Homoleptic zincate-promoted room-temperature halogen-metal exchange of bromopyridines

Article abstract of DOI:10.1002/chem.201001664

Homoleptic lithium tri- and tetraalkyl zincates were reacted with a set of bromopyridines. Efficient and chemoselective bromine-metal exchanges were realized at room temperature with a substoichiometric amount of nBu ₄ZnLi₂·TMEDA reagent (1/3 equiv; TMEDA=N,N,N′,N′-tetramethylethylenediamine). This reactivity contrasted with that of tBu₄ZnLi₂·TMEDA, which was inefficient below one equivalent. DFT calculations allowed us to rationalize the formation of N...Li stabilized polypyridyl zincates in the reaction. The one-pot difunctionalization of dibromopyridines was also realized using the reagent stoichiometrically. The direct creation of C-Zn bonds in bromopyridines enabled us to perform efficient Negishi-type cross-couplings. Mild zincation! nBu₄ZnLi₂·TMEDA (in substoichiometric amounts) promoted efficient and chemoselective room-temperature bromine-metal exchange of a range of bromopyridines (see scheme). DFT calculations strongly supported the formation of a stabilized tripyridylzincate, which could be reacted with electrophiles or be directly involved in palladium-catalyzed cross-coupling reactions.

Full text of DOI:10.1002/chem.201001664

FULL PAPER
DOI: 10.1002/chem.201001664
Homoleptic Zincate-Promoted Room-Temperature Halogen–Metal
Exchange of Bromopyridines
Nguyet Trang Thanh Chau,[a] Maxime Meyer,[a] Shinsuke Komagawa,[b]
Floris Chevallier,[c] Yves Fort,[a] Masanobu Uchiyama,[b] Florence Mongin,[c] and
Philippe C. Gros*[a]
Abstract: Homoleptic lithium tri- and
tetraalkyl zincates were reacted with a
set of bromopyridines. Efficient and
chemoselective bromine–metal ex-
changes were realized at room temper-
ature with a substoichiometric amount
of nBu4ZnLi2·TMEDA reagent (1/
3 equiv; TMEDA=N,N,N’,N’-tetrame-
thylethylenediamine). This reactivity
contrasted
with
that
of
formation of N···Li stabilized poly-
pyridyl zincates in the reaction. The
one-pot difunctionalization of dibromo-
pyridines was also realized using the
reagent stoichiometrically. The direct
tBu4ZnLi2·TMEDA, which was ineffi-
cient below one equivalent. DFT calcu-
lations allowed us to rationalize the
À
creation of C Zn bonds in bromopyri-
Keywords: bromopyridines · cross-
coupling · halogen–metal exchange ·
lithium · zinc
dines enabled us to perform efficient
Negishi-type cross-couplings.
Introduction
tives,[2] organozincates are promising reagents allowing
switchable selectivities by modifying substituents around the
À
Bromopyridines are highly important compounds due to
their unique reactivity opening the way to numerous func-
metal center and concomitant creation of a C Zn bond im-
mediately available for further Negishi-type cross-coupling
tionalizations. Indeed the C Br bonds can be involved in
reactions.[3]
À
metal-catalyzed cross-couplings and undergo bromine–lithi-
um exchange reactions. Bromine–lithium exchange requires
very low temperatures (typically À78 to À1008C) to avoid
side reactions, such as nucleophilic addition of the alkyllithi-
um reagent, isomerization, dimerization, or pyridyne forma-
tion.[1] Among recently reported non-cryogenic alterna-
Homoleptic polyalkylzincates (all substituents identical)
are attractive reagents, since they can be easily prepared
and should be able to transfer several reactive groups and
consequently be used in substoichiometric amounts. The
compound tBu4ZnLi2,[4] which has been reported by Uchiya-
ma and co-workers to be highly chemoselective for iodine
or bromine exchange in the aromatic series, was reacted
only in stoichiometric amounts and its reactivity was not
studied in the pyridine series. Curiously, nBu3ZnLi and
nBu4ZnLi2 generated from the safer nBuLi have been less
studied, probably due to their strong propensity to transfer
the butyl chain to the electrophile during the quenching
step.[5] The search for more applicable metalation methodol-
ogy in the pyridine series remains a challenge; hence we de-
cided to investigate the reactivity of lithium alkylzincates
toward a range of bromopyridines.
