Preparation of polyfunctional arylmagnesium, arylzinc, and benzylic zinc reagents by using magnesium in the presence of LiCl

Article abstract of DOI:10.1002/chem.200900575

The presence of LiCl considerably facilitates the insertion of magnesium into various aromatic and heterocyclic bromides. Several functional groups, such as -OBoc, -OTs, -Cl, -F, -CF₃, -OMe, -NMe₂, and -N ₂NR₂, are well tolerated. The presence of a cyano group leads in some cases to competitive reduction of the organic halide to the corresponding ArH compound. The presence of sensitive groups such as methyl or ethyl ester is tolerated upon in situ trapping of the intermediate magnesium reagent with ZnCl₂. This method can also be applied to the preparation of functionalized benzylic zinc reagents from benzylic chlorides. In the case of di- or tribromoaryl derivatives, directing groups such as -OPiv, -OTs, -N₂NR₂, or -OAc orient the zinc insertion (Zn/LiCl) to the ortho-position, while the reaction with Mg/LiCl or Mg/LiCl/ZnCl ₂ leads to regioselective insertion into the para-carbon-bromine bond. Large-scale experiments (20-100 mmol) for all of the metalation procedures are described.

Full text of DOI:10.1002/chem.200900575

DOI: 10.1002/chem.200900575
Preparation of Polyfunctional Arylmagnesium, Arylzinc, and Benzylic Zinc
Reagents by Using Magnesium in the Presence of LiCl
Fabian M. Piller, Albrecht Metzger, Matthias A. Schade, Benjamin A. Haag,
Andrei Gavryushin, and Paul Knochel*[a]
Dedicated to Professor Gernot Boche for his pioneering contributions in organometallic chemistry
Abstract: The presence of LiCl consid-
erably facilitates the insertion of mag-
nesium into various aromatic and het-
erocyclic bromides. Several functional
groups, such as -OBoc, -OTs, -Cl, -F,
-CF3, -OMe, -NMe2, and -N2NR2, are
well tolerated. The presence of a cyano
group leads in some cases to competi-
tive reduction of the organic halide to
the corresponding ArH compound.
The presence of sensitive groups such
as methyl or ethyl ester is tolerated
upon in situ trapping of the intermedi-
ate magnesium reagent with ZnCl2.
This method can also be applied to the
preparation of functionalized benzylic
zinc reagents from benzylic chlorides.
In the case of di- or tribromoaryl deriv-
atives, directing groups such as -OPiv,
-OTs, -N2NR2, or -OAc orient the zinc
insertion (Zn/LiCl) to the ortho-posi-
tion, while the reaction with Mg/LiCl
or Mg/LiCl/ZnCl2 leads to regioselec-
tive insertion into the para-carbon–bro-
mine bond. Large-scale experiments
(20–100 mmol) for all of the metalation
procedures are described.
Keywords: Grignard reaction
·
heterocycles · insertion · regioselec-
tivity · zinc
Introduction
halogen–metal exchange reaction could be catalyzed by the
[4]
addition of lithium salts such as LiACTHNUTRGNEUNG
(acac)2 or LiCl.[5] These
Organomagnesium reagents are key organometallics in or-
ganic synthesis. They display excellent reactivity towards a
range of important electrophiles,[1] and furthermore they are
compatible with a number of common functional groups,
such as ester, aryl ketone, and nitrile groups.[2] A major im-
pediment to the use of polyfunctional aryl- and heteroaryl-
magnesium species has been a lack of convenient prepara-
tion methods for such reagents. The iodine–magnesium ex-
change reaction has proved to be a practical method for pre-
paring functionalized magnesium reagents, but it suffers
from the drawback that expensive aryl iodides are used as
substrates. The corresponding Br/Mg exchange is often too
slow to be of practical use.[3] However, it was found that the
discoveries led to the development of a convenient mixed
lithium and magnesium reagent, iPrMgCl·LiCl (1), that
could be efficiently used to carry out Br/Mg exchange in
order to generate polyfunctional magnesium reagents. The
large-scale synthesis of this commercially available reagent[6]
led to the observation that the formation of iPrMgCl·LiCl
(1) from iPrCl and Mg is greatly accelerated by LiCl.[7] It
emerged that such a rate acceleration occurs with numerous
metals, and a detailed report on the LiCl-accelerated prepa-
ration of polyfunctional zinc[8] and indium[9] compounds has
already been published. Recently, we reported on the use of
magnesium in the presence of LiCl for preparing various
aryl- and heteroaryl-magnesium reagents 2 from the corre-
sponding organic chlorides and bromides 3.[10] We have also
reported that in the case of substrates bearing sensitive func-
tional groups, the highly reactive magnesium intermediates
can be efficiently trapped in situ by ZnCl2, leading to poly-
functional zinc compounds of type 4 (Scheme 1).[10,11]
[a] F. M. Piller, Dipl.-Chem. A. Metzger, M. A. Schade,
Dipl.-Chem. B. A. Haag, Dr. A. Gavryushin, Prof. Dr. P. Knochel
Department Chemie und Biochemie
Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstr. 5-13, 81377 Mꢁnchen (Germany)
Fax : (+49)89-2180-77680
Herein, we wish to report the scope and limitations of this
efficient insertion of magnesium into aryl, heteroaryl, and
benzylic bromides (or chlorides). A new orthogonal regiose-
lectivity pattern of zinc and magnesium insertions is also dis-
closed. Finally, scale-up of these insertion procedures has
E-mail: paul.knochel@cup.uni-muenchen.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900575.
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FULL PAPER
Scheme 1. LiCl-mediated preparation of functionalized Mg and Zn orga-
nometallics.
Scheme 2. Preparation and reactions of Boc-protected bromophenols
with magnesium turnings in the presence of LiCl. a) Mg (2.5 equiv), LiCl
(1.25 equiv), THF, À108C, 1 h; b) CuCN·2LiCl (20 mol%), 4-Cl-
C6H4COCl, À10 to 258C, 1 h; c) Mg (2.5 equiv), LiCl (1.25 equiv), THF,
À108C, 20 min; d) MeSO2SMe, À10 to 258C, 1 h.
been successfully achieved and full experimental details for
large-scale experiments are provided. Our procedure com-
plements the pioneering contributions of Rieke using highly
reactive magnesium powder prepared by the reduction of
MgCl2 with lithium in the presence of naphthalene
(20 mol%).[12,13] Although the present method does not
reach the insertion rates observed with Rieke magnesium, it
allows the preparation of several new classes of functional-
ized organomagnesium reagents using practical and econom-
ical reaction conditions.
