Transition metal catalyzed preparation of Grignard compounds

Article abstract of DOI:10.1002/1521-3773(20001215)39:24<4610::AID-ANIE4610>3.0.CO;2-O

The "inorganic Grignard reagents", in particular those of 1, have surprisingly been shown to be efficient homogeneous catalysts for the conversion of inactive chloroarenes and heteroarenes (via the aryl-iron intermediate 2) into the corresponding Grignard

Full text of DOI:10.1002/1521-3773(20001215)39:24<4610::AID-ANIE4610>3.0.CO;2-O

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the compound 1-naphthylmagnesium chloride <1) is formed in
7
Transition Metal Catalyzed Preparation of
Grignard Compounds**
6.7% yield in under 1 h <entry 1).[ The best results are
3]
obtained when the drop-wise addition of the organo halide is
rapid and is started within a few minutes of the addition of the
transition metal component, this is because the catalytic
activity decreases with time <entry 2). THF is the preferred
solvent, but mono- <entry 4) and diglyme can also be used. As
well as the iron compounds other compounds, in particular the
Borislav Bogdanovi c * and Manfred Schwickardi
A multitude of organo halide compounds, in particular
aromatic, heteroaromatic, and vinylic chloro compounds react
slowly in low yield, if at all, with magnesium powder or
turnings. In the course of our work on the so-called inorganic
Grignard reagents [IGR, see Eq. <1)][ we have developed
efficient transition metal catalysts for the transformation of
inactive organo chlorides into the corresponding Grignard
compounds, commercial magnesium powder is used in this
procedure.[ Herein this method is introduced for several
Grignard compounds that are considered to be difficult to
prepare and the possible catalytic role of the IGR is discussed.
The catalysts for the preparation of Grignard compounds
are produced through the reaction of transition metal halides,
alcohols, or amides <precatalysts) in the presence of an excess
of magnesium, and a Grignard or other organo magnesium
compounds, usually in THF. The Grignard compound re-
quired for the preparation of the catalyst is preferably
prepared in situ from an organo halide, such as ethyl bromide,
and the excess magnesium present. To date Fe catalysts have
been found to be the most active and the best cocatalysts are
corresponding manganese precatalysts, such as MnCl , can be
2
1]
considered <entry 5).
As precatalysts iron phthalocyanin <2a, b) or the porphine
complexes of iron, manganese, cobalt, or copper <3a ± d) can
be used. With these compounds, and particularly in the case of
2]
[2]
MgCl and 9,10-diphenylanthracene <DPA).
2
The influence that varying the precatalyst, the cocatalyst,
and the reaction conditions has on the catalysis of the
Grignard formation were investigated for, among others,
the iron complexes <entries 6 ± 8) highly active catalysts for
Grignard formation are generated even without a cocatalyst
1-chloronaphthaline as the inactive organo chloride <Table 1).
<
MgCl ). The catalysts formed from these amides seem to be
2
With the catalyst generated from Mg, EtBr, FeCl , and MgCl
2
2
more stable in THF than the catalysts generated from
transition metal halides such as FeCl . The aging of
2
the catalysts before the start of the Grignard reaction
Table 1. Catalytic preparation of 1-naphthylmagnesium chloride 1 from 1-chloro-
naphthaline and Mg powder in THF.