[a] Dr. N. T. T. Chau, M. Meyer, Prof. Y. Fort, Dr. P. C. Gros
SOR, SRSMC, Nancy Universitꢀ, CNRS
Boulevard des Aiguillettes
54506 Vandoeuvre-Lꢁs-Nancy (France)
Fax : (+33)38-3684785
E-mail: philippe.gros@srsmc.uhp-nancy.fr
[b] Dr. S. Komagawa, Prof. M. Uchiyama
Graduate School of Pharmaceutical Sciences
The University of Tokyo, 7-3-1 Hongo
Bunkyo-ku, Tokyo 113-0033 (Japan)
[c] Dr. F. Chevallier, Prof. F. Mongin
Chimie et Photonique Molꢀculaires, UMR 6510 CNRS
Universitꢀ de Rennes 1, Bꢂtiment 10 A, Case 1003
Campus Scientifique de Beaulieu
Results and Discussion
The lithium-zinc reagents were prepared following two pro-
cedures: by reacting the alkyllithium either with 1) commer-
cially available nBu2Zn [Eq. (1)] or 2) with weakly hygro-
35042 Rennes Cedex (France)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001664.
Chem. Eur. J. 2010, 16, 12425 – 12433
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
12425

scopic ZnCl2·TMEDA[6] (TMEDA=N,N,N’,N’-tetramethyl-
ACHTUNGTRENNUNGethylenediamine) [Eq. (2)].
ing the complete consumption along the process and making
likely single species instead of dissociated zinc and lithium
compounds. Additionally, when nBuLi was treated with 1/
5 equivalents of ZnCl2·TMEDA, besides the signals ob-
tained in for the reaction with 1/4 equivalents, signals corre-
sponding to unreacted nBuLi appeared, indicating that the
formed species could not accept another butyl chain. In
summary, the NMR analyses supported the formation of zin-
cate species nBu3ZnLi·TMEDA and nBu4ZnLi2·TMEDA.
Zincation of bromopyridines: The reactivity of the reagents
toward 2- and 3-bromopyridines was next investigated under
various conditions (Table 2). In preliminary experiments
with 3-bromopyridine (1), nBu3ZnLi was found unreactive
at À788C in tetrahydrofuran (THF) whatever the stoichiom-
etry, and increase of the temperature led to degradation. In
contrast, the exchange proceeded chemoselectively in tolu-
Before investigating the metalation ability of the reagents,
the
zincate
nature
of
nBu3ZnLi·TMEDA
and
7]
nBu4ZnLi2·TMEDA was checked.[4b,
The reagents were
thus prepared in C6D6/cyclohexane according to Equa-
tion (2) and studied by 1H and 13C NMR spectroscopy.[8]
Relevant chemical shifts of the lithium–zinc mixtures and
their components are collected in Table 1.
ene
at
room
temperature
with
nBu3ZnLi
or
nBu3ZnLi·TMEDA, but incomplete conversions were ob-
tained (Table 2, entries 1 and 2). The metalation with
nBu4ZnLi2 or nBu4ZnLi2·TMEDA was found particularly ef-
ficient, even with 1/3 equiv of the reagents (entries 3 and
4).[10] The presence of TMEDA in the reagent significantly
improved the exchange, exclusively affording compound 1a
Compared with those of nBuLi (Table 1, entry 1) and
1
TMEDA (entry 2), the H NMR spectra of the zinc-contain-
ing reagents were profoundly modified. The formation of
the nBuLi·TMEDA dimer resulted in a slight shielding of
the TMEDA methylene proton signal (entry 3). When
nBuLi was treated with ZnCl2·TMEDA (1/3 equiv), the a-
proton signal was downshifted from À0.94 to À0.18 ppm as
a consequence of the metal electronegativity increase during
Table 2. Conditions screening for zincation–iodination of bromo-
AHCTUNGTRENNUNG
pyridines.[a]
the
lithium–zinc
transmetalation
(entry 4).