sium reagents 2d,e. Pd-catalyzed Negishi cross-coupling[16]
reaction of the corresponding zinc reagent derived from 2d
using [Pd
ACHTUNGTRENNUNG
G
4-iodobenzoate as electrophile furnished the biphenyl 5d in
94% yield (entry 2). Copper(I)-catalyzed acylation of 2d
with pivaloyl chloride (0.7 equiv) gave the ketone 5e in
69% yield (entry 3). The Grignard reagent 2e derived from
1-bromo-4-chlorobenzene (3e) was found to add readily to
benzaldehyde to afford the benzhydryl alcohol 5 f in 89%
yield (entry 4). The bromofluorobiphenyl 3 f reacts with Mg/
LiCl within 30 min at 258C. Reaction of the resulting mag-
nesium reagent with MeSO2SMe led to the expected thio-
ether 5g in 84% yield (entry 5). The formation of magnesi-
um reagents containing a trifluoromethyl group is dangerous
and difficult to perform, especially at temperatures between
30 and 508C.[18] By using Mg turnings in the presence of
LiCl, Grignard reagents such as 2g–j can be safely prepared
within 30 min at 08C. After transmetalation to the corre-
sponding zinc reagents and Negishi cross-coupling reactions
with ethyl 4-iodobenzoate, the desired trifluoromethyl-sub-
stituted biphenyls 5h–j were obtained in yields of 83–97%
(entries 6–8). Alternatively, reaction of the Grignard reagent
2j with 4-chlorobenzaldehyde gave the alcohol 5k in 88%
yield (entry 9). Electron-rich bromobenzenes such as 3k–m
containing either a dimethylamino group or a methylene-
dioxo group also reacted with Mg/LiCl within 30 min to pro-
vide the corresponding magnesium reagents 2k–m. Addition
to an aldehyde or reaction with a thiosulfonate afforded the
polyfunctionalized anilines 5l,m in yields of 65–91% (en-
tries 10 and 11). The magnesium reagent 2m adds to methyl
benzyl ketone in the presence of LaCl3·3LiCl[19] to afford
the tertiary alcohol 5n in 91% yield (entry 12). Heterocyclic
halides such as 5-bromo-2-chloropyridine react rapidly with
Mg/LiCl (08C, 30 min) and the resulting magnesium com-
pound (2n) was found to undergo a Negishi cross-coupling
reaction or a copper(I)-catalyzed allylation reaction leading
to the pyridines 5o,p in yields of 62–84% (entries 13 and
14). Finally, we examined the LiCl-mediated insertion of Mg
into bromobenzonitrile derivatives. Despite the presence of
Results and Discussion
Preparation of functionalized aryl- and heteroaryl-magnesi-
um halides: The presence of LiCl (ca. 1.2 equiv) strongly ac-
tivates the insertion of Mg into various aryl bromides. Be-
cause of these mild conditions, some additional functional
groups can be present in the aromatic bromide. Thus, the
Boc-protected bromophenols 3a and 3b reacted readily
with magnesium turnings (2.5 equiv) in the presence of LiCl
(1.25 equiv) at À108C in THF. The magnesium turnings
were pre-treated with iBu2AlH (1 mol%), which ensures
smooth initiation of the reaction.[14] In the case of the meta-
substituted aryl bromide 3a, the insertion was completed
within 60 min, whereas for the para-substituted substrate 3b
the insertion required only 20 min. In the absence of LiCl,
no reaction was observed under otherwise identical condi-
tions. The resulting magnesium reagents 2a and 2b reacted
readily with electrophiles. In the presence of CuCN·2LiCl
(20 mol%),[15] acylation with 4-chlorobenzoyl chloride
(0.7 equiv) produced the ketone 5a in 95% yield. Alterna-
tively, reaction of the Grignard reagent 2b with MeSO2SMe
(0.7 equiv) furnished the functionalized thioether 5b in 92%
yield (Scheme 2). The Boc group was perfectly tolerated
during the organometallic reaction step.
Similarly, a tosyloxy group also proved to be compatible
with the Mg insertion conditions. Thus, treatment of 1-tosyl-
ACHTUNGTRENNUNGoxy-3-bromobenzene (3c) with Mg (2.5 equiv) and LiCl
(1.25 equiv) at 08C for 2 h provided the corresponding
Grignard reagent 2c, which reacted with DMF (0.7 equiv)
to give the aldehyde 5c in 77% yield (entry 1, Table 1). Var-
ious bromochlorobenzenes such as 3d,e undergo selective
insertion into the carbon–bromine bond to yield the magne-
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P. Knochel et al.
Product yield [%][c]
Table 1. Preparation of functionalized aromatics and heterocycles of type
5 by the reaction of Mg in the presence of LiCl with aryl bromides 3 fol-
lowed by quenching with an electrophile.
Table 1. (Continued)
Entry
Aryl bromide[a] (T
[8C], t [min])[b]
Electrophile
Entry
Aryl bromide[a] (T
[8C], t [min])[b]
Electrophile
Product yield [%][c]
12
1
3m (25, 30)
5n: 91[f]
3c (0, 120)
5c: 77
13
14
15
2
3
3n (0, 30)
5o: 84[d]
5p: 62[e]
3d (25, 10)
5d: 94[d]
3n
3d
5e: 69[e]
3o (25, 35)
3p (25, 45)
5q: 68[d]
4
5
16
17
3e (25, 10)
3 f (25, 30)
5 f: 89
5r: 57[e]
5g: 84
3q (25, 45)
5s: 60[e]
6
7
[a] Reaction stoichiometry: aryl bromide (1.0 equiv), electrophile
(0.7 equiv). [b] Reaction conditions for the insertion step. [c] Yield of an-
alytically pure product. [d] Obtained after transmetalation with ZnCl2
(1.0 equiv) and Pd-catalyzed cross-coupling. [e] The magnesium reagent
was transmetalated with CuCN·2LiCl (20 mol%). [f] Obtained in the
presence of LaCl3·3LiCl (1.0 equiv). Ts=para-toluenesulfonyl, DMF=
N,N-dimethylformamide.
3g (0, 30)
3h (0, 30)
5h: 97[d]
5i: 91[d]
mation of the Grignard reagents 2o–q was accompanied by
variable amounts of reduction products, showing a possible
limitation of this direct insertion. Nevertheless, the magnesi-
um reagents 2o–q could be prepared and reacted with typi-
cal electrophiles such as 1-bromo-4-(trifluoromethyl)ben-
8
9
zene by means of a cross-coupling reaction using PdACHTUNGTRENNUNG(OAc)2
3i (0, 30)
5j: 83[d]
(1 mol%) and (S)-Phos (2 mol%) as a catalytic system.[20]
The biphenyl 5q was thereby obtained in 68% yield
(entry 15). Copper(I)-catalyzed acylation of 2p,q with vari-
ous acid chlorides provided the expected ketones 5r,s in
yields of 57–60% (entries 16 and 17).
