LaMe allows
a
fast and convenient halogen-
nBu3La (2c) exchanged one butyl group at −50 °C in THF within
5 min leading to the corresponding aryllanthanum species of type
3 as indicated by protonation and iodolysis of reaction aliquots.[11]
Similarly, Me3La (2d) led to a fast exchange, but again of only one
methyl group. This partial transfer of alkyl groups, with an
unsatisfactory atom economy,[12] led us to examine mixed
alkyllanthanum reagents prepared from various amounts of
LaCl3·2LiCl, MeLi and nBuLi (Table 2). Thus, nBuLaMe2 (2e) led
to a selective exchange of the butyl group, and quenching of the
resulting aryllanthanum species (3e) with 3-methoxyben-
zaldehyde (4a) gave the desired alcohol (5a) in 72% GC-yield.
Unfortunately, alcohol 6a, resulting from a competitive transfer of
a methyl group present in 3e, was also formed in 28% GC-yield
(entry 1). This side reaction was mostly avoided by switching to
the mixed lanthanum reagent nBu2LaMe (2f). Thus, adding 1a
(1.0 equiv) to 2f (0.70 equiv) led to a fast formation of 3f
lanthanum exchange of aryl- and heteroaryl halides (X = Br, I) leading
to functionalized diaryl- and diheteroaryl-lanthanum derivatives. Their
subsequent trappings with selected electrophiles, such as ketones,
aldehydes and amides proceeded smoothly at −50 °C in THF
affording polyfunctionalized alcohols and carbonyl derivatives.
Competitive kinetic measurements show a similar reactivity trend as
the Br/Mg-exchange, but 106 faster rates making it comparable to the
Br/Li-exchange.
The halogen/lithium (Hal/Li)-exchange reaction is one of the most
powerful methods for preparing organolithium reagents.[1]
However, because of the low tolerance of aryllithiums towards
functional groups, there is a need for other Hal/Met-exchanges.
Thus, the Hal/Mg-exchange has found useful applications for the
preparation of polyfunctional magnesium compounds.[2] In
addition, I/Cu-[3] and I/Zn[4]-exchanges have been reported.
However, all these exchange reactions are relatively slow
compared to the Hal/Li-exchange. No other Hal/Met-exchange
has been reported, but we envisioned that La(III)-organometallics
may be good candidates for a Hal/Met-exchange, since the
lanthanum electronegativity (1.1) is very close to the lithium
electronegativity (0.98), and therefore a high reactivity of the
C−La bond is expected.
Organolanthanide(III)-reagents have found many applications in
organic synthesis.[5,6] Of special interest is the strong Lewis-acidic
character of La(III)-salts leading to an exceptional reactivity
towards carbonyl compounds.[7] These organometallics are
usually prepared by transmetalation[8] from organolithium
derivatives or by directed metalation.[9]
Herein, we wish to report a new and very fast Hal/La-exchange
allowing the preparation of functionalized diaryl- and heteroaryl-
lanthanum derivatives, which then undergo trappings with a
variety of electrophiles. As part of this study, we report an
especially attractive acylation reaction using N,N-dimethylamides
providing ketones.[7a,b,10]
In preliminary experiments, we have examined the I/La-exchange
involving the reaction of an electron-poor aryl iodide, namely 3,4-
difluoro-1-iodobenzene (1a), with various alkyllanthanum
organometallics of type 2 (Table 1). Thus, we have prepared
(ArF LaMe; ArF= 3,4-difluorophenyl). Treatment of 3f with 4a
2
(0.8 equiv) led to the alcohol 5a in 94% GC-yield (63% isolated
yield) and less than 6% GC-yield of the alcohol 6a (entry 2).
