Highly efficient reagents for Br/Mg exchange

Article abstract of DOI:10.1002/anie.200502220

(Chemical Equation Presented) The conversion of electron-rich aryl bromides into the corresponding Grignard compounds proceeds within 2 h at 25°C in the presence of 0.55 equivalents of the new reagent sBu₂Mg· LiCl. The high reactivity of magnes

Full text of DOI:10.1002/anie.200502220

Angewandte
Chemie
Grignard Reagents
DOI: 10.1002/anie.200502220
Highly Efficient Reagents for Br/Mg Exchange**
Arkady Krasovskiy, Bernd F. Straub,* and
Paul Knochel*
Dedicated to Professor Bernd Giese
on the occasion of his 65th birthday
Scheme 1. Halogen–metal exchange reactions through a one-step
transition-state pathway or a two-step ate complex intermediate
mechanism.
Functionalized aryl and heteroaryl magnesium compounds
have become readily available from the corresponding
organic iodides through an iodine–magnesium exchange by
[1]
using iPrMgCl in THF. Recently, we reported that aryl and
heteroaryl bromides also undergo a bromine–magnesium
[
2a]
exchange if the mixed complex iPrMgCl·LiCl (1) is used.
Herein, we report the exceptional reactivity of the new
exchange reagent iPr Mg·LiCl (2) and the principles on which
2
its reactivity is based. Synthetic applications as well as
quantum-chemical calculations provide a rationalization for
the reactivity differences and insight into the mechanism of
the halogen–magnesium exchange.
We have speculated that the high reactivity of the
bimetallic reagent 1 is due to the magnesiate character of
[
2,3]
this reagent solution in THF.
Indeed, our quantum-
chemical model calculations of halogen–metal exchange
reactions predict that the energy of the reaction barrier
decreases with increased electronic saturation at the magne-
[
4]
sium center. Both a higher magnesium coordination number
as well as more-strongly electron-donating ligands dramati-
cally facilitate the formation of 10-valence-electron ate
transition states (Scheme 1, Figure 1, and Table 1).
Experimentally, iodine ate complexes have been either
[
5]
observed or isolated as intermediates. In contrast, quantum-
chemical studies on halogen–metal exchange reactions with
Figure 1. Calculatedhalogen ate transition states andinterme di ates.
ꢀ
nakedꢁ lithium counter ions have so far only predicted
[
6]
hypervalent halogen ate transition states. Our model
calculations involve a more reasonable metal coordination
environment (Figure 1and Table )1 . Both pathways now
appear to be competitive alternatives (Figure 2).
À1
Table 1: Calculatedtotal electronic energies E [kJmol ] for aryl halides
0
[a]
andorganometallic substrates, hypervalent hali de s, andpro du cts.
X
M
Hypervalent halide Products
+
À
[
C H XiPr]
M
C H M + iPrX
6 5
6
5
The enthalpic stabilization of ate intermediates owing to
the additional magnesium–solvent bond is, however, entropi-
cally unfavorable. Thus, low temperatures and strong donor
transition state
DE (reaction)
0
°
°
°
°
A
B
C
D
D
Br Mg(m-Cl) Li(OMe )
147.7
129.3
99.2
À42.7
À37.3
À55.7
À58.0
–
À57.5
À64.6
À56.1
À65.0
2
2
Br Mg(OMe ) Cl
2
2
À
Br MgCl2
Br Mg(OMe )Cl
À
2
[*] Dr. A. Krasovskiy, Dr. B. F. Straub, Prof. Dr. P. Knochel
2
84.5
(49.3)
À
Br Mg(OMe ) Cl
2
[b]
Department Chemie undBiochemie
2
2
°
À
Ludwig-Maximilians-Universität München
Butenandtstrasse 5–13, Haus F, 81377 München (Germany)
Fax: (+49)89-2180-77680
E-mail: bernd.f.straub@cup.uni-muenchen.de
paul.knochel@cup.uni-muenchen.de
E
F
Br MgCl(iPr)
81.9
19.3
69.1
À11.5
[
c]
c]
Br Li(OMe )
2
3
°
À
G
I
I
MgCl2
Li(OMe2)3
[
H
[
a] Gibbs free activation energies will be higher, as two substrate
[
**] We thank the Fonds der Chemischen Industrie and Merck Research
Laboratories (MSD) for financial support. We also thank Chemetall
GmbH (Frankfurt) andBASF AG (Ludwigshafen) for generous gifts
of chemicals.
molecules have to combine in one entropically disfavored transition-
state molecule. As a consequence, the Gibbs free activation energies are
highly temperature-dependent. Energy values are given relative to the
energies of the substrates C H X + iPrM; [b] Ion pair, local minimum
6
5
À
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
(NIMAG 0), energy relative to PrMgCl (OMe ) , PhBr, andMe O model
2 2 2
structures. [c] Contact ion pair, local minimum (NIMAG 0).
Angew. Chem. Int. Ed. 2006, 45, 159 –162
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
159

