Highly regioselective preparation of heteroaryl-magnesium reagents by using a Br/Mg exchange

Article abstract of DOI:10.1002/chem.201202230

Disubstituted thienyl-, furyl- and pyridylmagnesium derivatives are regioselectively prepared from a Br/Mg exchange of the corresponding dibromo compounds by using either iPrMgCl·LiCl or hindered arylmagnesium reagents, such as isitylmagnesium bromide·lithium chloride (isityl=2,4,6-triisopropyl-phenyl) complexed with a diamine ligand, in difficult cases. The selective functionalisations of these heterocyclic scaffolds by using Negishi cross-coupling reactions, acylations or addition to aldehydes were readily achieved.

Full text of DOI:10.1002/chem.201202230

FULL PAPER
DOI: 10.1002/chem.201202230
Highly Regioselective Preparation of Heteroaryl–Magnesium Reagents by
Using a Br/Mg Exchange
Christoph Sꢀmann, Benjamin Haag, and Paul Knochel*[a]
Abstract: Disubstituted thienyl-, furyl- and pyridylmagnesium derivatives are re-
gioselectively prepared from a Br/Mg exchange of the corresponding dibromo
compounds by using either iPrMgCl·LiCl or hindered arylmagnesium reagents,
such as isitylmagnesium bromide·lithium chloride (isityl=2,4,6-triisopropyl-
phenyl) complexed with a diamine ligand, in difficult cases. The selective function-
alisations of these heterocyclic scaffolds by using Negishi cross-coupling reactions,
acylations or addition to aldehydes were readily achieved.
Keywords: copper · cross-coupling ·
Grignard reaction
regioselectivity
· palladium ·
Introduction
Results and Discussion
The functionalisation of heterocycles is of key importance
for the preparation of pharmaceuticals, agrochemicals and
materials (regioregular polymers) and has attracted a lot of
attention in recent years.[1] Especially important is the regio-
selective preparation of metalated five- and six-membered
heterocycles. Recently, we reported that iPrMgCl·LiCl (1a)
is a powerful reagent for performing Br/Mg-exchange reac-
tions at various aromatic bromides.[2] The presence of LiCl
was shown to enhance the Br/Mg exchange rates by generat-
ing reactive ate-intermediates
Preliminary experiments have shown that the treatment of
unsymmetrically substituted dibromoheterocycles, such as
2,5-dibromo-3-(methylthio)thiophene
(2a),
with
iPrMgCl·LiCl (1a; 1.05 equiv) in THF at 08C leads to the
corresponding magnesium reagent (3a) in >95% yield and
with a regioselectivity of >99:1 within 1 h. The addition of
1a to 3-chloro-4-methoxybenzaldehyde (4a, 0.9 equiv) at
À208C provided the corresponding alcohol 5a in 74% yield
(Scheme 1). With these conditions in hand, several unsym-
À
of the type iPrMgCl2 ·Li+.
Herein, we now report a regio-
selective Br/Mg-exchange reac-
tion of unsymmetrically substi-
tuted dibromoheterocycles by
using either iPrMgCl·LiCl (1a)
or, in difficult cases, hindered
arylmagnesium reagents, such
as 2,4,6-trimethylphenylmagne-
Scheme 1. Regioselective Br/Mg exchange on unsymmetrical 2,5-dibromothiophenes of type
iPrMgCl·LiCl (1a).
2 by using
sium bromide (1b) or 2,4,6-tri-
isopropylphenylmagnesium bro-
mide (1c) complexed with a di-
ACHTUNGTRENNUNG
amine ligand, to allow the preparation of various thienyl-,
furyl- and pyridylmagnesium derivatives. The further selec-
tive functionalisation of these heterocyclic scaffolds is also
disclosed.
metrically substituted dibromothiophenes and -thienothio-
phenes (2b–j) were converted into their corresponding mag-
nesium species (Table 1) and subsequently functionalised by
using a range of electrophiles, such as aldehydes, aryl io-
dides or acyl chlorides, in the presence of an appropriate
catalyst (Table 1).
This regioselective exchange has been performed with a
number of unsymmetrically substituted dibromothiophenes
and -thienothiophenes with good to excellent regioselectivi-
ties, even on 10 and 15 mmol scales (Table 1, entries 7 and
17). Thio substituents [MeS (2a; Table 1, entries 1–4), PhS
(2b; Table 1, entries 5–7) and PyrS (2c; Table 1, entry 8)] or
a trimethylsilyl substituent on the thiophene (2i; Table 1,
entries 16–18) directed the Br/Mg exchange at position 5
[a] C. Sꢀmann, Dr. B. Haag, Prof. Dr. P. Knochel
Department Chemie
Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5–13, Haus F, 81377 Mꢁnchen (Germany)
Fax : (+49)89-2180-77680
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.201202230. It includes the com-
plete experimental procedures, analytical data and NMR spectra.
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Table 1. Preparation of functionalised thiophenes and thienothiophenes of type 5 by reaction with heteroarylmagnesium reagents of type 3.
Entry
Mg Reagent:
Electrophile
Product:
Yield[b]
Entry
Mg Reagent:
Electrophile
Product:
Yield[b]
Regioselectivity[a]
Regioselectivity[a]
1
2
3
3a:>99:1
3a:>99:1
3a:>99:1
4a
4b
5a: 74%
5b: 82%[c]
5c: 82%
11
12
13
3d:>99:1
3e: 22:1
3 f: 39:1
4j
4g
4i
5k: 76%[c]
5l: 96%[c]
5m: 91%[c]
AHCTUNTGREN(GNUN tBuO2C)2O
4c
4d
4
5
3a:>99:1
5d: 84%[c]
14
15
3g: 20:1
4h
4k
5n: 89%[c]
3b:>99:1
4e
5e: 91%
3h[f]: 20:1
5o: 83%[c]
6
7
3b:>99:1
3b:>99:1
4 f
4g
5 f: 86%[c]
16
17
3i:>99:1
3i:>99:1
4l
5p: 86%
5g: 96%[c,d]
4g
5q: 87%[c,g]
8
9
3c:>99:1
3d:>99:1
4h
4i
5h: 92%[c]
18
19
3i:>99:1
3j:>99:1
4m
4e
5r: 72%[h]
5i: 90%[c]
5s: 81%
10
3d:>99:1
4j
5j: 60%[e]
20
3j:>99:1
4g
5t: 96%[c]
[a] Obtained after exchange reaction with iPrMgCl·LiCl (1a; 1.05 equiv) in THF at 08C for 1 h. Ratio of regioisomers determined by 1H NMR analysis
of the quenched crude reaction mixture (HOAc, 10 equiv). [b] Yield of analytically pure isolated product as determined by 1H NMR analysis. [c] Ob-
tained after a Negishi cross-coupling reaction [ZnCl2 (1 equiv) then [PdACHTNUTRGNEUNG(PPh3)4] (4%)] with ArI (0.9 or 1.1 equiv). [d] The reaction was performed on a
15 mmol scale. [e] Transmetalation with ZnCl2 (0.5 equiv) before addition to the aldehyde. [f] The exchange reaction was performed at À208C for 1 h.