<
40 ± 100 min) has in these cases no negative effect on
the catalytic activity <entry 6 ± 8). In general however,
for every single organohalide substrate the optimal
catalysts has to be identified. In most cases we use as
first choice the catalytic system derived from Mg, EtBr,
Entry EtBr[a]
Precatalyst[a] MgCl
[a]
Aging[b]
T
[8C]
Yield [%]
[c]
2
<t [h])[
d]
[
mol%] <2.0 mol%) [mol%] [min]
1
2
3
4
5
6
7
8
9
0
1.1
1.1
1.1
0.5
0.5
1.1
FeCl
FeCl
FeCl
FeCl
MnCl
2a
2
2
2
2
5.0
5.0
±
5.0
5.0
±
2
70
3
10
30
100
40
60
45
45
22 ± b.p. 76.7<1), 82.3<18)
22 ± 26 16.7<3), 35.2<18)
22 ± b.p. 68.5<1), 73.7<20)
21 ± b.p. 80.6<1), 82.7<4)
62.2<2), 66.5<19)
22 ± b.p. 77.0<1), 84.0<6)
22 ± b.p. 87<2)
[6]
FeCl , and MgCl . This system allows the conversion
2
2
[
e]
[7]
of the aminal-protected chlorbenzaldehyde 4a, the
oxygen substituted chloroarene 5-chloro-1,3-benzo-
dioxol 5a, and the oxygen substituted chloroheteroar-
ene 2-chloro-6-methoxypyridine 6a into the corre-
2
23 ± 62
0.5
2b
±
0.5
0.9
0.9
3a
±
22 ± b.p. 95<2)
22 ± b.p. 69<0.5)
22 ± b.p. 78<4)
3c
±
1
3d
±
[
a] Calculated from 1-chloronaphthaline. [b] Interval between the addition of the
precatalyst and commencement of the 1-chloronaphthaline addition. [c] Deter-
mined by acidimetric titration. [d] After the end of the 1-chloronaphthaline
addition. [e] Reaction in monoglyme; in addition to MgCl
2
in this experiment
DPA[ <2 mol%) was also used as cocatalyst.
a]
[
*] Prof. Dr. B. Bogdanovi c , M. Schwickardi
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1
4
5470 Mülheim an der Ruhr <Germany)
sponding Grignard compounds in high yield <Table 2). In the
preparation of the Grignard compound 5b the yield could be
increased from 40 to 76% <after 2.5 h) by increasing the
Fax : <‡49)208-306-2980
E-mail: bogdanovic@mpi-muelheim.mpg.de
[
**] This work was supported by the Fonds der Chemische Industrie. We
thank Prof. Dr. M. T. Reetz and Prof. Dr. P. Jolly for their support and
numerous helpful discussions.
[8]
EtMgBr/FeCl ratio from 0.2 to 2.0 <entries 2 and 3). After
2
hydrolysis and silation the corresponding benzodioxol and the
4610
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Angew. Chem. Int. Ed. 2000, 39, No. 24

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Table 2. Catalytic preparation of the Grignard compounds 4b ± 6b from 4a ± 6a and Mg powder.
EtBr[a]
mol%]
FeCl
[a]
MgCl
[a]
Aging[b]
[min]
Substrate
T
[8C]
Yield [%]
[c]
Entry
2
2
<t [h])[
d]
[
[mol%]
[mol%]
1
1.0
1.0
10.9
1.0
10.9
<2.1)
<5.1)
<5.1)
<5.1)
<5.1)
5.0
5.0
5.0
5.0
5.0
10 ± 15
4a[7]
5a
5a
6a
6a
20 ± 45
21 ± 36
22 ± 52
22 ± 33
22 ± 45
88<10)[e,f]
40<2.5)
[
[
g]
j]
2
3
4
5
3
3
3
3
76<2.5), 80.7<8.5), 82.9<23)[
37<2.5), 52<9)
h,i]
62<2.5), 83<9), 96<23.5)[
k]
[
a] Calculated from the substrate. [b] Interval between the addition of FeCl
acidmetric titration, unless otherwise stated. [d] After the end of the substrate addition. [e] Yield calculated from the amount of the trimethylsilyl derivative
c. [f] During the reaction the suspension was stirred with a paddle stirrer in the presence of glass sphere <i.d. ˆ 5 mm; 5 mL) grinding elements.
g] Comparative experiment to entry 3. [h] Yield derived from the GC analysis of the benzodioxol formed by hydrolysis. [i] Comparative experiment without
FeCl and MgCl : 1.3% yield after 38.5 h at 228C. [j] Comparative experiment to entry 5. [k] Comparative experiment without FeCl and MgCl : 12.8% yield
after 30 h at 228C.
2
and commencement of the substrate addition. [c] Determined through
4
[
2
2
2
2
5
8
-trimethylsilyl-1,3-benzodioxol 5c were isolated in yields of
3 and 70%, respectively. In the same manner the yield of the
Grignard compound 6b <entries 4 and 5) could be increased
from 52 to 83% <after 9 h). Without the Fe catalyst the
Grignard compounds 4b ± 6b could be prepared only in low
yield, if at all.