Communications
°
Figure 2. Ball-and-stick model structures of the transition state D and
the intermediate D.
Scheme 2. Preparation of iPr Mg·LiCl (2) by the reaction of
2
solvents favor two-step pathways via ate intermediates,
whereas high temperatures and weak donor ligands support
one-step reactions with ate transition states.
iPrMgCl·LiCl (1) with additives, and the Br/Mg-exchange reaction with
4-bromoanisole (3).
To increase the effective negative charge at the magne-
sium center through separation of the lithium cation from the
magnesiate anion, we added various strong s donors, partic-
ularly chelating ethers. Li selective [12]crown-4 is not,
however, efficient, and only a small rate enhancement was
Table 2: Effect of chelating additives on the conversion of the Br/Mg-
exchange reaction of 4-bromoanisole.
[a]
[
b]
+
Entry
Additive
Amount
Conversion [%]
31
100
77
55
60
1
2
3
4
5
6
7
8
9
–
–
[
c]
observed. This therefore indicates that 1 is already an ionic
[15]crown-5
[18]crown-6
PEG250
Me(O CH CH ) OMe
DME
1,4-dioxane
DMPU
TMEDA
1.0 equiv
1.0 equiv
10 vol%
10 vol%
10 vol%
10 vol%
10 vol%
10 vol%
+
reagent, presumably with the formula [Li(thf) ] [Mg(thf)-
4
À
(
iPr)Cl ] . Nevertheless, other additives such as 1,4-dioxane
2
2
2 4
or [15]crown-5 lead to a higher reactivity through the
enforcement of an ꢀanionic Schlenk equilibriumꢁ with the
70
100
60
[d]
formation of a MgCl ·additive precipitate and a solution
2
+
À
[7]
containing 2, presumably as [Li(thf) ] [Mg(thf)(iPr) Cl] .
77
4
2
We prepared reagent 2 by mixing iPrMgCl (2 equiv), LiCl
1 equiv), and 1,4-dioxane (10 vol%) in THF, and the
[
a] After 24 h at 258C; [b] The conversion of the reaction was determined
(
by gas chromatographic analysis of reaction aliquots; precision Æ2%;
resultant precipitate was removed by filtration. The solution
of 2 gave the same results as that prepared in situ. The new
reagent 2 displays exceptional reactivity for the conversion of
various aryl bromides into the corresponding Grignard
reagents (Scheme 2 and Table 2).
[c] After 6 h; [d] After 10 h.
related complexing molecules such as N,N’-dimethyl-N,N’-
propylene urea (DMPU) or N,N,N’,N’-tetramethylethylene-
diamine (TMEDA) similarly enhanced the exchange rate
Interestingly, no significant rate enhancements are
[
10]
observed in Br/Mg-exchange reactions with iPr Mg prepared
(Table 2, entries 8 and 9).
2
from iPrMgCl and 1,4-dioxane relative to reactions with
iPrMgCl. Apparently, the reactive species in solutions of
Several electron-rich aryl bromides, which react only
slowly with 1, undergo a smooth Br/Mg-exchange reaction
with 2. Thus, the reaction of 1-bromo-4-trimethylsilylbenzene
iPrMgCl is iPr Mg, which is formed in a Schlenk equilibrium
2
and thermodynamically shifted to the right side
by the higher magnesium coordination number
[
8]
of the MgCl by-product (Scheme 3).
2
Whereas the reaction of 1 with 4-bromoani-
sole (3) produces the corresponding Grignard
reagent 4 in 24 h with only 31% conversion, the
addition of [15]crown-5 (1 equiv) to 1 leads to
complete conversion within 6 h (Table 2,
entries 1and 2). The use of the larger
[
2
18]crown-6 leads to 77% conversion after
4 h. This correlates with a stronger complex-
ation of MgCl by [15]crown-5, which has the
2
II
perfect size for a seven-coordinated Mg center
[
9]
(
Scheme 3).
derivatives
OCH CH ) OMe, or dimethoxyethane (DME)
Conveniently, ethylene glycol
such as PEG250, Me-
(
2
2 4
also give significant rate enhancement (Table 2,
entries 4–6). However, the addition of 1,4-diox-
ane ( ꢀ 1.2 equiv, 10 vol%) provides 100% con-
Scheme 3. Schlenk equilibrium (without m-chloro dimers) and the proposed magnesi-
version after 10 h (Table 2, entry 7). Finally, ate equilibrium.
1
60
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Angewandte
Chemie
do not undergo Br/Mg
exchange with previously
known magnesium reagents;
however, the reaction of 14
(0.55 equiv) with a-bromos-
tyrene (18) provides the
desired magnesium reagent