[g] The reaction was performed on a 10 mmol scale. [h] Obtained after an acylation reaction [ZnCl2 (1 equiv) then CuCN·2LiCl (10%)] with ArCOCl
(0.9 equiv).
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Regioselective Preparation of Heteroaryl–Magnesium Reagents
FULL PAPER
with a regioselectivity of >99:1.[3] Interestingly, by using 2,5-
dibromo-3-phenylthiophene, no regioselective Br/Mg ex-
change could be achieved under various conditions. Howev-
er, by introducing a substituent at the ortho position of the
phenyl group [MeO (2d; Table 1, entries 9–11), Me (2e;
Table 1, entry 12) and Me2N (2 f; Table 1, entry 13)] selectiv-
ities from 20:1 up to>99:1 could be obtained. This effect
may be explained by assuming a conformational change by
moving the aryl group out of the plane due to the substitu-
ent on position 2’, and therefore shields the bromine at posi-
tion 2. It is worth noting that a satisfactory regioselectivity
of 20:1 has been also achieved with the use of heterocyclic
substituents such as a 2-pyridyl or a 2-thienyl group (2g and
h; Table 1, entries 14 and 15).
Scheme 2. The tuneable reactivity of the heteroarylmagnesium reagent
3d towards 4j by the presence or absence of PdACTHNUTRGNE(UNG PPh3)4.
Additionally, no chelating effect with the MeO- or Me2N-
substituent of the phenyl ring, nor with the pyridyl- or the
thienyl-substituents, could be observed. We assume that this
might be due to the too-long distance between the bromine
at position 2 of the thiophene ring and the heteroatom of
the MeO or Me2N group of the phenyl ring (or the pyridyl
or thienyl substituent) caused by the almost perpendicular
orientation of the thiophene ring and the substituents at po-
sition 3. Because thienothiophenes are important building
blocks for the preparation of organic materials,[4] we also
performed regioselective functionalisations of this scaffold
by using iPrMgCl·LiCl (1a) (Table 1, entries 19 and 20).
As mentioned above, a wide range of electrophiles have
been used for the selective functionalisation of the heterocy-
clic magnesium reagents. It was possible to directly add the
Mg species to aldehydes to form the corresponding alcohols
in 60–91% yield (Table 1, entries 1, 5, 10,[5] 16 and 19). Fur-
thermore, the thienylmagnesium reagent 3a reacted with di-
tert-butyl dicarbonate (4c) to provide the tert-butyl carboxy-
late 5c in 82% yield (Table 1, entry 3). After transmetala-
tion with ZnCl2 (1 equiv), Negishi cross-coupling reactions[6]
with various electron-withdrawing and electron-donating
In order to exemplify the further functionalisation of
monobromothiophenes of type 5 that were obtained after
the selective Br/Mg exchange (Table 1), the previously pre-
pared mono-bromothiophene 5g was submitted to a second
Br/Mg-exchange reaction by using iPrMgCl·LiCl (1a;
1.1 equiv) at ambient temperature. The resulting magnesium
reagent 6 was readily used in different types of quenching
reactions (Scheme 3 and Table 2).
The thienylmagnesium reagent 6 reacted easily with alde-
hyde 4n to provide the alcohol 7a in 77% yield (Table 2,
entry 1). After transmetalation with ZnCl2 (1 equiv), a Ne-
gishi cross-coupling reaction with aryl iodide 4h and Pd-
AHCTUNTGRENGUN(N PPh3)4 (5%) as the catalyst gave the expected product in
73% yield (7b; Table 2, entry 2). Moreover, transmetalation
with ZnCl2 (1 equiv) followed by a CuI-catalysed acylation
(10% CuCN·2LiCl) with the acyl chloride 4o gave the func-
tionalised ketone 7c in 70% yield (Table 2, entry 3).
The regioselective Br/Mg exchange was also extended to
various 3,5-dibromopyridine derivatives (Scheme 4). The
corresponding magnesium species 9a–d were obtained in
satisfactory regioselectivities of up to 28:1 (Table 3). Subse-
quent Negishi cross-coupling reactions, after transmetalation
with ZnCl2, led to the formation of the trisubstituted pyri-
dine derivatives 10a–d in good yields (60–88%; Table 3, en-
tries 1–4). Both electron-poor and electron-rich aryl iodides
were used successfully. The cross-coupling reactions were
usually complete within a reaction time of one hour at
258C.
aryl iodides and PdACHTUNGTRENNUNG(PPh3)4 (4%) as the catalyst were per-
formed at 258C to give the products in high yields (76–96%;
Table 1, entries 2, 4, 6–9, 11–15, 17 and 20). Moreover, trans-
metalation of 3i with ZnCl2 (1 equiv) followed by a CuI-cat-
alysed[7] acylation (10% CuCN·2LiCl) with furan-3-carbonyl
chloride (4m) gave the functionalised ketone 5r in 72%
yield (Table 1, entry 18).
By the reaction of magnesium species, such as 3d, with
formyl-substituted heterocyclic iodides (4j), we were able to
perform either an addition to an aldehyde or a Negishi
cross-coupling at the iodide substituent (Table 1, entries 10
and 11). After transmetalation with ZnCl2 (0.5 equiv), the
reaction with 5-iodofuran-2-car-
Preliminary experiments showed that the regioselectivity
of the Br/Mg-exchange reaction on 2,5-dibromothiophenes
with an alkyl substituent at position 3 was poor with the use
of iPrMgCl·LiCl (1a). Therefore, we envisioned that increas-
ing the steric hindrance of the Grignard reagent
baldehyde (4j) rapidly gave the
corresponding alcohol 5j in
60% yield.[5] By the addition of
PdACHTUNGTRENNUNG(PPh3)4 (4%), the formyl
group remained untouched and
the Negishi cross-coupling took
place to provide 5k in 76%
yield (Scheme 2).
