Preparation of Polyfunctional Organozinc Halides by an InX3- and LiCl-Catalyzed Zinc Insertion to Aryl and Heteroaryl Iodides and Bromides

Article abstract of DOI:10.1002/chem.201605139

A catalytic system consisting of InCl₃(3 mol %) and LiCl (30 mol %) allows a convenient preparation of polyfunctional arylzinc halides via the insertion of zinc powder to various aryl iodides in THF at 50 °C in up to 95 % yield. The use of a THF/DMPU (1:1) mixture shortens the reaction rates and allows the preparation of keto-substituted arylzinc reagents. In the presence of In(acac)₃(3 mol %) and LiCl (150 mol %), the zinc insertion to various aryl and heteroaryl bromides proceeds smoothly (50 °C, 2–18 h). Alkyl bromides are also converted to the corresponding zinc reagents in the presence of In(acac)₃(10 mol %) and LiCl (150 mol %) in 70–80 % yield.

Full text of DOI:10.1002/chem.201605139

A Journal of
Accepted Article
Title: Preparation of Polyfunctional Organozinc Halides by an InX₃- and
LiCl-Catalyzed Zinc Insertion to Aryl and Heteroaryl Iodides and
Bromides
Authors: Andreas Dominik Benischke, Grégoire Le Corre, and Paul
Knochel
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To be cited as: Chem. Eur. J. 10.1002/chem.201605139
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10.1002/chem.201605139
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COMMUNICATION
Preparation of Polyfunctional Organozinc Halides by an InX3- and
LiCl-Catalyzed Zinc Insertion to Aryl and Heteroaryl Iodides and
Bromides
Andreas D. Benischke,[a] Grégoire Le Corre,[b] and Paul Knochel*[a]
Dedicated to Professor Konstantin Karaghiosoff on the occasion of his 60th birthday
Abstract: A catalytic system consisting of InCl3 (3 mol%) and LiCl
(30 mol%) allows a convenient preparation of polyfunctional arylzinc
halides via the insertion of zinc powder to various aryl iodides in THF
at 50 °C in up to 95% yield. The use of a THF:DMPU (1:1) mixture
shortens the reaction rates and allows the preparation of keto-
substituted arylzinc reagents. In the presence of In(acac)3 (3 mol%)
and LiCl (150 mol%), the zinc insertion to various aryl and heteroaryl
bromides proceeds smoothly (50 °C, 2-18 h). Also alkyl bromides
are converted to the corresponding zinc reagents in the presence of
In(acac)3 (10 mol%) and LiCl (150 mol%) in ca. 70-80% yield.
insertion conditions of organic halides to commercial zinc
powder.
Herein, we report a convenient and effective zinc insertion to
saturated and unsaturated iodides or bromides using a catalysis
involving both InCl3 or In(acac)3 and LiCl. We have first
examined the optimum metal salt catalysis for inserting
commercial zinc powder in ethyl 4-iodobenzoate (1a). Whereas,
in the absence of LiCl, no zinc insertion to ethyl 4-iodobenzoate
(1a) is observed (Table 1, entry 1), the addition of LiCl
(150 mol%) allows to complete the zinc insertion within 24 h at
25 °C leading to the corresponding arylzinc reagent (2a) in 82%
yield as indicated by iodometric titration (entry 2).[14] Heating the
reaction mixture to 50 °C shortens the reaction time to 4 h at
the expense of a lower yield (65%; entry 3). Thus, an additional
metal salt-catalysis was envisioned. After extensive
experimentation testing various metallic salt additives (PbCl2,
VCl3, LaCl3·2LiCl[15], Sc(OTf)3, AlCl3, TiCl4 and InX3) it became
clear that only indium salts were effective.[16] Thus, a complete
conversion was reached after 12 h at 50 °C when performing the
zinc insertion in the presence of InCl3 (10 mol%) (90%; entry 4).
Using a catalysis involving InCl3 (3 mol%) and LiCl (30 mol%)
allows to further shorten the reaction time to 2 h at 50 °C with
the highest yield of arylzinc reagent 2a (92%; entry 5).
Alternatively, a further rate acceleration was obtained by using
DMPU as cosolvent (THF:DMPU (1:1)) leading to a full
conversion after 15 min at 50 °C at the cost of a slightly lower
yield (78%; entry 6).
The direct insertion of metal powders to organic halides[1] is a an
atom-economical[2] method for the preparation of organometallic
reagents. Pioneered by Frankland[3] in 1848 and Grignard[4] in
1900, this method is still one of the most used for preparing
various Zn- and Mg-organometallics.[5] This heterogeneous
reaction requires a zinc insertion on the adsorbed organic
halides at the metal surface. Several procedures have been
developed to facilitate such an oxidative addition. Among them,
the Rieke-method[6] involving an in situ reduction of Zn- or Mg-
halides with metallic lithium or the direct activation of Zn- or Mg-
powders with LiCl[7] have found the broadest applications. The
role of LiCl for the activation of zinc powder has been recently
elucidated by Blum.[8] Also, the use of polar solvents (or co-
solvents) such as DMA (N,N-dimethylacetamide)[9] or DMPU
(N,N’-dimethyl-propylenurea)[10] has improved the reaction rates.