1
9
within 1h at 25 8C.
Quenching with benzalde-
hyde leads to the allylic alco-
hol 20 in 93% yield. Finally,
1
4 allows the facile prepara-
tion of dimagnesium
reagents. After 2 h at 258C
in Me(OCH CH ) OMe, the
2
2 4
reaction of 1,4-diiodoben-
zene (21) with 14 (1.3 equiv)
furnishes the corresponding
magnesium reagent 22,which
in the presence of excess allyl
bromide forms the 1,4-dia-
Scheme 4. Br/Mg exchanges with iPr Mg·LiCl (2) generated by the addition of 1,4-dioxane (10 vol%) to
iPrMgCl·LiCl (1).
2
llylbenzene (23) in 85%
(
(
(
5) with 2 (0.525 equiv), generated by adding 1,4-dioxane
10 vol%) to 1 (1.05 equiv), is completed within 24 h at 258C
Scheme 4). The same exchange with 1 in THF led to a
yield.
In summary, we have presented model calculations that
correlate the structure of magnesium reagents and their
reactivity in Br/Mg-exchange reactions. Efficient procedures
for the shifting of alkyl magnesiate–dialkyl magnesiate
equilibria by additives or the alternative direct preparations
of dialkyl magnesiates have been developed. Compounds 2
and 14 display exceptional reactivities for otherwise challeng-
ing Br/Mg-exchange reactions, thus giving dialkyl magnesi-
ates general synthetic value.
conversion of only 36%. The reaction of the resultant
Grignard reagent 6 with furfural provided the alcohol 7 in
9
2% yield. Strongly electron-donating amine substituents
slow down the Br/Mg exchange considerably. However, the
reaction of 4-bromo-N,N-dimethylanilin (8) with 2, prepared
in the same way, furnishes the Grignard reagent 9 within 48 h
at 258C, whereas the use of 1 results in only 16% conversion.
Quenching of 9 with benzaldehyde leads to the benzhydrol 10
in 95% yield. For benzylic alcohols such as 11, the Br/Mg
exchange is nonselective with 1. On the other hand, the
reaction of the unprotected alcohol 11 with 2 in THF/dioxane
Received: June 24, 2005
Published online: November 24, 2005
(
1
9:1) provides cleanly the Grignard reagent
2 within 24 h at 258C. Its reaction with
tBuCHO furnishes the diol 13 in 90% yield
and as a separable mixture of two diaster-
eomers (1:1 ratio).
On the basis of these these results, we
independently prepared the dialkyl mag-
nesiate reagent sBu Mg·LiCl (14) directly
2
by combining sBuLi (1equiv) with
sBuMgCl (1equiv) in THF at 25 8C
(
Scheme 5). No precipitate was formed,
and the resulting clear solution (1.0m in
THF) is stable at 258C and again proved to
be a superior reagent for of Br/Mg-
exchange reactions. For example, the reac-
tion of 3 with 14 (0.55 equiv) results in the
formation of the corresponding diaryl mag-
nesium reagent 4 within 6 h at 258C. Also,
the highly electron-rich aryl bromide 15 is
smoothly converted into the diaryl magne-
sium reagent 16, which (after trapping with
benzaldehyde) affords the alcohol 17 in
9
0% yield (Scheme 5). Alkenyl bromides Scheme 5. Preparation andreactivity of sBu Mg·LiCl (14) in halogen–magnesium exchange reactions.
2
Angew. Chem. Int. Ed. 2006, 45, 159 –162
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
161

Communications
Keywords: bromine–magnesium exchange · density functional
.
calculations · Grignardreaction · lithium · Schlenk equilibrium
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[
[
[
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[
10] Solutions of tBuMgCl·LiCl (1m in THF) and tBu Mg·LiCl (1m in
2
THF) were also prepared and applied in Br/Mg-exchange
reactions with 3. However, these tert-butylmagnesiates featured
slightly lower reaction rates than the secondary reagents 1 and
14. For full conversion of the aryl bromides into the Grignard
reagents, 1.1 equiv of both types of reagents was enough,
therefore indicating that no elimination of HBr from the
tBuBr byproduct by magnesiates takes place. Further work on
magnesiates with different alkyl groups is in progress in our
laboratories.
1
62
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Angew. Chem. Int. Ed. 2006, 45, 159 –162