Scheme 3. Further functionalisation of the cross-coupling product 5g by Br/Mg exchange and subsequent reac-
tions with different electrophiles.
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16147

P. Knochel et al.
Table 2. Preparation of functionalised thiophenes of type 7 by reaction
with the regioselectively generated heteroarylmagnesium reagent 6.
Table 3. Preparation of functionalised pyridines of type 10 by reaction
with regioselectively generated heteroarylmagnesium reagents of type 9.
Entry
Electrophile
Product:
Yield[a]
Entry Mg Reagent (condi-
tions [T, t]):
Electrophile
Product:
Yield[b,c]
Regioselectivity[a]
1
2
9a (À558C, 2 h): 27:1
4h
10a: 88%
10b: 64%
1
2
4n
4h
7a: 77%
7b: 73%[b]
9b (À788C, 2 h): 13:1
9c (08C, 1 h): 28:1
4h
4i
3
4o
7c: 70%[c]
3
4
10c: 74%
10d: 60%
[a] Yield of analytically pure isolated product as determined by 1H NMR
analysis. [b] Obtained after Negishi cross-coupling reaction [ZnCl2
(1 equiv) then Pd(PPh3)4 (5%)] with ArI (0.9 equiv). [c] Obtained after
an acylation reaction [ZnCl2 (1 equiv) then CuCN·2LiCl (10%)] with
ArCOCl (0.9 equiv).
a
ACHTUNGTRENNUNG
9d (À658C, 1 h):[d] 17:1 4g
[a] Obtained after exchange reaction with iPrMgCl·LiCl (1a; 1.05 equiv)
in THF. The ratio of regioisomers was determined by 1H NMR analysis
of the quenched crude reaction mixture (HOAc, 10 equiv). [b] Yield of
analytically pure isolated product as determined by 1H NMR analysis.
[c] Obtained after a Negishi cross-coupling reaction [ZnCl2 (1 equiv) then
PdACHTNURTGNEG(UN PPh3)4 (4%)] with ArI (0.9 equiv). [d] The exchange reaction was per-
formed by using iPr2Mg·LiCl (0.55 equiv).
Scheme 4. Regioselective Br/Mg exchange on unsymmetrical 2,5-dibro-
mopyridines of type 8 by using iPrMgCl·LiCl (1a).
R1MgX·LiCl of type 1 and its aggregation in solution, by
adding typical chelating amines such as ligand L1 or L2,
would improve the regioselectivity of the Br/Mg-exchange
reaction (Scheme 5).[8]
Thus, the treatment of 2,5-dibromo-3-methylthiophene
(11a) with iPrMgCl·LiCl (1a; 1.05 equiv) gave a regioiso-
meric mixture of the thienylmagnesium chlorides 12a and
13a in a ratio of 80:20 (Table 4, entry 1). However, the addi-
tion of a tridentate ligand, such as N-[2-(dimethylamino)eth-
yl]-N,N’,N’-trimethylethane-1,2-diamine (L1; 1.05 equiv) or
2,2’-oxy-bis(N,N-dimethylethanamine)[9] (L2; 1.05 equiv),
which led to the formation of the sterically more hindered
complexes 1a·L1 and 1a·L2, significantly improved the re-
gioisomeric ratio of the resulting magnesium reagents in
favour of 12a (85:15 and 87:13; Table 4, entries 2 and 3).
Moreover, lower temperatures (À608C, 1 h) further in-
creased the regioisomeric ratio up to 90:10 in favour of the
formation of 12a (Table 4, entry 4). Additives such as
Scheme 5. Regioselective Br/Mg-exchange on unsymmetrical 2,5-dibro-
mohetero-cycles of type 11. Hex=n-hexyl.
change reaction with 11a. In comparison to secondary alkyl-
magnesium reagents such as 1a, arylmagnesium bromides,
such as 1b or 1c, displayed lower exchange reaction rates
but led to a better regioselectivity, increasing from 84:16 to
96:4 (compare Table 4, entry 1 with entries 5 and 7). Re-
markably, the addition of L2 (1.05 equiv) to LiCl-solubilised
mesitylmagnesium bromide (1b, 1.05 equiv; À208C, 12 h)
predominantly converted 11a into the Grignard species 12a
with a regioisomeric ratio of 97:3 (Table 4, entry 6). The re-
action of 11a with the even more sterically hindered ex-
TMEDA
DABCO (1,4-diazabicyclo
little influence on the regioselectivity of the Br/Mg-ex-
(N,N,N’,N’-tetramethylethan-1,2-diamine),
AHCTUNGTRENNUNG
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Regioselective Preparation of Heteroaryl–Magnesium Reagents
FULL PAPER
Table 4. Regioselective Br/Mg exchange on unsymmetrical 2,5-dibromo-
heterocycles by using various complexed and uncomplexed Grignard re-
agents of type 1.
Table 5. Preparation of functionalised five-membered heterocycles of
type 14 by reaction with regioselectively generated heteroarylmagnesium
reagents of type 12.