To investigate the catalyst generation a catalyst solution,
prepared with a Mg/n-C H Br/FeCl ratio of 25/4/1, was
7
15
2
analyzed. After a reaction time of 8.5 h the centrifuged
catalyst solution contained an amount of magnesium and of
bromine equivalent to the amount of n-heptyl bromide
Scheme 1. Proposed mechanism for the iron-catalyzed preparation of
Grignard compounds; Ar ˆ aryl, heteroaryl.
initially present and 95 and 89% of the initial FeCl as iron
2
and chlorine, respectively. A GC analysis of the vacuum
distillate of the catalyst solution showed 58.6% of a 1-hep-
tene/heptane mixture <calculated from heptyl bromide) was
found by GC analysis.[ From these results and based on the
formation of Pd- and Pt-IGR from PdCl and PtCl , respec-
probably to stabilize the catalytically active species, in
9]
0
particular 8, by preventing the precipitation of Fe , the MgCl2
is also necessary for the transmetalation step.
2
2
tively, and ethylmagnesium halides [Eq. <1)] or diethylmag-
nesium[ allows the formation of the catalyst to be described
according to Eq. <2).
With the transition metal catalyzed preparation of
Grignard compounds the IGR species have demonstrated
themselves to be useful homogenous catalysts, which extends
the applications of the Grignard reaction to include inactive
1a,c]
MCl
2
‡ 4C
2
H
5
MgX À! [M<MgX)
2
][10] ‡ MgX
2
‡ 2<C
2
H
4
‡ C
2
H
6
) "
<1)
[13]
chloroarene compounds.
M ˆ Pd, Pt; X ˆ Cl, Br
FeCl
2
‡ 4n-C
7
H
15MgBr À!
Fe<MgX)
Experimental Section
<
2)
[
2
][10] ‡ 2MgX
2
‡ 2<1-C
7
H
14 ‡ C
7 16
H )
X ˆ Cl, Br
Typical procedure: The reactions were carried out under an argon
atmosphere. THF was distilled over magnesium anthracene ´ 3THF.
Magnesium was used in the form of a commercially available <Eckart
If in the generation of the catalyst the Grignard compound
is not available in sufficient quantities for the reaction to
Werke, Fürth, Germany) powder <270 mesh). Anhydrous MgCl
prepared from 1,2-dichloroethane and Mg powder in THF. The anhydrous
FeCl was obtained from Alfa. The organo chloride was dried over
2
was
proceed according to Eq. <2) then the known Fe-IGR
2
FeMgCl][ [Eq. <3)] can be formed from the FeCl and the
1a]
molecular sieves.
[
2
excess Mg powder. In the preparation of the Fe catalysts for
Mg powder <2.43 g; 100 mmol) in THF <30 mL) was treated with ethyl
bromide <0.22 mL; 3 mmol to 0.56 mL 7.5 mmol depending upon the
reactivity of the organo chloride to be used) and the mixture stirred for 1 h
by using a magnetic stirrer bar. To mechanically activate the Mg surface,
grinding elements <ca. 5 vol%), for example, glass spheres with a diameter
the Grignard reaction Fe-IGR [Fe<MgCl) ] [Eq. <1)] and
2
[FeMgCl] [Eq. <3)] can be formed together.
[
10]
[8]
FeCl
2
‡ 1.5 Mg À! [FeMgCl] ‡ 0.5MgCl
2
<3)
of 5 mm can be added <Table 2, entry 1). After the addition of FeCl2
<
0.19 g, 1.5 mmol to 0.48g, 3.8 mmol) and a solution of MgCl
2
<7.7 mL,
0
.485 molar in THF, 3.7mmol) the reaction mixture was then stirred for a
For the Fe-catalyzed Grignard formation <Scheme 1) we
assume that the aryl iron intermediate 8 is formed from the
mixture 7 and the chloroarene. This step is plausible bearing
in mind the known high reactivity of IGR compared to
perchlorovinyl and aryl compounds.[1e] In the next step of the
total of 3 min during which time the solution turned dark brown.