3j (25, 30)
5k: 88
Reactive heterocyclic chlorides also react with magnesium
turnings in the presence of LiCl. Thus, 2,5-dichlorothio-
phene (6) underwent a selective mono-insertion of Mg
(2.5 equiv) in the presence of LiCl (1.25 equiv) within 3 h at
À508C. The resulting Grignard reagent could be transmeta-
lated with ZnCl2 and underwent a smooth Negishi cross-
coupling reaction with iodobenzene to provide the arylated
thiophene 7 in 82% yield. Repeating this process led to a
second insertion of Mg in the presence of LiCl (À508C, 3 h)
and furnished, after copper(I)-catalyzed allylation, the tetra-
substituted thiophene 8 in 88% yield (Scheme 3).
10
11
3k (25, 30)
3l (25, 30)
5l: 91
5m: 65
the electronegative cyano substituent, the insertion reaction
employing Mg turnings required 35–45 min at 258C. The for-
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Organomagnesium and -Zinc Reagents
FULL PAPER
within 2 h at 258C. This procedure is of special interest since
this bromide does not react directly with Zn and LiCl. How-
ever, the strong reduction potential of Mg compared to that
of Zn ensures rapid formation of the organometallic species.
A Negishi cross-coupling with 2-iodocyclohexenone[22] using
PdACTHNUTRGNEUNG
(OAc)2 (1 mol%) and (S)-Phos[20] (2 mol%) as a ligand
Scheme 3. Synthesis of the highly functionalized thiophene derivative 8.
a) Mg (2.5 equiv), LiCl (1.25 equiv), THF, À508C, 3 h; b) ZnCl2
provided the cyclohexenone 5w in 91% yield (entry 3).
Five-membered rings incorporating two heteroatoms often
require mild conditions for their metalation, since these
metalated ring systems often display a tendency to undergo
fragmentation reactions.[23] Thus, 4-bromo-3,5-dimethylisoxa-
zole (3v) was smoothly converted to the corresponding zinc
reagent within 15 min at 258C by treatment with Mg/LiCl/
ZnCl2. After a Negishi cross-coupling reaction with 3-bro-
moanisole, the arylated isoxazole 5x was isolated in 90%
yield (entry 4). Activated heterocyclic chlorides such as
chloropyrazole 3w react with Mg/LiCl/ZnCl2 at 258C (3.5 h)
to yield the corresponding zincated pyrazole. In this in-
stance, CuCN·2LiCl-mediated acylation with 4-tolyl chloride
provided the ketone 5y in 91% yield (entry 5).
As an example of a more highly functionalized substrate,
chloropyrimidine 9 was reacted with Mg/LiCl/ZnCl2 (258C,
9 h) and a subsequent copper(I)-catalyzed allylation led to
the allylated uracil derivative 10 in 68% yield (Scheme 5).
As mentioned above, aryl halides bearing a cyano group
often generate considerable amounts of reduction side prod-
ucts. By performing the magnesium insertion in the presence
of ZnCl2, the amount of reduced product is suppressed.
Thus, 4-chlorobenzonitrile (11) was reacted with Mg/LiCl
(2.5 equiv) in the presence of ZnCl2 (0.5 equiv) in DME/
THF (4:1) at 508C for 40 min. This solvent mixture gave the
best results and furnished 4-cyanophenylzinc chloride in
about 50% yield. A copper(I)-catalyzed allylation with
(1.0 equiv); c) PdACHTUNGTRENNUNG(dba)2 (3 mol%), tfp (6 mol%), PhI (0.7 equiv), 258C,
3 h; d) CuCN·2LiCl (20 mol%), ethyl 2-(bromomethyl)acrylate, 258C,
30 min.
Preparation of functionalized aryl and heteroaryl zinc re-
agents via in situ generated magnesium reagents: In the case
of sensitive heterocycles or aromatics bearing reactive func-
tional groups, an alternative procedure has been developed
in which the organic halide 3 is treated with Mg/LiCl in the
presence of ZnCl2 (1.0 equiv). Under these conditions, the
unstable magnesium intermediate 2 is transmetalated in situ
to the corresponding comparatively stable zinc derivative 4.
Thus, methyl 2-bromobenzoate (3r) was treated with Mg
powder (1.6 equiv) and LiCl (1.5 equiv) in the presence of
ZnCl2 (1.0 equiv) at 08C in THF. Mg powder was used in
these experiments in preference to Mg turnings since shorter
reaction times can be achieved in this way. The reaction
mixture was allowed to warm to 258C and complete conver-
sion was obtained after a reaction time of 3 h, furnishing the
zinc reagent 4r in high yield. The sensitive magnesium re-
agent 2r generated in situ would not be stable in the ab-
sence of ZnCl2, since aromatic methyl esters react with aryl-
magnesium reagents at À108C. After a copper(I)-catalyzed
acylation with 4-chlorobenzoyl chloride (0.7 equiv), the ben-
zophenone derivative 5r was isolated in 77% yield
(Scheme 4).
ethyl
(2-bromomethyl)acry-
late[21] (0.5 equiv) furnished the
allylated product 12 in 80%
yield (Scheme 5). Using THF as
solvent, neither 2- nor 4-chloro-
benzonitrile gave reproducible
results.[24]
Scheme 4. Synthesis of the zinc reagent 4r bearing a sensitive methyl ester group via the intermediate magne-
sium reagent. a) Mg (1.6 equiv), LiCl (1.5 equiv), ZnCl2 (1.0 equiv), 0 to 258C, 3 h; b) CuCN·2LiCl (1.0 equiv),
4-Cl-C6H4COCl.
Preparation of benzylic zinc re-
agents by the reaction of ben-
zylic chlorides with Mg, LiCl,
and ZnCl2: Benzylic organome-
Similarly, methyl 4-bromobenzoate (3s) was converted to
the corresponding zinc reagent by treatment with Mg/LiCl/
ZnCl2, and a subsequent copper(I)-catalyzed allylation with
ethyl (2-bromomethyl)acrylate[21] furnished the diester 5u in
83% yield (entry 1, Table 2). Similarly, the bromo-substitut-
ed benzylic pivalate 3t was treated with Mg/LiCl/ZnCl2
tallics are valuable synthetic intermediates. Because of the
more ionic nature of the benzylic carbon–metal bond, these
organometallics have especially high reactivity. Thus, benzyl-
ic magnesium reagents are incompatible with ester or nitrile
groups, even at À788C.[25] The new procedure described
above, using Mg in the presence of ZnCl2 and LiCl, has
been successfully used to prepare a range of functionalized
benzylic zinc reagents of type 13 starting from the corre-
sponding benzylic chlorides 14. The reaction proceeds via an
intermediate benzylic magnesium compound 15, which is
transmetalated in situ to 13. Quenching of the functionalized
benzylic zinc reagents 13 with various electrophiles (E+)
(08C, 2 h) and gave, after a Negishi cross-coupling [PdACTHNUTRGNEUNG(dba)2
(2 mol%), tfp (4 mol%), 258C, 1 h], the expected biphenyl
derivative 5v in 87% yield (entry 2). Heterocyclic bromides
are also suitable substrates for this metalation procedure.