Entry
R1MgX·LiCl·L1,2
Conditions
[T, t][a]
Product of Type 10:
Entry Mg Reagent:
Regioselectivity[a]
Electrophile
Product:
Yield[b]
N
Regioselectivity[b]
AHCTUNTGREN(GNUN tBuO2C)2O
1
2
3
4
5
6
7
8
1a
À208C, 20 min
À208C, 20 min
À208C, 20 min
À608C, 1 h
12a: 80:20
12a: 85:15
12a: 87:13
12a: 90:10
12a: 84:16
12a: 97:3
1
2
12a: >99:1
4c
14a: 83%
1a·L1
1a·L2
1a·L2
1b
À208C, 12 h
À208C, 12 h
À108C, 12 h
À108C, 16 h
12a: >99:1
4h
14b: 86%[c]
1b·L2
1c
12a: 96:4
1c·L2
12a: >99:1[c]
3
4
12a: >99:1
12a: >99:1
4p
14c: 85%[d]
9
10
1a·L2
1c·L2
À108C, 20 min
À108C, 16 h
12b: 85:15
12b: >99:1[c]
11
12
1a·L2
1c·L2
À108C, 6 h
12c: 80:20
12c: 95:5
–
14d: 87%[e]
À108C, 16 h
13
14
1a·L2
1c·L2
À108C, 6 h
12d: 75:25
12d: 91:9
À108C, 16 h
5
6
12b: >99:1
4e
14e: 71%
[a] Complete conversion as determined by GC analysis of an iodolysed
reaction aliquot. [b] Determined by 1H NMR anaylsis of the quenched
crude reaction mixture (HOAc, 10 equiv). [c] The regioisomer of type 13
was not observed in 1H NMR analysis of the hydrolysed crude reaction
mixture (HOAc, 10 equiv, À20 to 258C).
change reagent 2,4,6-triisopropylphenylmagnesium bromide
(1c) furnished with L2 (1.05 equiv) at À108C in 16 h the
products 12a/13a in a ratio of >99:1 (Table 4, entry 8).[10]
These results were extended to the reaction of various
2,5-dibromoheterocycles (11b–d; Table 4, entries 9–14). In
each case, the use of the sterically hindered Grignard re-
agent 1c in combination with L2 (1.05 equiv) gave the best
results (compare Table 4, entries 9, 11 and 13 with 10, 12
and 14). However, the use of the bulky reagent 1c·L2 led to
significantly lower exchange rates and the Br/Mg exchange
required a reaction time of about 16 h compared to 1–6 h.
With these conditions in hand (1c·L2, À108C, 16 h) we
have selectively formed the magnesium derivatives of vari-
ous five-membered heterocyclic species with a regioselectivi-
ty of>99:1 (Table 5). The newly generated magnesium spe-
cies reacted readily with aldehydes to provide the corre-
sponding alcohols 14e, 14i, 14l and 14n in 71–88% yield
(Table 5, entries 5, 9, 12 and 14). Furthermore, the thienyl-
magnesium derivative 12a reacted with di-tert-butyl dicar-
bonate (4c) to give the tert-butyl carboxylate 14a in 83%
yield (Table 5, entry 1). Transmetalation of 12a with ZnCl2
(0.5 equiv) followed by the addition of CuCN·2LiCl
(0.5 equiv) and chloranil (1.5 equiv) generated the substitut-
ed thiophenyl dimer 14d in 87% yield (Table 5, entry 4).[11]
12b: >99:1
4q
4p
14 f: 70%
7
12c: >99:1
12c: >99:1
12c: >99:1
12e:[f] >99:1
14g: 79%[d]
14h: 78%[c]
14i: 73%
8
4i
tBuCHO
9
4r
10
4i
14j: 77%[c]
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P. Knochel et al.
It is worth mentioning that the Br/Mg-exchange reaction
of 2,5-dibromo-3-methoxythiophene with the bulky reagent
1c·L2 led to the formation of the 2-magnesium-substituted
thiophene (12 f; Table 5, entries 14–16) and not to the 5-
magnesium-substituted product (as occurs for the reactions
of the other dibromothiophene derivatives 11a–c and 11e).
We assume that this selectivity resulted from a preliminary
coordination of the bulky magnesium reagent to the oxygen
of the methoxy substituent. This complexation seemed to be
essential for the Br/Mg-exchange reaction to proceed. In
contrast, by using iPrMgCl·LiCl (1a) in the Br/Mg-exchange
reaction, the opposite selectivity has been observed (4:1
ratio in favour of the 5-magnesium-substituted thio-
phene).[13] This might be a result of the high reactivity of
iPrMgCl·LiCl (1a), which allows the exchange reaction to
proceed without prior chelation in an etheral solvent such as
THF.
Table 5. (Continued)
Entry Mg Reagent:
Electrophile
Product:
Yield[b]
14k: 86%[d]
Regioselectivity[a]
11
12
13
12e:[f] >99:1
4s
12e:[f] >99:1
4e
14l: 88%
12e:[f] >99:1
4q
14m: 94%
The regioselective Br/Mg exchange with 1c·L2 was also
extended to 3,5-dibromo-2-(trimethylsilyl)pyridine (15) lead-
ing to the corresponding magnesium reagent 16 at À258C in
2 h (Scheme 6). The subsequent Negishi cross-coupling reac-
tions, after transmetalation with ZnCl2, led to the formation
of the trisubstituted pyridine derivatives 17a–b in satisfacto-
ry yields (60–61%, Scheme 6).
14
15
12 f: >99:1
12 f: >99:1
4a
4i
14n: 73%
14o: 69%[c]
16
12 f: >99:1
4o
14p: 66%[d]
[a] Ratio of regioisomers determined by 1H NMR analysis of the
quenched crude reaction mixture (HOAc, 10 equiv). [b] Obtained after
an exchange reaction with 1c (1.05 equiv) and L2 (1.05 equiv) in THF at
À108C in 16 h. Yield of analytically pure isolated product as determined
Scheme 6. Preparation of functionalised pyridines of type 17 by reaction
with the regioselectively generated heteroarylmagnesium reagent 16.
TMS=trimethylsilyl.
1
by H NMR analysis. [c] Obtained after a Negishi cross-coupling reaction
[ZnCl2 (1 equiv) then PdACHTNURGTNEUNG(PPh3)4 (4%)] with ArI (0.9 or 1.2 equiv).
[d] Obtained after an acylation reaction [ZnCl2 (1 equiv) then
CuCN·2LiCl (10 mol%)] with ArCOCl (0.9 or 1.2 equiv). [e] Obtained
after transmetalation with ZnCl2 (0.5 equiv) and a copper-mediated oxi-
dative dimerisation [CuCN·2LiCl (0.5 equiv) then addition of chloranil
(1.5 equiv)]. [f] Exchange reaction performed at 08C for 1 h.
Conclusions
We have described a highly regioselective preparation of
five- and six-membered heteroarylmagnesium derivatives by
using the efficient Br/Mg-exchange reagents iPrMgCl·LiCl
(1a) and isitylmagnesium bromide·lithium chloride (1c).
iPrMgCl·LiCl (1a) underwent highly regioselective Br/Mg-
exchange reactions with dibromoheterocycles derived from
thiophenes, thienothiophenes and pyridines. Ring substitu-
ents, such as thioether or trimethylsilyl groups, as well as
pyridyl and thienyl groups or ortho-substituted aryl groups,
directed the Br/Mg exchange at position 5 with a regioselec-
tivity of up to >99:1.