Immediately afterwards the organo chloride <75 mmol) was added drop
wise over 30 min. In the course of the reaction the solution heated up,
sometimes even reaching the boiling point of the solvent used. During the
reaction samples were removed, and, after removal of the excess
magnesium and hydrolysis, acidimetric titrated <Tables 1 and 2). To identify
and quantify the reaction product an aliquot of the reaction solution was
hydrolyzed and the organic phase examined by gas chromatography
<Table 2, entry 3). When a sample of the Grignard reaction was treated with
catalysis the Grignard can be released from 8 by a Fe/Mg
transmetalation[
11, 12]
with the excess Mg, this regenerates the
catalytic species 7. The cocatalytic function of MgCl2 is
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chlorotrimethylsilane, the corresponding organotrimethylsilane compound
of the Grignard compound was obtained, which could be identified and
quantified by GC/MS coupling <Table 2, entry 1).
tabolites show strong antitumor activity against L1210 leuke-
[2]
mia, B16 melanoma, and solid lymphosarcoma cells. Lan-
kacyclinol <1), which is also identified as T-2636 G,[ is a rare
example of a seventeen-membered carbocycle, and incorpo-
rates two independent pentadienyl alcohol systems as well as
a novel b-amido ketone moiety. The assignments of relative
3]
Received July 6, 2000 [Z15395]
[
1] a) L. E. Aleandri, B. Bogdanovi c , P. Bons, C. Dürr, A. Gaidies, T.
Hartwig, S. C. Huckett, M. Lagarden, U. Wilczok, Chem. Mater. 1995,
7
, 1153 ± 1170; b) L. E. Aleandri, B. Bogdanovi c , C. Dürr, D. J. Jones, J.
Áre, U. Wilczok, Adv. Mater. 1996, 8, 600 ± 604; c) L. E. Aleandri,
O
HO
OH
H
O
H
CH3
Rozie
H
H
O
1
1
4
O
14
CH3
B. Bogdanovi c , C. Dürr, S. C. Huckett, D. J. Jones, U. Kolb, M.
Lagarden, J. Rozi eÁ re, U. Wilczok, Chem. Eur. J. 1997, 3, 1710 ± 1718;
d) B. Bogdanovi c , W. Leitner, C. Six, U. Wilczok, K. Wittmann,
Angew. Chem. 1997, 109, 518 ± 520; Angew. Chem. Int. Ed. Engl. 1997,
3
O
O
CH3
OH
1
H
N
3
H
H
N
CH3
H
H
O
8
8
3
6, 502 ± 504; e) G. Siedlaczek, M. Schwickardi, U. Kolb, B. Bogda-
H
H
HO
HO
novi c , D. G. Blackmond, Catal. Lett. 1998, 55, 67 ± 72.
2] a) B. Bogdanovi c , M. Schwickardi <Studiengesellschaft Kohle mbH),
PCT-WO 98/02443; b) B. Bogdanovi c , M. Schwickardi <Studienge-
sellschaft Kohle mbH), PCT-WO 99/33844.
Lankacyclinol 1
Lankacidin C 2
[
stereochemistry at C3, C8, and C14, and the absolute
configuration of 1 have been considered by comparison with
lankacidin C <2) which was unambiguously characterized by
X-ray crystallography.[ Indeed, biosynthesis studies have
suggested that enzymatic reduction of the 2'-oxopropion-
amide of 2 followed by base-induced decarboxylation pro-
[
3] According to the literature 1 is generated from 1-chloronaphthaline
[
4]
and Mg turnings in boiling THF in 40% yield <6 h) and by the
entrainment method [ in boiling diethyl ether in 66% yield <12 h).
4] H. E. Ramsden, A. E. Balint, W. R. Whitford, J. J. Walburn, R. Cserr,
J. Org. Chem. 1957, 22, 1202 ± 1206.
5]
4]
[
[
[
[
5] D. A. Pearson, D. Cowan, J. D. Becker, J. Org. Chem. 1959, 24, 504 ±
5
09.
[5]
vides lankacyclinol.
6] Grignard reactions, which proceed without a catalyst but first start
after a long induction period can be initiated with this catalyst system.