More importantly,
a metal salt-catalysis was shown to
considerably facilitate the metal insertion to organic halides.
Thus, Gosmini[11] has reported a CoBr2-catalyzed oxidative zinc
addition to aryl iodides and bromides in acetonitrile. Later,
Yoshikai[12] showed that cobalt-Xantphos and LiCl allow the
preparation of arylzinc derivatives in THF. Takai[13] has reported
the exceptional activation of aluminum, gallium and manganese
with PbCl2 or InCl3 for the preparation of allylic organometallics.
The use of InCl3 as catalyst considerably facilitates the formation
of 1,2-bis-zincated aromatics.[10] Despite the availability of these
experimental procedures, there is still a need for more efficient
catalyses allowing a faster metal insertion and a broader
functional group tolerance providing higher reaction yields. With
these objectives in mind, we have searched for novel improved
Table 1. InCl3-catalyzed oxidative insertion of zinc powder to ethyl 4-iodo-
benzoate (1a).
InCl3
LiCl
(mol%)
0
Entry
Time (h)
Yield (%)a
(mol%)
1
2
3
4
5
6
7
8
0
0
24
24b
4.0
< 5
82
150
150
0
0
65
10
3
12
90
30
2.0
92
[a]
[b]
M. Sc. A. D. Benischke, 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
B. Sc. G. Le Corre
3
30
0.25
0.25
0.25
78b
70b
50b
3
50
3
80
Laboratoire de Chimie Moléculaire, CNRS, Ecole Polytechnique,
Route de Saclay, 91128 Palaiseau, France
[a] Yield determined by iodometric titration. [b] Reaction performed at 25 °C. [c]
A mixture of THF:DMPU (1:1) was used.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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This small yield drop when changing from THF to a more
polar solvent mixture has been observed in several optimization
experiments and may be tentatively rationalized by side
reactions of radical intermediates escaping the solvent-cage
leading to the reduced product (PhCO2Et).
Table 2. (Continued).
A: 50; 2.0; 80
B: 50; 0.5; 68
These side reactions become more important if more LiCl is
added increasing the ionic force of the reaction medium (50-
70%; entries 7 and 8). The use of other cosolvents such as DMA,
DMF, NMP, dioxane or tert-BuOMe led to only moderate
metalation yields (43-63%).[16,17] Based on these optimization
studies, we have defined two optimal reaction conditions
depending on the solvent used. In both cases, InCl3 (3 mol%)
and LiCl (30 mol%) were used, but in Method A the reaction was
performed in pure THF and in Method B the reaction was
performed in THF:DMPU (1:1). Generally, the highest yields
were obtained with Method A, but the fastest oxidative insertions
proceeded via Method B. As shown below, both methods allow a
broad range of trappings with electrophiles such as aryl or
heteroaryl halides (Negishi cross-coupling),[18] allylic bromides
(copper-catalyzed allylic substitution)[19] and acid chlorides
(Negishi-acylation).[20]
6
2f
3f
4f: 85%f
A: 50; 4.0; 57
B: 50; 0.5; 60
7
8
2g
2h
3c
3g
4g: 75%e
4h: 78%d
A: 25; 0.25; 90
B: 25; 0.25; 90
A: 50; 18; 93
B: 50; 2.0; 50
9
2i
3h
4i: 88%d
Table 2. InCl3- and LiCl-catalyzed insertion of zinc powder to organic iodides
and further trapping reactions with electrophiles.
A: 50; 6.0; 56
B: 50; 3.0; 64
10
11
2j
3i
4j: 60%e
4k: 87%d
A: 25, 0.5; 45
B: 25; 0.5; 62
2k
3g
A: 25, 0.25; 27
B: 25; 0.25; 50
Reaction
Arylzinc
Entry
Conditions
Electrophile
Product, Yieldc
Reagent
(°C; h; %)a,b
12
13
14
2l
2m
2n
3j
3k
3l
4l: 64%d
4m: 77%f
4n: 60%d
A: 50; 2.0; 92
B: 50; 0.25; 78
A: 50; 6.0; 62
B: 25; 0.25; 50
1
2
2a
2b
3a
3b
4a: 96%d
A: 50; 2.0; 90
B: 50; 0.25; 78
A: 25; 0.5; 50
B: 25; 0.5; 62
4b: 97%d
[a] The reactions completion was determined by GC-analysis of quenched
aliquots. [b] Yield determined by iodometric titration. [c] Isolated yield of pure
product. [d] Pd(OAc)2 (4 mol%) and SPhos (8 mol%) were used. [e]
CuCN·2LiCl (20 mol%) was used. [f] [Pd(PPh3)4] (10 mol%) was used.