Similarly, after transmetalation with ZnCl2 (1 equiv), Ne-
gishi cross-coupling reactions with various aryl iodides and
PdACHTUNGTRENNUNG(PPh3)4 (4%) as the catalyst at 258C led to the expected
products in 69–86% yield (Table 5, entries 2, 8, 10 and 15).
By transmetalation with ZnCl2 (1 equiv) followed by a CuI-
catalysed acylation (10% CuCN·2LiCl) with a range of acyl
chlorides, the functionalised ketones 14c, 14g, 14k and 14p
were obtained in 66–86% yield (Table 5, entries 3, 7, 11 and
16). The direct reaction of 4-methoxybenzenesulfinyl chlor-
ide (4q) with the heterocyclic magnesium species furnished
the sulfoxides 14 f and 14m in 70–94% yield (Table 5, en-
tries 6 and 13).[12]
In the case of alkyl-substituted dibromothiophene or
-furan derivatives, the sterically hindered Grignard reagent
2,4,6-triisopropylphenylmagnesium bromide (1c) in combi-
nation with the chelating diamine 2,2’-oxy-bis(N,N-dimethy-
16150
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ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 16145 – 16152

Regioselective Preparation of Heteroaryl–Magnesium Reagents
FULL PAPER
lethanamine) (L2) gave the best results. The bulky complex
1c·L2 gave regioselectivities of >99:1 in the Br/Mg-ex-
change reactions.
purification on silica gel (pentane/Et2O=9:1+1% NEt3) gave 10a
(354 mg, 88%) as a white solid. M.p.: 97.5–99.18C; 1H NMR (600 MHz,
CDCl3): d=8.80 (d, J=2.2 Hz, 1H), 7.99–8.02 (m, 2H), 7.92 (d, J=
2.2 Hz, 1H), 7.51 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H), 7.23–7.26
(m, 2H), 4.39 (q, J=7.1 Hz, 2H), 1.41 ppm (t, J=7.1 Hz, 3H); 13C NMR
(150 MHz, CDCl3): d=166.0, 154.0, 150.0, 142.4, 142.2 (q, J=1.1 Hz),
140.7, 136.8, 130.3 (q, J=32.8 Hz), 130.2, 130.0, 129.9, 129.4, 125.1 (q, J=
3.7 Hz), 123.9 (q, J=272.4 Hz), 119.9, 61.2, 14.3 ppm; MS (EI, 70 eV) m/
z (%): 451 (M+, 97), 450 (M+, 100), 449 (M+, 95), 448 (M+, 85), 421
(32), 419 (35), 406 (21), 404 (21), 378 (15), 376 (17), 297 (31), 296 (15),
228 (11), 227 (11); IR (ATR): n˜ =3055, 2982, 2940, 2904, 1705, 1608,
1426, 1368, 1323, 1310, 1288, 1273, 1166, 1120, 1111, 1101, 1068, 1024,
All selectively formed, heterocyclic magnesium-derivative
scaffolds were subsequently funtionalised with a broad
range of electrophiles, such as aldehydes, aryl iodides, acyl
chlorides or aryl sulfinyl chlorides. This gave access to a
wide range of highly functionalised thiophene or pyridine
derivatives from readily available dibromo-precursors.
Moreover, the resulting mono-bromoheterocycles could
readily be submitted to a second Br/Mg-exchange reaction
followed by further functionalisation reactions.
This method is very versatile and one example of its possi-
ble application is the synthesis of poly(3-hexylthiophene)
(P3HT),[14] in which the regioregularity determines macro-
scopic physical properties of the polymers.[15]
1009, 854, 783, 769, 715, 706 cmÀ1
; HRMS (EI): m/z calcd for
C21H15BrF3NO2: 449.0238 (M+); found: 449.0231.
Regioselective Br/Mg-exchange on unsymmetrical 2,5-dibromoheterocy-
cles of type 11:
Synthesis of (5-bromo-4-methylthiophen-2-yl)(thiophen-2-yl)methanone
(14c): A dry and argon-flushed Schlenk flask, equipped with a magnetic
stirring bar and a septum, was charged with 2,4,6-triisopropylmagnesium
bromide (1c; 0.7m in THF, 3.0 mL, 2.1 mmol) and 2,2’-oxy-bis(N,N-dieth-
ylethanamine) (L2; 337 mg, 2.1 mmol). After stirring for 15 min at 258C,
2,5-dibromo-3-methylthiophene (11a; 512 mg, 2 mmol) was added as a
solution in THF (1.0m) at À108C and stirred continuously for 16 h (the
completion of the Br/Mg exchange was monitored by GC analysis of io-
dolysed reaction aliquots with the use of undecane as an internal stand-
ard). ZnCl2 (1.0 mL, 1.0m in THF, 1 equiv) was added to the freshly pre-
pared heteroarylmagnesium reagent 12a and the reaction mixture was
stirred for 15 min at À108C. CuCN·2LiCl (0.2 mL, 1.0m in THF,
0.2 mmol) and thiophene-2-carbonyl chloride (4p; 352 mg, 2.4 mmol)
were added and the reaction mixture was warmed to 258C. After stirring
for 4 h, the reaction mixture was quenched with saturated aqueous
NH4Cl/NH3 solution (10:1), extracted three times with EtOAc, dried
over Na2SO4 and concentrated in vacuo. Flash column chromatographic
purification on silica gel (pentane/Et2O=95:5) gave 14c (488 mg, 85%)
as an off-white solid. M.p.: 100.2–101.48C; 1H NMR (300 MHz, CDCl3):
d=7.85 (dd, J=3.8, 1.1 Hz, 1H), 7.69 (dd, J=4.9, 1.1 Hz, 1H), 7.57 (s,
1H), 7.17 (dd, J=5.0, 3.8 Hz, 1H), 2.25 ppm (s, 3H); 13C NMR (75 MHz,
CDCl3): d=177.6, 142.2, 141.8, 138.7, 134.6, 133.6, 133.0, 128.0, 120.0,
15.4 ppm; MS (EI, 70 eV) m/z (%): 289 (11), 288 (M+, 100), 287 (11),
286 (M+, 93), 207 (13), 205 (37), 203 (36), 111 (77), 96 (11); IR (ATR):
n˜ =3004, 2362, 2340, 1740, 1658, 1582, 1522, 1432, 1366, 1228, 1222, 1204,
1098, 1056, 780, 706 cmÀ1; HRMS (EI): m/z calcd for C10H7BrOS2:
285.9122 (M+); found: 285.9117.