Table 1. Evaluation of alkyllanthanum(III) organometallics as exchange reagents.
entry
exchange reagent 2
nBuLaCl2·3LiCl (2a)
nBu2LaCl·4LiCl (2b)
nBu3La·5LiCl (2c)
Me3La·5LiCl (2d)
product 3
conversion (%)[a]
1
2
3
4
ArFLaCl2 (3a)
nBuArFLaCl (3b)
nBu2ArFLa (3c)
ArFLaMe2 (3d)
0
68
100
100
[a] Conversion of 1a determined by GC-analysis. ArF= 3,4-difluorophenyl
These experiments show that nBu2LaMe (2f) is a promising
exchange reagent in which both butyl groups undergo the I/La-
exchange, whereas the methyl group plays the role of a
non-transferable moiety when a subsequent electrophile is added.
Table 2. Mixed alkyllanthanum(III) reagents and their reactivities towards 1a.
alkyllanthanum reagents
2
starting from THF-soluble
LaCl3·2LiCl[7c] and organolithium reagents like tBuLi, sBuLi, nBuLi
or MeLi. While tBuLi or sBuLi derived lanthanum reagents gave
unsatisfactory results,[11] combinations of n-butyl, methyl and
chloride residues provided the most promising results. Whereas
nBuLaCl2 (2a) was unreactive towards 1a, nBu2LaCl (2b) and
exchange
reagent 2
aryllanthanum
reagent 3
entry
5a (%)[a]
72
6a (%)[a]
nBuLaMe2·5LiCl
(2e, 1.2 equiv)
1
2
ArFLaMe2 (3e)
ArF2LaMe (3f)
28
6
[*]
M. Sc. A. D. Benischke,[+] Dr. Ing. Lucile Anthore-Dalion,[+] Dr.
Guillaume Berionni, Prof. Dr. P. Knochel
nBu2LaMe·5LiCl
(2f, 0.70 equiv)
94 (63)[b]
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.
[a] Ratio of product 5a and side-product 6a were determined by GC-analysis.
[b] Isolated yield; ArF = 3,4-difluorophenyl; m-An = 3-MeOC6H4
[+]
Thus, several aryl iodides (1b-h; 1.0 equiv) were treated at
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−50 °C with 2f (0.70 equiv) in THF for 5 min producing the
diaryl(methyl)lanthanum species (7a-h) in ca. 70-80% yield as
shown by GC-analysis of reaction aliquots.[11] Their trapping with
a range of aldehydes and ketones of type 4 (0.65 equiv) led to
secondary or tertiary alcohols (5b-h) in 70-93% yield. In addition,
trapping with (BuS)2 at −50 °C provided the thioether 5i in 70%
yield (Scheme 1). In all these reactions, unwanted methyl-transfer
products of type 6 were only detected in trace amounts.
OMe, SiMe3, SMe substituents undergo this Br/La-exchange
affording diaryl(methyl)lanthanum reagents of type 9. Trapping
with aldehydes, ketones of type 4 or a disulfide (0.80 equiv) gives
products of type 10 in 57−90% yield (Scheme 2). Whereas nBuLi
decomposes 1-bromo-2-fluorobenzene (8c) at −50 °C, the
reaction of 8c with nBu2LaMe (2f) proceeds smoothly, providing
after the addition of cyclohexanone, the tertiary alcohol 10c in
72% yield. Similarly, nBuLi decomposes 3-bromo- or 4-
bromobenzonitrile (8d,e), whereas nBu2LaMe (2f) undergoes a
clean Br/La-exchange, furnishing after quenching with an al-
dehyde or a ketone, the alcohols 10d-e in 68−69% yield.
Furthermore, the trifluoromethyl-substituted lanthanum reagents
(9g-i) underwent trappings with ketones and an aldehyde leading
to products (10g-i) in 81−90% yield. The reaction of an enone with
aryllanthanum 9j selectively provided the 1,2-addition product 10j
in 85% yield. Additionally, electron-rich aryl bromides 8k-m also
underwent the exchange at −50 °C within 5 min, and the resulting
aryllanthanum reagents 9k-m were trapped with acetophenone,
4-fluorobenzaldehyde and (BuS)2 yielding 10k-m in 75−88% yield.