Thus, 3-bromobenzofuran (3u) was converted to the corre-
sponding zinc reagent by treatment with Mg/LiCl/ZnCl2
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P. Knochel et al.
Table 2. Products of type 5 obtained by magnesium insertion into aryl
and heteroaryl chlorides or bromides of type 3 in the presence of LiCl
and ZnCl2 and subsequent reaction with an electrophile.
Entry Aryl halide[a] (T
[8C], t [h])[b]
Electrophile
Product yield [%][c]
Scheme 6. Preparation of functionalized benzylic zinc reagents using Mg/
LiCl/ZnCl2.
1
3s (0 to 25, 3)
5u: 83[e]
of LiCl (2.0 equiv) provides the corresponding zinc reagent
13a after a reaction time of 24 h at 258C. On the other
hand, reaction of 14a with Mg turnings (2.5 equiv), ZnCl2
(1.1 equiv), and LiCl (1.25 equiv) in THF results in complete
conversion within 45 min (Scheme 7).
2
3t (0, 2)
5v: 87[d]
3
3u (25, 2)
5w: 91[d]
4
3v (25, 0.25)
5x: 90[d]
5
3w (25, 3.5)
5y: 91[e]
[a] Reaction stoichiometry: aryl bromide (1.0 equiv), electrophile
(0.7 equiv). [b] Reaction conditions for the insertion step. [c] Yield of an-
alytically pure product. [d] Obtained after a Pd-catalyzed cross-coupling.
[e] The magnesium reagent was transmetalated with CuCN·2LiCl
(1.0 equiv).
Scheme 7. Preparation and reactions of polyfunctional benzylic zinc re-
agents. a) Mg (2.5 equiv), LiCl (1.25 equiv), ZnCl2 (1.1 equiv), THF,
258C, 2 h; b) CuCN·2LiCl (1.0 equiv), 4-Cl-C6H4COCl, 1.5 h, 08C then
30 min at 258C; c) 3,4-Cl-C6H3CHO, 258C, 2 h.
Pd-catalyzed cross-coupling of 13a with 4-bromobenzoni-
trile (0.7 equiv) provided the expected diarylmethane 16a in
75% yield (entry 1, Table 3). Functional groups such as
ester or nitrile are also tolerated. Thus, reaction of 3-carbe-
thoxybenzyl chloride (14b) with Mg/LiCl/ZnCl2 at 258C for
2 h provided the corresponding zinc reagent 13b. Its cop-
per(I)-mediated reaction with 4-chlorobenzoyl chloride, as a
representative acid chloride, led to the benzylic ketone 16b
in 82% yield (Scheme 7). Further electrophiles, such as
ethyl (2-bromomethyl)acrylate[21] and (S)-(4-chlorophenyl)-
benzenethiosulfonate,[27] furnished the corresponding prod-
ucts 16c,d in yields of 67–75% (entries 2 and 3, Table 3).
Negishi cross-coupling reaction of 13b with 4-iodoanisole
using PEPPSI-IPr[16e–g] (0.25 mol%) as catalyst led to the ex-
pected product 16e in 78% yield (entry 4). The 3-cyano-sub-
stituted benzylic chloride was cleanly converted to the cor-
responding zinc reagent 13c, and reaction of the latter with
3,4-dichlorobenzaldehyde afforded the polyfunctional ben-
zylic alcohol 16 f in 83% yield (Scheme 7). Similarly, cop-
per(I)-catalyzed 1,4-addition to 3-iodocyclohexenone[28] and
Scheme 5. Mg/LiCl/ZnCl2-mediated insertion into functionalized aryl and
heteroaryl chlorides.
provides
a range of benzylic derivatives of type 16
(Scheme 6).[11]
Although Zn in the presence of LiCl[8c,26] also leads to a
smooth reaction with various benzylic chlorides, the use of a
more strongly reducing metal such as magnesium allows
faster insertion times. Thus, treatment of 4-fluorobenzyl
chloride (14a) with Zn powder (2.0 equiv) in the presence
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Organomagnesium and -Zinc Reagents
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Table 3. Preparation of benzylic zinc reagents from the corresponding
benzylic chlorides using Mg, LiCl, and ZnCl2 and their subsequent reac-
tions.
Table 3. (Continued)
Entry Benzylic chloride[a]
Electrophile
Product yield [%][c]
(t [h])[b]
Entry Benzylic chloride[a]
Electrophile
Product yield [%][c]
(t [h])[b]
12
1
14a (0.75)
16a: 75[d]
14i (0.5)
16n: 86
16o: 70
2
13
16c: 67[e]
14j (1)
14b (2)
[a] Reaction stoichiometry: aryl bromide (1.0 equiv), electrophile
(0.7 equiv). [b] Reaction time for the insertion step at 258C. [c] Yield of
analytically pure product. [d] Obtained after Pd-catalyzed cross-coupling.
[e] The magnesium reagent was transmetalated with CuCN·2LiCl
(0.5 mol%). [f] The magnesium reagent was transmetalated with CuCN·2
LiCl (1.0 equiv).
3
14b
16d: 75
16e: 78[d]
16g: 77[f]
4
5
14b
and 6). Electron-rich benzylic zinc reagents such as 13d–g
reacted with typical electrophiles to furnish the expected
benzylated products 16i–l in yields of 56–89% (entries 7–
10). Halogenated benzylic chlorides were likewise efficiently
converted to the corresponding benzylic zinc reagents 13h,i.
Quenching with (S)-aryl and (S)-benzylic benzenethiosulfo-
nates provided the thioethers 16m,n, each in 86% yield (en-
tries 11 and 12). As an example of a substituted benzylic
chloride, (1-chloroethyl)benzene gave the corresponding
benzylic zinc reagent 13j within 1 h at 258C. After quench-
ing with 4-bromobenzaldehyde (0.7 equiv), the benzylic al-
cohol 16o was obtained in 70% yield (entry 13). However,
treatment of a tertiary benzylic chloride such as cumyl chlo-
ride or trityl chloride with Mg, LiCl, and ZnCl2 led only to
decomposition products.