Experimental Section
Regioselective Br/Mg exchange on unsymmetrical 2,5-dibromothiophenes
of type 2:
Synthesis of 2-bromo-5-(4-nitrophenyl)-3-(phenylthio)thiophene (5f): A
dry and argon-flushed Schlenk flask, equipped with a magnetic stirring
bar and a septum, was charged with iPrMgCl·LiCl (1a; 1.2m in THF,
0.88 mL, 1.05 mmol). 2,5-Dibromo-3-(phenylthio)thiophene (2b; 350 mg,
1 mmol) was added as a solution in THF (1.0m) at 08C and stirred con-
tinuously for 1 h (the completion of the Br/Mg exchange was monitored
by GC analysis of iodolysed reaction aliquots with the use of undecane
as an internal standard). ZnCl2 (1.0 mL, 1.0m in THF, 1 mmol) was
added to the freshly prepared heteroarylmagnesium reagent 3b and the
reaction mixture was stirred for 15 min at 08C. PdACTHNUTRGNE(UNG PPh3)4 (46 mg,
0.04 mmol) and 1-iodo-4-nitrobenzene (4 f; 224 mg, 0.9 mmol) were
added and the reaction mixture was warmed to 258C. After stirring for
1 h, the reaction mixture was quenched with saturated aqueous NH4Cl
solution, extracted three times with EtOAc, dried over Na2SO4 and con-
centrated in vacuo. Flash column chromatographic purification on silica
gel (pentane/Et2O=100:3) gave 5 f (302 mg, 86%) as a yellow solid.
1
M.p.: 129.0–130.98C; H NMR (300 MHz, CDCl3): d=8.21–8.29 (m, 2H),
7.62–7.69 (m, 2H), 7.42 (s, 1H), 7.25–7.39 ppm (m, 5H); 13C NMR
(75 MHz, CDCl3): d=147.3, 144.5, 138.7, 135.2, 132.1, 129.4, 129.3, 128.9,
127.5, 125.9, 124.5, 119.9 ppm; MS (EI, 70 eV): m/z (%): 395 (M+, 10),
393 (M+, 100), 391 (95), 312 (13), 267 (15), 266 (72), 265 (24), 234 (14),
221 (36), 189 (13), 121 (11), 113 (15), 77 (14), 43 (14); IR (ATR): n˜ =
3092, 3076, 3061, 2932, 2842, 1591, 1578, 1516, 1506, 1477, 1341, 1332,
1108, 1022, 851, 819, 740, 726, 687 cmÀ1; HRMS (EI): m/z calcd for
C16H10BrNO2S2: 390.9336 (M+); found: 390.9333.
Regioselective Br/Mg exchange on 3,5-dibromo-2-(trimethylsilyl)pyridine
(15):
Synthesis of ethyl 4-(5-bromo-6-(trimethylsilyl)pyridin-3-yl)benzoate
(17b): A dry and argon-flushed Schlenk flask, equipped with a magnetic
stirring bar and a septum, was charged with 2,4,6-triisopropylmagnesium
bromide (1c; 0.7m in THF, 1.5 mL, 1.05 mmol) and 2,2’-oxy-bis(N,N-di-
ethylethanamine) (L2; 168 mg, 1.05 mmol). After stirring for 15 min at
258C, 3,5-dibromo-2-(trimethylsilyl)pyridine (15; 309 mg, 1 mmol) was
added as a solution in THF (1.0m) at À258C and stirred continuously for
2 h (the completion of the Br/Mg exchange was monitored by GC analy-
sis of iodolysed reaction aliquots with the use of undecane as an internal
standard). ZnCl2 (1.0 mL, 1.0m in THF, 1 mmol) was added to the freshly
prepared heteroarylmagnesium reagent 16 and the reaction mixture was
Regioselective Br/Mg exchange on unsymmetrical 2,5-dibromopyridines
of type 8:
Synthesis of ethyl 4-(5-bromo-2-(4-(trifluoromethyl)phenyl)pyridin-3-yl)-
benzoate (10a): A dry and argon-flushed Schlenk flask, equipped with a
magnetic stirring bar and a septum, was charged with iPrMgCl·LiCl (1a;
1.2m in THF, 0.88 mL, 1.05 mmol). 3,5-Dibromo-2-(4-(trifluoromethyl)-
phenyl)pyridine (8a; 381 mg, 1 mmol) was added as a solution in THF
(1.0m) at À558C and stirred continuously for 1 h (the completion of the
Br/Mg exchange was monitored by GC analysis of iodolysed reaction ali-
quots with the use of undecane as an internal standard). ZnCl2 (1.0 mL,
1.0m in THF, 1 mmol) was added to the freshly prepared heteroarylmag-
nesium reagent 9a and the reaction mixture was stirred for 15 min at
stirred for 15 min at À208C. Pd
ACHTUNGTRNE(NUNG PPh3)4 (46 mg, 0.04 mmol) and ethyl 4-io-
dobenzoate (4h; 249 mg, 0.9 mmol) were added and the reaction mixture
was warmed to 258C. After stirring for 2 h, the reaction mixture was
quenched with saturated aqueous NH4Cl solution, extracted three times
with EtOAc, dried over Na2SO4 and concentrated in vacuo. Flash column
chromatographic purification on silica gel (pentane/Et2O=95:5) gave
17b (208 mg, 61%) as a pale-yellow solid. M.p.: 88.2–89.88C; 1H NMR
(400 MHz, [D6]DMSO): d=9.02 (d, J=2.0 Hz, 1H), 8.25 (d, J=2.0 Hz,
1H), 7.95–8.03 (m, 2H), 7.84–7.90 (m, 2H), 4.29 (q, J=7.1 Hz, 2H), 1.29
(t, J=7.2 Hz, 3H), 0.37 ppm (s, 9H); 13C NMR (100 MHz, [D6]DMSO):
d=165.8, 165.7, 146.7, 140.4, 136.5, 135.8, 130.3, 130.2, 129.3, 127.9, 61.3,
14.6, À0.5 ppm; MS (EI, 70 eV) m/z (%): 379 (M+, 44), 377 (M+, 44),
À208C. Pd
ACHTUNGTRENNUNG(PPh3)4 (46 mg, 0.04 mmol) and ethyl 4-iodobenzoate (4h;
249 mg, 0.9 mmol) were added and the reaction mixture was warmed to
258C. After stirring for 1 h, the reaction mixture was quenched with satu-
rated aqueous NH4Cl solution, extracted three times with EtOAc, dried
over Na2SO4 and concentrated in vacuo. Flash column chromatographic
Chem. Eur. J. 2012, 18, 16145 – 16152
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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16151