The silyl-substituted diaryllanthanum reagents (9n,o) underwent
an addition to 3,4,5-trimethoxybenzaldehyde and 2,4’-
dichlorobenzophenone to give alcohols (10n,o) in 77−86% yield.
Also, an amino-substituted aryllanthanum reagent 9p reacted with
(BuS)2 to afford the thioether 10p in 59% yield. Finally, a
thiomethyl-substituted lanthanum species (9q) was prepared and
added to a bulky ketone leading to the tertiary alcohol 10q in 80%
yield.
Scheme 1. I/La-exchanges of aryl iodides 1 with 2f and subsequent trappings.
These first promising results with aryl iodides led us to examine
the more important Br/La-exchange reaction, because aryl
bromides (8) are commercially available and less expensive than
aryl iodides. Using the same exchange reagent (2f), lanthanum
derivatives Ar’’2LaMe (9) were obtained in ca. 90% yield. The
better reactivity of aryl bromides compared to aryl iodides is
ascribed to the detrimental presence of butyl iodide generated
during the I/La-exchange.[13]
Scheme 3. [a] Br/La-exchanges of heteroaryl bromides 12 with 2f and
subsequent trappings; [b] Synthesis of fenarimol (13g).
The Br/La-exchange was extended to a range of heterocyclic
bromides of type 11. Hence, bromopyridines (11a-b) were
converted into the corresponding diheteroaryl(methyl)lanthanum
reagents 12a-b, and further additions to a ketone or aldehydes of
type 4 led to alcohols 13a-b in 73-75% yield. Similarly, sulfur- and
oxygen-containing heterocycles (11c-f) underwent a Br/La-
exchange and added to selected ketones and aldehydes affording
the desired products (13c-f) in 71-84% yield (Scheme 3a).
Interestingly, 5-bromopyrimidine (11g) was converted to the
lanthanum reagent 12g and addition to ketone 4b furnishes the
fungicide fenarimol[14] (13g) in 58% yield (Scheme 3b).
Scheme 2. Br/La-exchanges of aryl bromides 8 with 2f and trappings.
This Hal/La-exchange was extended to alkenyl and cyclopropyl
halides using nBu2LaMe (2f) as exchange reagent. Thus, the
Thus, functionalized aryl bromides bearing Cl, F, CN, CF3, OCF3,
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exchange on E-1-iodooctene (14) with 2f (0.70 equiv) at −50 °C
produced the alkenyllanthanum derivative 15 within 5 min.
Subsequent trapping with 3,4,5-trimethoxybenzaldehyde (4c) led
to the desired allylic alcohol 16 with retention of configuration.
Additionally, cyclopropyl bromide (17) underwent a similar
exchange with 2f (0.70 equiv) furnishing the cyclopropyl
derivative 18. Further reaction with 4,4’-dimethoxybenzophenone
(4d) provided the tertiary alcohol 19 in 69% yield (Scheme 4).
aryl bromides with substoichiometric amounts of nBu2LaMe (2f,
0.50 equiv) and further trapping of the resulting aryllanthanum
reagent with benzaldehyde (4e) gave the benzhydrols P1 and P2
in different ratios (Scheme 6). The competition constants K were
determined from the ratios [P1]t/[R1]t and [P2]t/[R2]t calculated by
GC-analysis,[11] and 4-bromoanisole (R1) was used as reference
substrate in all cases (rate of Br/La-exchange = 1.00). While a
similar relative reactivity trend is observed for Br/La- and Br/Mg-
exchanges,[15] the exchange with nBu2LaMe (2f) proceeded with
absolute rates at least 106 faster than for iPrMgCl·LiCl. Indeed,
we observed that the Br/La-exchange with 2-bromo-1,3-
dimethylbenzene R6 proceeded within 1 min, whereas the
corresponding Br/Mg-exchange using iPrMgCl·LiCl has a half-life
time of 29 days at 0 °C.[15b]
Scheme 4. Hal/La-exchanges of E-1-iodooctene (14) and cyclopropyl bromide
(17) with 2f and subsequent trappings.