This in situ method (Mg, LiCl, ZnCl2) also has the advant-
age of producing more reactive benzylic zinc reagents due
to the in situ generation of MgCl2, which accelerates the ad-
dition to carbonyl derivatives. Thus, for benzylzinc chloride
(13k) generated by using Zn/LiCl, the addition to 4-dime-
thylaminobenzaldehyde was only 20% complete after a re-
action time of 20 h at 258C. In contrast, by generating 13k
using Mg/LiCl/ZnCl2, the desired benzylic alcohol 16p was
obtained in 98% isolated yield after a reaction time of only
1 h at 258C (Scheme 8).
14c (2)
6
14c
16h: 79[e]
7
8
14d (1)
14e (1)
16i: 56[f]
16j: 89[d]
9
14 f (2)
16k: 88
10
Highly regioselective metal-directed insertion: In the case of
di- or tribromo aromatics, such as 17, the question of regio-
selective metal insertion arises. Recently, we reported that
Zn/LiCl favors ortho-insertion,[29] leading to zinc organome-
tallics of type 18. On the other hand, we have since found
that Mg/LiCl[30] or Mg/LiCl/ZnCl2 leads selectively to the
para-substituted magnesium compound of type 19 or, after
in situ transmetalation with ZnCl2, to the corresponding ar-
ylzinc derivative (Scheme 9).
14g (1.5)
16l: 62[f]
11
14h (0.75)
16m: 86
allylation with ethyl (2-bromomethyl)acrylate[21] produced
the desired products 16g,h in yields of 77–79% (entries 5
This behavior can be explained by assuming that zinc in-
sertion requires coordination to the directing group (DG) of
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7197

P. Knochel et al.
Scheme 8. Reactivity of benzylzinc chloride (13k) depending on its prep-
aration method.
Scheme 9. Regioselectivity of zinc and magnesium insertion into func-
tionalized dibromo- or tribromoarenes.
17, whereas magnesium metal, which has a much stronger
reducing power, does not need this ortho-coordination site
and prefers to insert into the least sterically hindered
carbon–bromine bond. This behavior has been at least parti-
ally supported by quantum mechanical calculations.[31] Reac-
tion of tert-butyl 2,4-dibromophenyl carbonate (17a) with
Zn/LiCl led only to the zinc reagent derived from ortho-in-
sertion. After cross-coupling with 3-iodo-trifluoromethyl-
benzene, the biphenyl 20a was isolated in 60% yield. How-
ever, by treating 17a with Mg/LiCl (THF, À208C) the mag-
nesium was inserted only in the para-position, providing the
biphenyl derivative 21a in 97% isolated yield after Pd-cata-
lyzed cross-coupling with ethyl 4-iodobenzoate (Scheme 10).
Similar behavior was observed with 2,4,6-tribromo-1-piva-
loyloxybenzene (17b), the insertion with Zn/LiCl providing
the corresponding ortho-inserted zinc reagent. After trans-
metalation with CuCN·2LiCl and acylation with 2-fluoro-
benzoyl chloride, the polyfunctional ketone 20b was isolated
in 81% yield (Scheme 10). Alternatively, the reaction of
17b with Mg/LiCl/ZnCl2 led only to insertion in the para-
position. The presence of ZnCl2 in the reaction mixture
does not interfere with the regioselectivity of the reaction
since the reducing metal is magnesium and this determines
the regioselectivity of the insertion. ZnCl2 is only added to
convert the highly reactive intermediate arylmagnesium spe-
cies into a more stable zinc reagent. This method can also
be advantageously applied to substrates bearing sensitive
functionalities such as a triazene group, which is a synthetic
equivalent of a diazonium salt.[33] Thus, treatment of the 2,4-
dibromoaryltriazene derivative 17c with Mg/LiCl (THF,
08C, 30 min) regioselectively afforded the para-inserted
magnesium derivative 19c. After the addition of pivalde-
hyde, the functionalized benzylic alcohol 21c was obtained
in 76% yield (Scheme 10). This regioselective insertion is
triggered by several directing groups. Thus, as described
above, a pivaloyloxy group facilitates zinc insertion in the
Scheme 10. Regioselective Zn and Mg insertion mediated by LiCl. a) Zn
(2.0 equiv), LiCl (2.0 equiv), THF, 258C, 14 h; b) Pd
(4 mol%), 3-I-C6H4CF3, THF, 258C, 12 h; c) Mg (2.5 equiv), LiCl
(dba)2]
ACHTUNGRTEN(NGNU dba)2 (2 mol%), tfp
(1.25 equiv), THF, À108C, 30 min; d) ZnCl2 (1.1 equiv), [Pd
ACHTUNGTRENNUNG
(2 mol%), tfp (4 mol%), 4-I-C6H4CO2Et, THF, 258C, 3 h; e) Zn
(2.0 equiv), LiCl (2.0 equiv), THF, 258C, 1 h; f) CuCN·2LiCl (1.0 equiv),
2-F-C6H4COCl, 258C, 14 h; g) Mg (2.5 equiv), LiCl (1.25 equiv), ZnCl2
(1.1 equiv), THF, 258C, 45 min; h) CuCN·2LiCl (1.0 equiv), tBuCOCl,
258C, 6 h; i) Mg (2.5 equiv), LiCl (1.25 equiv), THF, 08C, 30 min;
j) tBuCHO, THF, 0 to 258C, 15 min.
ortho-position (entries 1 and 2 in Table 4). Similarly, a tosyl-
AHCTUNGTREGoNNUN xy moiety orients zinc insertion into tribromo- or dibromo-
substituted aromatics to the ortho-position, thereby provid-
ing after quenching with standard electrophiles the expected
products 20e–i in yields of 61–75% (entries 3–7). A more
sensitive group, such as acetate, also directs the zinc inser-
tion to the ortho-position, in the cases of both 2,4,6-tribro-
mo-1-acetoxybenzene (17 f) and 2,4-dibromo-1-acetoxyben-
zene (17g), leading regiospecifically to the corresponding
polyfunctional arylzinc reagents 18 f,g. After copper-mediat-
ed acylation or cross-coupling, the expected products 20j,k
were obtained in yields of 79–84%. By using Mg/LiCl or
Mg/LiCl/ZnCl2, various functional groups are compatible
with para-magnesium insertion. As shown in Scheme 10, the
tribromopivaloyloxybenzene derivative 17b provided only
the para-insertion zinc derivative 19b. After Negishi cross-
coupling with 4-iodotoluene, the expected product 21d was
obtained in 90% yield (entry 10, Table 4). The dibromopiva-
late 17d was cleanly converted to the para-magnesiated in-
termediate 19d. Quenching with benzaldehyde or copper-
mediated acylation with 4-chlorobenzoyl chloride afforded
the expected compounds 21e,f in yields of 78–86% (en-
tries 11 and 12).