7] We thank the firm Bayer AG, Leverkusen, for providing a sample of
However, the asymmetry at C2 of 1 has remained undefined
in spite of substantial advancements leading to the synthesis
of 2 by Kende and co-workers.[ Our recent studies, stemming
from 4,5-dihydrofurans, of tandem acyl nitrene insertions and
Wittig reactions have demonstrated a stereocontrolled route
to unique b-amido esters.[ These results have provided the
opportunity to address the challenges inherent in a proposed
synthesis of 1, particularly with regard to serious issues of acid
and base instability and stereochemical concerns. In this
communication, we describe the first enantioselective syn-
thesis of <À)-lankacyclinol by a convergent pathway which
establishes the relative and absolute configuration as illus-
trated in 1.
6]
4
a.
[
[
8] Patent registered.
9] The rest is most likely to be the dimerization product C14
30
H .
[
10] In light of EXAFS investigations <EXAFS ˆ extended x-ray absorp-
7]
]º,[1c] we assume that
tion fine structure), particularly of ª[Pt<MgCl)
2
the empirical formula [M<MgCl)
the metal clusters M that are bound directly to the ligands MgCl<thf).
The simplified form, such as ª[Fe<MgCl) ]º etc. denotes a fragment
/p of this sort of cluster.
11] C. Elschenbroich, A. Salzer, Organometallchemie, Teubner, Stuttgart,
968, p. 28.
m
]
p
<thf)
x
<m ˆ 1,2,3; p ꢀ 2) refers to
p
2
1
[
1
[
[
12] Y. Gao, F. Sato, J. Chem. Soc. Chem. Commun. 1995, 659 ± 660.
13] V. V. Grushin, H. Alper in Activation of Unreactive Bonds and
Organic Synthesis <Ed.: S. Murai), Springer, Berlin, 1999, p. 194.
An enantiocontrolled preparation of the C1 ± C6 fragment
was developed, which utilized cis-disubstituted dihydrofuran
8
and incorporated a ring-closing metathesis <RCM) strategy
<
Scheme 1). Addition of the <Z)-crotyl-di-<2-isocaranyl)bor-
[8]
ane 4, as described by Brown and co-workers, to aldehyde 3
gave the syn-homoallylic alcohol 5 as a single diastereomer.
Total Synthesis of Lankacyclinol**
[9]
Transetherification to afford the vinyl ether 6 was induced by
David R. Williams,* Guillermo S. Cortez,
St e phane L. Bogen, and Christian M. Rojas
treatment with ethyl vinyl ether in the presence of small
[10]
amounts of mercuric trifluoroacetate. Cyclization with the
RCM protocol using the ruthenium Grubbsꢁ catalyst 7[
11]
The lankacidins are a family of structurally unique anti-
biotics isolated from the fermentation broths of Streptomyces
griseofuscus, S. violaceoniger, and S. rochei var.[ These me-
1]
H
)B
OH
2
H
OTBDPS
[
*] Prof. D. R. Williams, G. S. Cortez, Dr. S. L. Bogen, C. M. Rojas
Department of Chemistry
OTBDPS
4
O
a
H
3
CH3 5 ( 98% de, 96% ee)
Indiana University
8
00 East Kirkwood Avenue, Bloomington, IN 47405 <USA)
PCy3
Ru
b
Fax : <‡1)812-855-8300
Cl
Cl
Ph
E-mail: williamd@indiana.edu
7
O
[
**] Generous financial support for this research was provided by the
National Institutes of Health <Award no.: GM41560). Additionally, a
National Institutes of Health Minority Predoctoral Fellowship <Award
no.: GM18547) to G.S.C. is gratefully acknowledged. We also wish to
thank Dr. Tsuneaki Hida and Dr. Yoshio Kozai, Takeda Chemical Ltd.
O
PCy3
c
H
H
H3C
H
OTBDPS
OTBDPS
H
CH3
8
6
Scheme 1. a) 4, BF
vinyl ether, Et
3
´ Et
2
O, THF, À788C, 62%; b) Hg<O
2
CCF
3 2
) , ethyl
<Japan), for providing us with an authentic sample of lankacyclinol as
N, reflux, 60%; c) 7, CH
Cl
, reflux, 48%. TBDPS ˆ tert-
3
2
2
1
well as copies of the original H NMR spectrum.
butyldiphenylsilyl, Cy ˆ cyclohexyl.
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Angew. Chem. Int. Ed. 2000, 39, No. 24