Remarkably, the lanthanum derivatives of type 9 or 12 underwent
useful acylations with several amides 20, leading selectively to
ketones 21. In a preliminary experiment, we have used the
Weinreb amide 20a at −50 °C and have obtained the expected
ketone 21a in 83% yield (Scheme 5a). However, we soon realized
that regular N,N-dimethylamides 20 could be employed to
achieve the same transformation (Scheme 5b). Thus, the reaction
of the electron-rich diaryllanthanum reagent 9m with 4-(tert-butyl)-
N,N-dimethylbenzamide provided the diarylketone 21b in 85%
yield. Similarly, an electron deficient diaryllanthanum species 9r
reacted with the same amide to give the ketone 21c in 76% yield.
In addition, alkyl-substituted N,N-dimethylamides underwent such
efficient acylations with the electron-donating lanthanum reagents
(9p,s) affording the desired ketones 21d,e in 82-85% yield. Based
on this general procedure, acylations using N,N-diethyl-m-
toluamide or N,N-dimethylformamide and dimethoxyaryl-
lanthanum reagents proceeded well leading to the products 21f,g
in 64-74% yield.
Scheme 6. a) Competition experiment of aryl bromides with R1; b) Relative
reactivities of aryl bromides.
In summary, we developed a new alkyllanthanum reagent
(nBu2LaMe) which allows a fast and convenient Hal/La-exchange
reaction. Starting from a variety of aryl and heteroaryl iodides or
bromides, a range of functionalized diaryl- and diheteroaryl-
lanthanum derivatives have been prepared at −50 °C within 5 min.
Their strong oxophilicity enables efficient additions to various
ketones, aldehydes and amides. Finally, this expedient Hal/La-
exchange was used for convenient syntheses of fenarimol (13g)
and an analogue of penfluridol 10g.[16] Further investigations
towards the preparation and applications of organolanthanum
compounds are underway in our laboratories.
Scheme 5. Acylation reactions of aryllanthanum reagents 9 or 12 with amides.
We have also performed kinetic measurements of this fast Br/La-
exchange reactions. Thus, treatment of mixtures of two different
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Experimental Section
See Supporting Information.
Acknowledgements
[11] See Supporting Information.
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 the generous gift of chemicals.
[12] B. M. Trost, Science 1991, 254, 1471.
[13] The addition of BuI to Ar2LaMe prepared from ArBr led to the formation
of ArI (reverse exchange). For details, see SI.
[14] J. D. Davenport, R. E. Hackler, H. M. Taylor (Lilly Co Eli), GB1218623
1971.
Keywords: halogen-lanthanum exchange • lanthanum • 1,2-
additions • acylations • kinetic studies
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Entry for the Table of Contents
COMMUNICATION
A.D. Benischke,+ L. Anthore-Dalion,+ G.
Berionni, P. Knochel*
Page No. – Page No.
Preparation of Functionalized Diaryl-
and Diheteroaryl- Lanthanum
Reagents via a Fast Halogen-
Lanthanum Exchange
Filling up the gap: lanthanum, an alternative to lithium. nBu2LaMe allows a fast
and convenient halogen-lanthanum exchange of aryl and heteroaryl halides (X= Br,
I) leading to functionalized diaryl- and diheteroaryl-lanthanum derivatives. Trappings
with ketones, aldehydes or amides proceeded smoothly at −50 °C affording
polyfunctionalized alcohols and carbonyl derivatives. Kinetic measurements show a
similar reactivity trend compared to the Br/Mg-exchange, but 106 faster rates making
it comparable to the Br/Li-exchange.
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