A: 25; 0.25; 83
B: 25; 0.25; 50
3
4
5
2c
2d
2e
3c
3d
3e
4c: 94%e
4d: 94%d
4e: 93%d
Thus, the treatment of ethyl 4-iodobenzoate (1a) with
commercial zinc dust activated with a few drops of TMSCl[16] in
the presence of InCl3 (3 mol%) and LiCl (30 mol%) in THF led to
the corresponding zinc reagent (2a, X = Cl or I) within 2 h at
50 °C in 92% yield as indicated by iodometric titration[14] (Method
A). Alternatively, the same arylzinc species has been prepared
in 15 min at 50 °C using a THF:DMPU (1:1) mixture in 78% yield
(Method B). This trend in yield and reaction time difference
between Methods A and B proved to be quite general. Trapping
2a (obtained by Method B) with 4-bromobenzaldehyde (3a;
0.8 equiv) in the presence of Pd(OAc)2 (4 mol%) and SPhos[21]
(8 mol%) provided the expected biphenyl derivative 4a (25 °C,
2 h)[22] in 96% yield (Table 2 , entry 1).
A: 50; 0.5; 95
B: 50; 0.5; 60
A: 50; 0.5; 88
B: 50; 0.5; 60
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Table 3. In(acac)3- and LiCl-catalyzed insertion of zinc powder to organic
bromides and further trapping reactions with electrophiles.
Similarly ethyl 3-iodo-benzoate (1b) was converted into the
corresponding zinc reagent 2b (Method A: 90% yield; Method B:
78% yield). Pd-catalyzed cross-coupling with 2-bromoaniline
(3b; 0.8 equiv) gave the product 4b in 97% yield. No protection
of the free amino group was required (entry 2).[22] The 2-
carbethoxy-phenylzinc halide (2c) prepared in 83% yield
according to Method A was allylated with the allylic bromide (3c)
in the presence of CuCN·2LiCl (20 mol%)[19] leading to the
benzoate derivative (4c) in 94% yield. Cyano-substituted
arylzinc species such as (2d,e) were prepared in the same way
in 88-95% yield (Method A). Negishi cross-coupling with 2-
chloropyridines (3d,e) furnished the pyridines (4d,e) in 93-94%
yield (entries 4 and 5). Various fluoro-substituted aryl iodides
such as 1f-h were converted to the zinc reagents 2f-h in 57-90%
yield (Method A) and trapped with various electrophiles leading
to the products 4f-h in 75-85% yield (entries 6-8). Interestingly,
the acylation of 2f with the acid chloride 3f was best performed
via a Negishi-acylation[20] ((Pd(PPh3)4 (10 mol%), 50 °C, 18 h)
leading to ketone 4f in 85% yield (entry 6). Electron-donating
substituted arylzinc halides such as 2i-j were prepared in the
same way (Method A: 56-93% yield) and were arylated or
allylated leading to the products 4i-j in 60-88% yield (entries 9
and 10). Remarkably, various iodoaryl ketones such as (1k-n)
including 4-iodoacetophenone (1k) led under our mild reaction
conditions to the corresponding zinc reagents 2k-n in 50-62%
Reaction
Arylzinc
Entry
Conditions
Electrophile
Product, Yieldc
Reagent
(°C; h; %)a,b
50; 18; 70
50; 6.0; 55
1
2
6a
3m
3c
7a: 86%f
6b
7b: 75%e
50; 2.0; 67
yield using in this case Method
B and quenched with
electrophiles affording the polyfunctional ketones 4k-n in 60-
87% yield (entries 11-14).
3
4
6c
6d
3f
7c: 92%f
In order to insert zinc to the less reactive aryl and heteroaryl
bromides, we performed a further optimization of the indium
catalyst and found that In(acac)3 was clearly a superior catalyst
for such an insertion.[16] Thus, the treatment of ethyl 2-bromo-
benzoate (5a) with zinc powder in the presence of In(acac)3
(3 mol%) and LiCl (150 mol%) in THF led to the desired arylzinc
reagent 6a within 18 h at 50 °C in 70% yield. Subsequent
Negishi-acylation with 2-thiophenecarbonyl chloride (3m) gave
the heteroaryl ketone 7a in 86% yield (Table 3, entry 1). Using
this In(acac)3-promoted reaction procedure, several fluoro-
substituted aryl bromides (5b-d) led to the corresponding
functionalized arylzinc reagents 6b-d within 2-6 h at 50 °C in 55-
77% yield (entries 2-4). After further trapping reactions with an
allylic bromide (3c), 4-tert-butylbenzoyl chloride (3f) and ethyl 2-
chloronicotinate (3d) the polyfunctionalized products 7b-d were
obtained in 75-92% yield (entries 2-4). Additionally, also
heteroaryl bromides proved to be good substrates. Thus, ethyl
5-bromothiophene-2-carboxylate (5e) and 3-bromopyridine (5f)
were converted to the heteroarylzinc reagents (6e,f) within 2 h at
50 °C in 64-74% yield and underwent Pd-catalyzed acylations
with acid chlorides (3n,m) leading to the desired ketones (7e,f)
in 82-95% yield (entries 5 and 6).