When
ZnCl2·TMEDA (1/4 equiv) was added, the nBuZn a proton
signal was significantly upshifted (from À0.18 to
À0.28 ppm), in agreement with a metal electronegativity de-
crease by reaction of the metal center with the additional
butyl chain (entry 5). The TMEDA signals were found dra-
BrPy
Zincate (equiv)
t
BrPy
[%][b]
1a or 2a
[h]
[%][b]
matically
shielded
in
nBu3ZnLi·TMEDA
and
1
2
3
4
5
6
7
8
9
1
1
1
1
2
2
1
2
1
2
1
2
nBu3ZnLi (1)
nBu3ZnLi·TMEDA (1)
nBu4ZnLi2 (1/3)
nBu4ZnLi2·TMEDA (1/3)
nBu4ZnLi2 (1/3)
nBu4ZnLi2·TMEDA (1/3)
nBu4ZnLi2·TMEDA (1/4)
nBu4ZnLi2·TMEDA (1/4)
tBu4ZnLi2·TMEDA (1)
tBu4ZnLi2·TMEDA (1)
tBu4ZnLi2·TMEDA (1/3)
tBu4ZnLi2·TMEDA (1/3)
2
2
1
0.5
1
1
3
3
0.5
1
7
12
8
0
0
0
50
6
0
0
86
88
72
>95 (75)
>95 (78)
>95 (77)
50
nBu4ZnLi2·TMEDA, in particular the methylene protons
(from 2.05 to 1.37 ppm). Such chemical shifts indicated a
profound change in coordination and were characteristic of
TMEDA-chelated metal[9] (entries 4 and 5). Taking into ac-
count the identical TMEDA shifts for both reagents, a simi-
lar coordination mode was likely. Although less sensitive,
13C NMR spectra displayed signals matching the 1H NMR
spectra. Indeed the carbon linked to the metal was deshield-
ed upon addition of ZnCl2·TMEDA (entries 4 and 5). It is
worth mentioning that no residual nBuLi or nBuLi-
TMEDA signals were detected in the reactions with 1/3 and
1/4 equivalents of ZnCl2·TMEDA (entries 4 and 5), indicat-
75(60)
70
10
11
12
60[c]
0.5
1
23
4
50[c]
35[c]
[a] Reaction performed on 3 mmol of BrPy. [b] Conversions and yields
estimated by 1H NMR spectroscopy. Isolated yields in brackets. [c] Im-
portant material loss was observed due to degradation.
Table 1. 1H and 13C NMR chemical shifts of the lithium–zinc mixtures and their components.[a]
Putative
species
1H NMR
13C NMR
nBu (Ha) TMEDA (CH3) TMEDA (CH2) nBu (Ca) nBu (Cb) nBu (Cd) nBu (Cg) TMEDA (CH3) TMEDA (CH2)
1
2
3
4
5
G
À0.91
À
–
–
12.2
–
12.8
13.3
13.0
31.6
–
34.9
31.3
31.4
32.0
–
36.4
32.3
32.3
13.8
–
14.5
14.2
14.4
–
–
2.10
2.12
1.88
1.87
2.27
2.05
1.37
1.37
46.0
46.6
46.0
46.0
58.6
57.6
57.0
57.0
À0.94
[a] Performed in C6D6–cyclohexane at 208C (300 and 75 MHz for H and 13C spectra, respectively).
1
12426
www.chemeurj.org
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 12425 – 12433

Tetraorganozincates
FULL PAPER
(75% isolated yield) in short reaction time (entry 4). In a
separate experiment, LiCl-containing nBu4ZnLi2 was pre-
pared from ZnCl2 and experiment of from entry 3 was re-
peated. Similar conversion and yield were obtained indicat-
ing that LiCl had no effect on the reaction as expected from
the low solubility of this salt in toluene. Excellent conver-
sions and yields were also obtained with 2-bromopyridine
(2) regardless of the presence of TMEDA in the reagent
(entries 5 and 6).
An additional decrease of reagent amount (1/4 equiv)
while not allowing to complete the reactions led to 1a and
2a in 50 and 75% yields, respectively (Table 2, entries 7 and
8). This is in agreement with the transfer of three butyl li-
gands from the tetrabutylzincate. The tBu4ZnLi2·TMEDA
reagent was also used for comparison, and gave a complete
exchange with notable amount of degradation products in
contrast with nBu4ZnLi2·TMEDA when used stoichiometri-
cally (entries 9 and 10). Another important discrepancy was
the inability of tBu4ZnLi2·TMEDA to complete the reaction
under substoichiometric conditions (entries 11 and 12). Such
a sluggish reaction probably results of zincate tBu groups
consumption by formed tBuBr to generate isobutene (a
well-known reaction between tBuLi and tBuBr), making
these ligands unavailable for the exchange reaction
(Scheme 1).
Scheme 2. Ligand exchange reaction of MenPy4ÀnZnLi2. Energy changes
(DE0) in kcalmolÀ1 at the B3LYP/631SVPs level.[11]
À
competitive coordination of lithium impeding N Li interac-
tions.