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Organomagnesium and -Zinc Reagents
FULL PAPER
Table 4. Regioselective zinc or magnesium insertions into functionalized
di- or tribromoarenes followed by reaction with an electrophile to furnish
products of types 20 and 21.
Table 4. (Continued)
Entry Organometallic re-
agent (T [8C], t [h])[a]
Electrophile
Product yield [%][b]
Entry
Organometallic re-
Electrophile
Product yield [%][b]
agent (T [8C], t [h])[a]
10
1
18b (25, 1)
18c (50, 14)
20c: 78[c]
19b (25, 0.75[e]
)
21d: 90[c]
2
3
11
12
20d: 75[d]
19d (À20, 1)
21e: 86
18d (25, 1)
20e: 73[c]
19d
4
5
6
18d
21 f: 78[d]
[a] Reaction conditions for the insertion step. [b] Yield of analytically
pure product. [c] Obtained after Pd-catalyzed cross-coupling with [Pd-
AHCTUNGRTEG(NNNU dba)2] (2 mol%), tfp (4 mol%). [d] The organometallic reagent was
transmetalated with CuCN·2LiCl. [e] The insertion was performed in the
presence of ZnCl2 (1.0 equiv).
20 f: 74[d]
20g: 75[d]
20h: 61[d]
18d
applications. Thus, we treated 2-bromo-1-pivaloyloxyben-
zene (3x, 40 mmol) with Mg (2.5 equiv) and LiCl
(1.25 equiv) in THF at À208C. After slow addition and stir-
ring for 30 min at À208C, the conversion of the starting bro-
mide 3x was complete and the magnesium reagent 2x was
obtained in 93% yield, as indicated by titration.[34] An ali-
quot of 10 mmol of 2x was then used to perform a formyla-
tion (DMF, À20 to 258C, 30 min), which led to 2-pivaloyl-
18e (50, 14)
7
18e
AHCTUNGTREGoNNNU xybenzaldehyde (5z) in 83% yield (Scheme 11). The func-
20i: 70[d]
tionalized aromatic bromides 3y, 3b, 3z, and 3t were con-
verted to the corresponding magnesium reagents on a simi-
lar scale (40–86 mmol) in 86–97% yield (Table 5, entries 1–
4). As an example of a heterocyclic bromide, 3-bromopyri-
dine (3aa) was converted to the corresponding Grignard re-
agent (2aa) in 90% yield on a 100 mmol scale (entry 5). The
in situ method involving the use of Mg/LiCl and ZnCl2 was
also applied on a 25 mmol scale to ethyl 4-bromobenzoate
(3ab), which afforded the zinc compound 2ab in 90% yield
according to a titration. After transmetalation of the zinc re-
agent 2ab with CuCN·2LiCl (1.0 equiv) and quenching with
pivaloyl chloride, the desired ketone 5ab was obtained in
85% yield (Scheme 11).
8
9
18 f (25, 1)
18g (50, 6)
20j: 79[d]
20k: 84[c]
Typical benzylic chlorides, such as 2-chlorobenzyl chloride
(14h) and 4-methoxybenzyl chloride (14 f), were prepared
on a 50 mmol scale (08C, 1 h) in 89–90% yield (entries 6
and 7, Table 5). Finally, the tribromoaryl triazene 17e was
converted to the corresponding magnesium reagent 19e on
a 25 mmol scale (À208C, 1.5 h) in 88% yield. After trans-
Large-scale preparation of magnesium and zinc reagents: Fi-
nally, the utility of all of the above procedures would be
greatly enhanced if large-scale preparations of these magne-
sium or zinc organometallics were possible. We have studied
this aspect, which is of importance for potential industrial
Chem. Eur. J. 2009, 15, 7192 – 7202
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7199

P. Knochel et al.
Conclusion
In summary, we have shown that the presence of LiCl great-
ly facilitates the insertion of magnesium into various aryl
and heteroaryl bromides as well as activated aryl and het-
ACHUTNGRENeNUG roACHUTNGTRENaNGUN ryl chlorides. A number of functional groups are toler-
ated in this procedure. Sensitive functionalities such as ethyl
or methyl esters are also tolerated if ZnCl2 is added to the
Mg and LiCl. The highly reactive magnesium intermediate
is directly transmetalated to the corresponding zinc species
under such conditions. A range of functionalized benzylic
zinc compounds can be prepared in this way. We have also
reported a highly useful regioselective insertion procedure
for di- or tribromoarenes. In the presence of Zn/LiCl, pref-
erential insertion of Zn at the ortho-position with respect to
the directing group occurs, whereas with Mg/LiCl or Mg/
LiCl/ZnCl2 selective insertion at the para-position is ob-
served. Finally, we have demonstrated that these prepara-
tions of magnesium and zinc reagents can be performed on
a large scale (20–100 mmol). Further extensions of this
methodology as well as applications in natural product syn-
thesis and materials chemistry are currently underway in
our laboratories.
Scheme 11. Scale-up procedures for the preparation of magnesium and
zinc reagents.
metalation with ZnCl2 and Pd-catalyzed cross-coupling with
4-iodobenzonitrile, the expected biaryl 21g was isolated in
71% yield (Scheme 11).
Experimental Section
For experimental procedures, analytical data, and NMR spectra, see the
Supporting Information.
Table 5. Large-scale preparation of functionalized Mg and Zn reagents.
Preparation of a functionalized arylmagnesium halide using Mg/LiCl and
subsequent acylation: tert-butyl 3-(4-chlorobenzoyl)phenyl carbonate
(5a): A dry, argon-flushed Schlenk flask equipped with a magnetic stir-
ring bar and a septum was charged with magnesium turnings (122 mg,
5 mmol). LiCl (5.0 mL, 0.5m in THF, 2.5 mmol) was added and the mag-
nesium was activated with iBu2AlH (0.2 mL, 0.1m in THF, 0.02 mmol).
After stirring for 5 min, the suspension was cooled to À108C whereupon
3-bromophenyl tert-butyl carbonate (3a, 546 mg, 2.0 mmol) was added
and the reaction mixture was stirred for 1 h at this temperature. The su-
pernatant solution was then cannulated into a new dry, argon-flushed
Schlenk flask at À108C, CuCN·2LiCl (0.4 mL, 1m in THF, 20 mol%)
was added, and the reaction mixture was stirred for 15 min at À108C.