50; 2.0; 77
3d
7d: 83%d
50; 2.0; 74
50; 2.0; 64
7e: 95%f
7f: 82%f
5
6
6e
6f
3n
3m
[a] The reactions completion was determined by GC-analysis of quenched
aliquots. [b] Yield determined by iodometric titration. [c] Isolated yield of pure
product. [d] Pd(OAc)2 (4 mol%) and SPhos (8 mol%) were used. [e]
CuCN·2LiCl (20 mol%) was used. [f] [Pd(PPh3)4] (10 mol%) was used.
Table 4. In(acac)3-catalyzed insertion of zinc powder to alkyl bromides and
further trapping reactions with electrophiles.
Finally, polyfunctionalized alkyl bromides underwent such zinc
insertions leading to the corresponding alkylzinc reagents using
In(acac)3 (10 mol%) and LiCl (150 mol%) within 0.5-4 h at 50 °C
(Table 4). Thus, ethyl 6-bromohexanoate (8a) was converted to
the zinc reagent (9a) within 3 h at 50 °C in 68% yield and
subsequent Negishi-acylation with 4-methoxybenzoyl chloride
(3o) gave the ketone (10a) in 90% yield (Table 4, entry 1).
Similarly, the zinc insertion to 4-bromobutyronitrile (8b) gave the
cyano-substituted alkylzinc reagent (9b) within 0.5 h in 79%
Reaction
Alkylzinc
Entry
Conditions
Electrophile
Product, Yieldc
Reagent
(°C; h; %)a,b
yield.
A Pd-catalyzed cross-coupling with ethyl 2-chloro-
nicotinate (3d) afforded the functionalized pyridine (10b) in 98%
yield (entry 2). Finally, the alkyl bromides (8c-e) were converted
to the corresponding alkylzinc species 9c-e within 1-4 h at 50 °C
in 70-73% yield. After further trapping with electrophiles the
products (10c-e) were obtained in 66-90% yield (entries 3-5).
50; 3.0; 68
50; 0.5; 79
1
2
9a
9b
3o
3d
10a: 90%f
10b: 98%d
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Table 4. (Continued).
50; 1.0; 70
50; 3.0; 72
50; 4.0; 73
3
9c
3e
10c: 90%d
[8]
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In summary, a catalytic system involving InCl3 (3 mol%) and
LiCl (30 mol%) allows an efficient zinc insertion to a range of
functionalized aryl iodides in THF at 50 °C in up to 95% yield.
The use of THF:DMPU (1:1) as solvent mixture facilitates the
preparation of various keto-substituted arylzinc halides in 50-
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and heteroaryl bromides in 70-80% yield. This catalysis can also
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Experimental Section
For experimental details and typical procedures see supporting information.
[16] See Supporting Information.
[17] Acetonitrile was an excellent cosolvent, since THF:MeCN (1:1) allowed
the preparation of 2a using LiCl and InCl3 catalysis within 15 min at
50 °C in 87% yield. However, quenching with electrophiles were
unsatisfactory.
Acknowledgements
We thank the Fonds der Chemischen Industrie and the Ludwig-
Maximilians-Universität München for financial support. We also
thank the Rockwood Lithium GmbH (Frankfurt) and BASF
(Ludwigshafen) for the generous gift of chemicals.
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10.1002/chem.201605139
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
Layout 2:
COMMUNICATION
Andreas D. Benischke, Grégoire Le
Corre, Paul Knochel*
Page No. – Page No.
Preparation of Polyfunctional
Organozinc Halides by an InX3- and
LiCl-Catalyzed Zinc Insertion to Aryl
and Heteroaryl Iodides or Bromides
Two are better than one: A catalytic system consisting of InCl3 (3 mol%) and LiCl (30 mol%) allows a new and convenient preparation of
polyfunctionalized arylzinc halides via the insertion of zinc powder to various aryl iodides. The use of a THF:DMPU (1:1) mixture shortens the
reaction rates and enables the preparation of keto-substituted arylzinc reagents. Additionally, the insertion to a range of aryl, heteroaryl and alkyl
bromides proceeds smoothly in the presence of In(acac)3 (3-10 mol%) and LiCl (150 mol%).
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