Zincation of dibromopyridines: After having demonstrated
the exchange chemoselectivity with tetrabutylzincates on 1
and 2 we investigated the possible scope extension with di-
bromopyridines. Thus substrates 3, 4, and 5 were reacted
with zincates under various conditions with the aim to con-
trol both mono and dizincation at room temperature
(Table 3). When 2,6-dibromopyridine (3) was treated with
nBu4ZnLi2, a clean exchange occurred giving exclusively the
monozincation product 3a (entry 1). An extended reaction
time (3.5 h) led reaction to completion with the quantitative
formation of 3a without any trace of diiodo compound 6a
(entry 2). In contrast, reaction with nBu4ZnLi2·TMEDA
showed a notable effect of TMEDA that favored the forma-
tion of 6a. An increase of base amount up to stoichiometry
produced 6a in high yield as a single product (entry 5). This
exchange selectivity in 3 has been studied with nBuLi by
Gilman,[1a] Newkome,[1b] and later by Cai.[1c] Cai et al. found
that, even at low temperatures, the selectivity was hardly
controlled leading to a mixture of 2-lithio-6-bromopyridine,
2,6-dilithiopyridine as well as pyridine deprotonation prod-
ucts. Control of monolithiation could be achieved by precip-
itation of the monolithiopyridine in diethylether at À788C.
Thus our room-temperature zincation is a useful methodolo-
gy, the reaction being driven easily toward mono- or dizinca-
tion by changing ligand and stoichiometry. The same set of
conditions was applied to 3,5-dibromopyridine (4).
Scheme 1. Plausible pathway for tert-butylzincate consumption.
To get a better understanding of the multiple zincation of
2-bromopyridine with Bu4ZnLi2, we carried out DFT calcu-
lations using Me4ZnLi2 as a model compound (Scheme 2).
Coordination of lithium by TMEDA was not computed at
this stage. An alkyl group on zincate (CP1) is exchanged to
a pyridyl group to give a heteroleptic zincate (CP2) and
alkyl bromide with considerable energy gain (alkyl=Me,
19.0 kcalmolÀ1 at the B3LYP/631SVPs level[11]). The calcula-
tion clearly showed that the pyridyl-coordinated zincate is
thermodynamically much more stable than the (homo)alkyl-
À
coordinated zincate thanks to creation of the stable N Li
bond favored in non-coordinating toluene. Therefore, the
more pyridine coordinates to the zincate, the more the re-
sultant zincate is stabilized. Based on these calculations, we
consider that the zincation reactions of bromopyridines with
a catalytic amount of tetraalkylzincate proceeds smoothly to
produce tripyridyl (RPy3ZnLi2) or tetrapyridyl (Py4ZnLi2)
zincates, depending on the character of the resultant zin-
cates, such as solubility or reactivity (Table 2, entries 5, 6,
and 8). The solubility issue is consistent with our observa-
tions since precipitation of the reaction medium occurred
during the exchange process. From these calculations, the
absence of reactivity in THF could be rationalized by a
The use of nBu4ZnLi2, and nBu4ZnLi2·TMEDA favored
the monozincation (Table 3, entries 6–8) when used in sub-
stoichiometric amount (1/3 equiv). By comparing with re-
sults obtained given in Table 3 entry 2 with 3, the bromine
at C-3 was less easily exchanged here, since reaction with
nBu4ZnLi2 was incomplete after 4 h of reaction. This was in
agreement with the weaker activation by the azomethine
Chem. Eur. J. 2010, 16, 12425 – 12433
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12427

P. C. Gros et al.
Table 3. Zincation–iodination of dibromopyridines.[a]
cess was obtained by using
two reagents: 1) nBu4ZnLi2·
TMEDA
(1 equiv)
with
TMEDA (1.5 equiv) (entry 15),
and 2) 1.5 equivalents of
nBu4ZnLi2·TMEDA (entry 16),
the latter giving the best selec-
tivity and producing 8a quanti-
tatively.