After the addition of 4-chlorobenzoyl chloride (245 mg, 1.4 mmol), the
mixture was allowed to warm to 258C. The reaction was quenched after
1 h with saturated aqueous NH4Cl solution (10 mL) and the resulting
mixture was extracted with Et2O (3ꢃ10 mL). The combined organic
layers were dried over Na2SO4 and concentrated in vacuo. The crude resi-
due was purified by flash column chromatography (pentane/CH2Cl2 3:2)
to give 5a as a colorless solid (440 mg, 95%). M.p. 83–848C; 1H NMR
(300 MHz, CDCl3): d=7.75 (d, J=9 Hz, 2H), 7.62 (td, J=2 Hz, J=8 Hz,
1H), 7.59–7.58 (m, 1H), 7.51–7.45 (m, 3H), 7.42–7.39 (m, 1H), 1.55 ppm
(s, 9H); 13C NMR (75 MHz, CDCl3): d=194.1, 151.5, 151.0, 139.1, 138.5,
135.4, 131.4, 129.4, 128.7, 127.2, 125.6, 122.8, 84.1, 27.7 ppm; IR (ATR):
n˜ =2985, 1749, 1653, 1580, 1439, 1369, 1248, 1138, 1085, 1004, 906, 824,
778 cmÀ1; MS (70 eV, EI): m/z (%): 232 (45) [M+ÀBoc], 139 (52), 57
(100); HRMS (EI): m/z: calcd for C13H9O2Cl: 232.0291 [M+ÀBoc];
found: 232.0275.
Entry
Aryl bromide
T [8C], scale
[mmol]
Organometallic reagent,
Yield [%][a]
1
À20, 40
3y
3b
3z
2y, 86
2b, 91
2z, 97
2
3
À20, 86
0, 50
4
5
À20, 100
3t
2t, 89
0, 100
3aa
14h
14 f
2aa, 90
13h, 90
13 f, 89
6
7
0, 50
0, 50
Preparation of an ester-substituted arylzinc compound and subsequent
copper(I)-mediated acylation: methyl 2-(4-chlorobenzoyl)benzoate (5t):
A dry, argon-flushed Schlenk flask equipped with a magnetic stirring bar
and a septum was charged with LiCl (127 mg, 3 mmol) and heated with a
heat gun under high vacuum for 5 min. ZnCl2 (300 mg, 2.2 mmol) was
added and was similarly heated under high vacuum. Magnesium powder
(78 mg, 3.2 mmol) and THF (3 mL) were added and the magnesium was
[a] Yields were determined by iodometric titration.[34]
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Organomagnesium and -Zinc Reagents
FULL PAPER
activated with iBu2AlH (0.2 mL, 0.1m in THF, 0.02 mmol). After stirring
for 5 min, methyl 2-bromobenzoate (3r, 428 mg, 2.0 mmol) was added at
08C and the reaction mixture was allowed to warm to 258C and was
stirred for 3 h. The supernatant solution was then cannulated into a new
dry, argon-flushed Schlenk flask, CuCN·2LiCl (2.0 mL, 1m in THF,
2 mmol) was added, and the reaction mixture was stirred for 15 min.
After the addition of 4-chlorobenzoyl chloride (245 mg, 1.4 mmol), the
mixture was stirred for a further 2 h at 258C. The reaction was then
quenched with saturated aqueous NH4Cl solution (10 mL) and the result-
ing mixture was extracted with Et2O (3ꢃ10 mL). The combined organic
layers were dried over Na2SO4 and concentrated in vacuo. The crude resi-
due was purified by flash column chromatography (pentane/Et2O 2:1) to
give 5t as a colorless solid (296 mg, 77%). M.p. 111–1128C; 1H NMR
(300 MHz, CDCl3): d=8.04 (dd, J=7.8 Hz, J=1.5 Hz, 1H), 7.71–7.52 (m,
4H), 7.41–7.36 (m, 3H), 3.64 ppm (s, 3H); 13C NMR (75 MHz, CDCl3):
d=195.8, 166.2, 141.3, 139.5, 135.5, 132.6, 130.5, 130.2, 129.8, 129.0, 128.8,
127.6, 52.3 ppm; IR (ATR): n˜ =1720, 1672, 1586, 1276, 1089, 930, 746,
711 cmÀ1; MS (70 eV, EI): m/z (%): 274 (32), 243 (25), 163 (100), 141
(16), 139 (46), 111 (17); HRMS (EI): m/z: calcd for C15H11ClO3:
274.0397; found: 274.0400.
2978, 2964, 2952, 2930, 2900, 2868, 2830, 2360, 1908, 1748, 1728, 1682,
1598, 1554, 1476, 1464, 1452, 1446, 1410, 1394, 1360, 1342, 1310, 1290,
1268, 1236, 1224, 1210, 1188, 1176, 1160, 1134, 1102, 1066, 1040, 1010,
972, 934, 908, 894, 876, 856, 830, 792, 766, 726, 710, 664, 638, 606, 580,
570, 556 cmÀ1; MS (70 eV, EI): m/z (%): 482 (1) [M+], 399 (91), 372 (18),
355 (19), 248 (13), 138 (10), 57 (100); HRMS (EI): m/z: calcd for
C20H20Br2O4: 481.9728; found: 481.9723.
Large-scale preparation of magnesium reagents: Preparation of 2-[(2,2-
dimethylpropanoyl)oxy]phenylmagnesium bromide (2x): A dry, argon-
flushed Schlenk flask equipped with a magnetic stirring bar and a septum
was charged with LiCl (2.12 g, 50 mmol) and heated with a heat gun
under high vacuum for 20 min. Magnesium turnings (2.43 g, 100 mmol)
and THF (100 mL) were added and the magnesium was activated with
iBu2AlH (0.07 mL, 57 mg, 0.4 mmol). After stirring for 5 min, the suspen-
sion was cooled to À208C and 2-bromo-1-pivaloyloxybenzene (10.3 g,
40 mmol) was slowly added at such a rate that the temperature of the
mixture remained below À158C. After completion of the addition, the
reaction mixture was stirred for an additional 30 min at À208C. GC anal-
ysis of a quenched aliquot of the mixture showed complete conversion.
The supernatant solution was then cannulated into a new dry, argon-
flushed Schlenk flask and the yield of the magnesium reagent was deter-
mined by iodometric titration (106 mL, 0.35m, 37.1 mmol, 93%).