P. Knochel et al.
365 (22), 364 (100), 363 (20), 362 (94), 334 (31), 332 (17), 299 (47), 298
(79), 284 (30), 270 (12), 139 (11), 137 (11), 44 (32), 43 (30); IR (ATR):
n˜ =3045, 3041, 2976, 2953, 2899, 1701, 1608, 1573, 1479, 1410, 1365, 1355,
1288, 1274, 1244, 1226, 1184, 1115, 1103, 1046, 1022, 1012, 855, 838, 807,
724, 699 cmÀ1; HRMS (EI): m/z calcd for C17H20BrNO2Si: 379.0426 (M+
); found: 379.0417.
Hu, E. Negishi, Angew. Chem. 2004, 116, 2309; Angew. Chem. Int.
Ed. 2004, 43, 2259; e) A. de Meijere, P. von Zezschwitz, S. Braese,
Acc. Chem. Res. 2005, 38, 413; f) J.-X. Wang, J. McCubbin, M. Jin,
R. Laufer, Y. Mao, A. Crew, M. Mulvihill, V. Snieckus, Org. Lett.
2008, 10, 2923; g) G. Manolikakes, M. Schade, C. Munoz Hernandez,
H. Mayr, P. Knochel, Org. Lett. 2008, 10, 2765; h) Z. Dong, G. Man-
olikakes, J. Li, P. Knochel, Synthesis 2009, 681.
[7] P. Knochel, M. C. P. Yeh, S. C. Berk, J. Talbert, J. Org. Chem. 1988,
53, 2390.
[8] a) S. Schrçter, C. Stock, T. Bach, Tetrahedron 2005, 61, 2245; b) Y.
Garcia, F. Schoenebeck, C. Y. Legault, C. A. Merlic, K. N. Houk, J.
Am. Chem. Soc. 2009, 131, 6632.
Acknowledgements
We thank the Deutsche Forschungsgemeinschaft (SFB 749) for financial
support. We also thank BASF AG (Ludwigshafen), W. C. Heraeus
(Hanau) and Chemetall GmbH (Frankfurt) for the generous gift of
chemicals.
[9] a) X.-J. Wang, L. Zhang, X. Sun, Y. Xu, D. Krishnamurthy, C. Sena-
nayake, Org. Lett. 2005, 7, 5593; b) C.-S. Da, J.-R. Wang, X.-G. Yin,
X.-Y. Fan, Y. Liu, S.-L. Yu, Org. Lett. 2009, 11, 5578; c) Y. Liu, C.-S.
Da, S.-L. Yu, X.-G. Yin, J.-R. Wang, X.-Y. Fan, W.-P. Li, R. Wang, J.
Org. Chem. 2010, 75, 6869; d) X.-Y. Fan, Y.-X. Yang, F.-F. Zhuo, S.-
L. Yu, X. Li, Q.-P. Guo, Z.-X. Du, Z.-S. Da, Chem. Eur. J. 2010, 16,
7988.
[1] a) T. L. Gilchrist, Heterocylic Chemistry, Longman, London, 1998;
b) J. F. Miller, A. Termin, K. Koch, A. D. Piscopio, J. Org. Chem.
1998, 63, 3158; c) M. Abarbri, F. Dehmel, P. Knochel, Tetrahedron
Lett. 1999, 40, 7449; d) J. Clayden, Organolithiums: Selectivity for
Synthesis. Tetrahedron Organic Chemistry Series, Vol. 23, Pergamon,
2002; e) S. Hauptmann, T. Eicher, The Chemistry of Heterocycles,
Wiley-VCH, Weinheim, 2003; f) A. Krasovskiy, V. Krasovskaya, P.
Knochel, Angw. Chem. Int. Ed. 2006, 45, 2958; g) H. Ila, O. Baron,
A. J. Wagner, P. Knochel, Chem. Commun. 2006, 583; h) K. L. Tan,
A. Vasudevan, R. G. Bergman, J. A. Ellman, A. J. Souers, Org. Lett.
2003, 5, 2131; i) J. P. Wolfe, J. S. Thomas, Curr. Org. Chem. 2005, 9,
625; j) I. V. Seregin, V. Gevorgyan, Chem. Soc. Rev. 2007, 36, 1173;
k) I. J. S. Fairlamb, Chem. Soc. Rev. 2007, 36, 1036; l) C. Schmuck,
D. Rupprecht, Synthesis 2007, 3095; m) S. J. Hwang, S. H. Cho, S.
Chang, J. Am. Chem. Soc. 2008, 130, 16158; n) R. Ponce Ortiz, J.
Casado, V. Hernꢃndez, J. T. Lꢄpez Navarrete, J. A. Letizia, M. A.
Ratner, A. Facchetti, T. J. Marks, Chem. Eur. J. 2009, 15, 5023; o) P.
Thansandote, M. Lautens, Chem. Eur. J. 2009, 15, 5874; p) F. M.
Piller, P. Knochel, Org. Lett. 2009, 11, 445; q) P. Thansandote, C.
Gouliaras, M.-O. Turcotte-Savard, M. Lautens, J. Org. Chem. 2009,
74, 1791; r) C. J. OꢅConnor, M. D. Roydhouse, A. M. Przybył, M. D.
Wall, J. M. Southern, J. Org. Chem. 2010, 75, 2534; s) M. Jeganmo-
han, P. Knochel, Angew. Chem. 2010, 122, 8699; Angew. Chem. Int.