Preparation of a benzylic zinc chloride using Mg/LiCl/ZnCl2 and subse-
quent reaction with an aldehyde: 3-[2-(3,4-dichlorophenyl)-2-hydroxy-
ACHTUNGTRENNUNGethyl]benzonitrile (16 f): A dry, argon-flushed Schlenk flask, equipped
with a magnetic stirring bar and a septum, was charged with magnesium
turnings (122 mg, 5.0 mmol) and then LiCl (5.0 mL, 0.5m in THF,
2.5 mmol) and ZnCl2 (2.2 mL, 1.0m in THF, 2.2 mmol) were added. 3-Cy-
anobenzyl chloride (303 mg, 2.0 mmol) was added at 258C and the reac-
tion mixture was stirred for 2 h at this temperature. The supernatant solu-
tion was then cannulated into a new dry, argon-flushed Schlenk flask con-
taining a solution of 3,4-dichlorobenzaldehyde (245 mg, 1.4 mmol) in
THF (1 mL) at 08C. The mixture was stirred for 2 h at 258C and then the
reaction was quenched with saturated aqueous NH4Cl solution (50 mL)
and the resulting mixture was extracted with CH2Cl2 (3ꢃ50 mL). The
combined organic layers were dried over MgSO4 and concentrated in
vacuo. Flash column chromatography (pentane/Et2O 7:3) furnished 16 f
as a colorless solid (341 mg, 83%). M.p. 96–978C; 1H NMR (300 MHz,
CDCl3): d=7.55–7.47 (m, 2H), 7.44–7.33 (m, 4H), 7.11 (dd, J=8.2 Hz,
2.0 Hz, 1H), 4.86 (q, J=6.4 Hz, 1H), 2.99 (d, J=6.4 Hz, 2H), 1.92 ppm
(brs, 1H); 13C NMR (75 MHz, CDCl3): d=143.5, 138.9, 134.1, 133.1,
132.7, 131.8, 130.5, 130.5, 129.2, 127.8, 125.1, 118.7, 112.5, 73.6, 45.1 ppm;
IR (ATR): n˜ =3328, 3260, 2232, 1484, 1470, 1426, 1398, 1202, 1142, 1058,
1028, 1014, 904, 818, 798, 690, 650, 602 cmÀ1; MS (70 eV, EI): m/z (%):
291 (2) [M+], 179 (13), 177 (100), 175 (61), 147 (29), 117 (71), 111 (19),
90 (13), 75 (12); HRMS (EI): m/z: calcd for C15H11Cl2NO: 291.0218;
found: 291.0214.
Acknowledgements
We thank the Fonds der chemischen Industrie, the ERC (European Re-
search Council), the DFG, and SFB749 for financial support. We also
thank Chemetall GmbH (Frankfurt), Evonik Industries AG (Hanau),
and BASF AG (Ludwigshafen) for generous gifts of chemicals.
[1] a) G. S. Silverman, P. E. Rakita (Eds.), Handbook of Grignard Re-
agents, CRC Press, New York, 1996; b) H. G. Richey, Jr. (Ed.),
Grignard Reagents, New Developments, Wiley-VCH, Weinheim,
2000, p. 185.
[2] a) P. Knochel, W. Dohle, N. Gommermann, F. F. Kneisel, F. Kopp, T.
Korn, I. Sapountzis, V. A. Vu, Angew. Chem. 2003, 115, 4438;
Angew. Chem. Int. Ed. 2003, 42, 4302; b) A. Boudier, L. O. Bromm,
M. Lotz, P. Knochel, Angew. Chem. 2000, 112, 4584; Angew. Chem.
Int. Ed. 2000, 39, 4414.
Procedure for regioselective zinc insertion: ethyl 3’,5’-dibromo-2’-[(2,2-di-
methylpropanoyl)oxy]biphenyl-4-carboxylate (20c): A dry, argon-flushed
Schlenk flask equipped with a magnetic stirring bar and a septum was
charged with LiCl (254 mg, 6 mmol) and heated with a heat gun under
high vacuum for 5 min. After cooling to 258C, zinc dust (374 mg,
6 mmol) was added, followed by THF (3 mL). The zinc powder was acti-
vated using 1,2-dibromoethane (5 mol%) and Me3SiCl (2 mol%). Then,
2,4,6-tribromophenyl pivalate (17b, 1.25 g, 3 mmol) was added neat at
258C. The reaction mixture was stirred at 258C for 1 h. After complete
conversion, the remaining zinc was allowed to settle and the supernatant
solution was carefully transferred to a second dry, argon-flushed Schlenk
[3] a) L. Boymond, M. Rottlꢀnder, G. Cahiez, P. Knochel, Angew.
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Shinokubo, K. Oshima, J. Org. Chem. 2001, 66, 4333; e) R. I.
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flask. [PdACHTUNGTRENNUNG(dba)2] (32 mg, 2 mol%), trisACHTUNTRGEG(NNUN 2-furyl)phosphine (26 mg, 4
mol%), and ethyl 4-iodobenzoate (773 mg, 2.8 mmol) were added and
the reaction mixture was stirred for 12 h at 258C. The reaction was then
quenched with saturated aqueous NH4Cl solution (10 mL) and the result-
ing mixture was extracted with EtOAc (3ꢃ20 mL). The combined ex-
tracts were washed with brine (10 mL) and dried over Na2SO4. After re-
moval of the solvents in vacuo, flash column chromatography (pentane/
Et2O 19:1) of the crude residue furnished 20c as a colorless oil (961 mg,
71%). 1H NMR (300 MHz, CDCl3): d=8.06 (d, J=8.1 Hz, 2H), 7.76 (d,
J=2.2 Hz, 1H), 7.43 (d, J=2.2 Hz, 1H), 7.39 (d, J=8.6 Hz, 2H), 4.39 (q,
J=7.1 Hz, 2H), 1.40 (t, J=7.1 Hz, 3H), 1.12 ppm (s, 9H); 13C NMR
(75 MHz, CDCl3): d=175.0, 166.1, 145.1, 140.2, 138.0, 135.1, 132.5, 130.3,
129.4, 129.0, 119.3, 118.5, 61.2, 39.1, 27.0, 14.3 ppm; IR (ATR): n˜ =3352,
[5] a) A. Krasovskiy, P. Knochel, Angew. Chem. 2004, 116, 3396;
Angew. Chem. Int. Ed. 2004, 43, 3333; b) A. Krasovskiy, B. Straub,
P. Knochel, Angew. Chem. 2006, 118, 165; Angew. Chem. Int. Ed.
2006, 45, 159; c) H. Ren, A. Krasovskiy, P. Knochel, Org. Lett. 2004,
6, 4215; d) H. Ren, A. Krasovskiy, P. Knochel, Chem. Commun.
2005, 543; e) F. Kopp, A. Krasovskiy, P. Knochel, Chem. Commun.
2004, 2288; f) F. Kopp, P. Knochel, Org. Lett. 2007, 9, 1639; g) F.
Kopp, S. Wunderlich, P. Knochel, Chem. Commun. 2007, 2075.
[6] iPrMgCl·LiCl is commercially available from Aldrich and Chemetall
GmbH (Frankfurt, Germany); christoph.krinninger@chemetall.com.
[7] P. Knochel, A. Gavryushin, V. Malakhov, A. Krasovskiy, DE
102006015378A1 20071004, 2007.
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Received: March 3, 2009
Published online: June 19, 2009
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