Ed. 2010, 49, 8520; t) F. Miege, C. Meyer, J. Cossy, Angew. Chem.
2011, 123, 6054; Angew. Chem. Int. Ed. 2011, 50, 5932; u) S. Benetti,
C. De Risi, G. P. Pollini, V. Zanirato, Chem. Rev. 2012, 112, 2129;
v) D. C. Behenna, Y. Liu, T. Yurino, J. Kim, D. E. White, S. C.
Virgil, B. M. Stoltz, Nat. Chem. 2012, 4, 130.
1
[10] The regioisomer 13a was not observed in H NMR measurements of
the hydrolysed crude reaction mixture (HOAc, 10 equiv, À20 to
258C).
[11] A. Krasovskiy, A. Tishkov, V. DelAlmo, H. Mayr, P. Knochel,
Angew. Chem. 2006, 118, 5132; Angew. Chem. Int. Ed. 2006, 45,
5010.
[12] a) C. B. Rauhut, L. Melzig, P. Knochel, Org. Lett. 2008, 10, 3891;
b) L. Melzig, C. B. Rauhut, P. Knochel, Synthesis 2009, 6, 1041; c) L.
Melzig, C. B. Rauhut, N. Naredi-Rainer, P. Knochel, Chem. Eur. J.
2011, 17, 5362.
[13] The exchange reaction was carried out under the same conditions as
those described in Scheme 1 and Table 1 but at À788C. Higher tem-
peratures worsened the product ratio. At ambient temperature, the
observed ratio was 2.4:1 in favour of the 5-magnesium-substituted
derivative.
[14] a) T.-A. Chen, R. D. Rieke, J. Am. Chem. Soc. 1992, 114, 10087;
b) R. D. McCullough, R. D. J. Lowe, J. Chem. Soc. Chem. Commun.
1992, 70; c) R. D. McCullough, R. D. Lowe, M. Jayaraman, D. L.
Anderson, J. Org. Chem. 1993, 58, 904; d) R. D. McCullough, R.
Lowe, S. Tristram-Nagle, M. Jayaraman, D. L. Anderson, P. C.
Ewbank, Synth. Met. 1993, 55, 1198; e) R. D. McCullough, S. Tris-
tam-Nagle, S. P. Williams, R. D. Lowe, M. Jayaraman, J. Am. Chem.
Soc. 1993, 115, 4910; f) R. D. McCullough, S. Williams, J. Am.
Chem. Soc. 1993, 115, 11608; g) T.-A. Chen, R. D. Rieke, Synth.
Met. 1993, 60, 175; h) T.-A. Chen, R. A. OꢅBrien, R. D. Rieke, Mac-
romolecules 1993, 26, 3462; i) R. D. McCullough, S. P. Williams, S.
Tristram-Nagle, M. Jayaraman, P. C. Ewbank, L. Miller, Synth. Met.
1995, 69, 279; j) T.-A. Chen, X. Wu, R. D. Rieke, J. Am. Chem. Soc.
1995, 117, 233; k) R. S. Loewe, S. M. Khersonsky, R. D. McCullough,
Adv. Mater. 1999, 11, 250; l) R. S. Loewe, P. C. Ewbank, J. Liu, L.
Zhai, R. D. McCullough, Macromolecules 2001, 34, 4324; m) A. Yo-
koyama, R. Miyakoshi, T. Yokozawa, Macromolecules 2004, 37,
1169; n) R. Miyakoshi, A. Yokoyama, T. Yokozawa, Macromol.
Rapid Commun. 2004, 25, 1663; o) R. Miyakoshi, A. Yokoyama, T.
Yokozawa, J. Am. Chem. Soc. 2005, 127, 17542; p) Y.-J. Cheng, S.-H.
Yang, C.-S. Hsu, Chem. Rev. 2009, 109, 5868; q) A. Gadisa, W. D.
Oosterbaan, K. Vandewal, J.-C. Bolsee, S. Bertho, J. D’Haen, L.
Lutsen, D. Vanderzande, J. V. Manca, Adv. Funct. Mater. 2009, 19,
3300.
[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. Krasovskiy, P. Knochel,
Angew. Chem. 2004, 116, 3396; Angew. Chem. Int. Ed. 2004, 43,
3333; c) A. Krasovskiy, B. F. Straub, P. Knochel, Angew. Chem.
2006, 118, 165; Angew. Chem. Int. Ed. 2006, 45, 159.
[3] The corresponding regioisomers of 3a–c and 3i–j were not observed
in 1H NMR measurements of the hydrolysed crude reaction mix-
tures (HOAc, 10 equiv, À208C to 258C).
[4] a) A. R. Katritzky, L. Serdyuk, L. Xie, I. Ghiviriga, J. Org. Chem.
1997, 62, 6215; b) S. S. Mandal, S. S. Samanta, C. Deb, A. De, J.
Chem. Soc. Perkin Trans. 1 1998, 2559; c) T. Kunz, P. Knochel,
Chem. Eur. J. 2011, 17, 866; d) M. Raduꢃn, J. Padrosa, A. Pla-Quin-
tana, T. Parella, A. Roglans, Adv. Synth. Catal. 2011, 353, 2003; e) T.
Kunz, P. Knochel, Angew. Chem. 2012, 124, 1994; Angew. Chem. Int.
Ed. 2012, 51, 1958.
[15] a) M. Urien, L. Bailly, L. Vignau, E. Cloutet, A. de Cuendias, G.
Wantz, H. Cramail, L. Hirsch, J.-P. Parneix, Polym. Int. 2008, 57,
764; b) T. Yokozawa, A. Yokoyama, Chem. Rev. 2009, 109, 5595.
[5] A preliminary transmetalation with ZnCl2 (0.5 equiv) was necessary
for the addition to the carbonyl group. Otherwise, only an I/Mg ex-
change was observed.
[6] a) A. King, N. Okukado, E. Negishi, J. Org. Chem. 1977, 42, 1821;
b) E. Negishi, Acc. Chem. Res. 1982, 15, 340; c) Ø. Rist, M. Begtrup,
J. Chem. Soc. Perkin Trans. 1 2001, 1566; d) X. Zeng, M. Quian, Q.
Received: June 23, 2012
Revised: September 7, 2012
Published online: October 15, 2012
16152
www.chemeurj.org
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 16145 – 16152