BrPy
Zincate (equiv)
t [h]
BrPy
[%][b]
Monoiodo
[%][b]
Diiodo
[%][b]
1
2
3
4
5
6
7
8
9
3
3
3
3
3
4
4
4
4
4
5
nBu4ZnLi2 (1/3)
nBu4ZnLi2 (1/3)
nBu4ZnLi2·TMEDA (1/3)
nBu4ZnLi2·TMEDA (1/2)
nBu4ZnLi2·TMEDA (1)
nBu4ZnLi2 (1/3)
1
32
0
0
0
0
25
25
0
0
–
3a, 68
3a,>95
3a, 75
3a, 45
3a, 0
4a, 64
4a, 61
4a, 87
4a, 17
4a, 0
6a, 0
6a, 0
Reaction of pyridylzincates
with electrophiles: As new
tools were now available for
room-temperature zincation of
bromo- and dibromopyridines
giving access to mono and bi-
functional derivatives, we inves-
tigated further the scope of the
methodology by reacting a set
of bromopyridines and ana-
logues and trapping the zincates
3.5
1.5
1.5
1.5
1
4
1
1.5
1
1
6a, 25
6a, 55
6a, >95
7a, 11
7a, 15
7a, 13
7a, 83
7a, >98
8a, 0
nBu4ZnLi2 (1/3)
nBu4ZnLi2·TMEDA (1/3)
nBu4ZnLi2·TMEDA (1.5)
nBu4ZnLi2·TMEDA (2)
nBu4ZnLi2 (1/3)
10
11
12
5a, 8
5b, 80
5a, 21
5b, 63
5a, 41
5b, 23
5a, 37
5b, 0
5a, 2
5b, 0
5a, 0
5b, traces
12
13
14
15
16
5
5
5
5
5
nBu4ZnLi2 (1/3)
3.5
1
12
23
35
0
8a, 4
nBu4ZnLi2·TMEDA (1/3)
8a, 13
8a, 28
8a, 98
8a, >98
with
several
electrophiles
(Table 4).
nBu4ZnLi2·TMEDA (1/3) + TMEDA (1)
nBu4ZnLi2·TMEDA (1) + TMEDA (1.5)
nBu4ZnLi2·TMEDA (1.5)
1
The substrates were function-
alized in moderate to excellent
yields depending on the electro-
phile used. The iodine-trapping
gave the best results and gener-
ally excellent yields of iodopyri-
dines. Aldehydes were convert-
1
1
0
[a] Reaction performed on 3 mmol of BrPy. [b] Conversions and yields estimated by 1H NMR spectroscopy.
À
bond of pyridine, which was more distant from the C Br
bond than in 3. Completion was achieved by using
nBu4ZnLi2·TMEDA. In contrast with 3, TMEDA increased
the mono/bis ratio leading to 4a in 87% yield (entry 8). Di-
zincation was obtained cleanly thanks to an increase to two
equivalents of nBu4ZnLi2·TMEDA, affording 7a quantita-
tively (entry 10). The control of regioselectivity in 2,5-dibro-
mopyridine (5) was more challenging due to the ease of mi-
gration of the halogen at C-5 to the C-2 position, leading to
a more stable derivative, a well-known process with organo-
lithium reagents.[1d,2d] Reaction with nBu4ZnLi2 (1/3 equiv)
preferentially zincated the C-2 position (product 5b, 80%)
with 8% of zincation at C-5 (entry 11). Extension of the re-
action time to 3.5 h to complete the reaction resulted in an
increase of zincation at C-5 (entry 12). Attempts to optimize
the formation of 5a by additional increase of reaction time
up to 12 h only gave unidentified degradation products.
TMEDA also had an impact on the reaction pathway, since
nBu4ZnLi2·TMEDA (1/3 equiv) reversed the C-2/C-5 ratio
favoring zincation at C-5 with concomitant dizincation
(entry 13). It was thought that TMEDA could help in a
better control of C-5 zincation. Thus an additional amount
(1 equiv) was added to the reagent and C-2 zincation was to-
tally suppressed leading to 5a and increased amount of di-
zincation product 8a (entry 14). Although it was possible to
control the C-2/C-5 ratio we were unable to avoid dizinca-
tion, and attempts were made to obtain it exclusively. Suc-
ed into the corresponding pyridylcarbinols in poor to accept-
able yields. Alcohols resulting from the reduction of alde-
hydes were always isolated besides the target products. The
pyridylzinc intermediates themselves or the in situ formed
metal alkoxides could be responsible of such a reduction.[12]
It is worth noting that no product arising from zincate nBu-
ligand addition to the carbonyl bond was observed indicat-
ing that the pyridyl group was exclusively transferred. Di-
bromopyridines were monofunctionalized in moderate
yields. The deuteration experiments gave exclusively com-
pounds 3c and 4b with full deuterium content as an addi-
tional proof for quantitative zincation. The dizincated pyri-
dines were trapped with anisaldehyde or PhSSPh giving the
new diol 6b and sulfide 7b. All synthetically useful diiodo-
pyridines 6a, 7a, and 8a were isolated in excellent 85, 85
and 88% yields respectively. Bromopicolines 9 and 10 were
metalated cleanly, leaving the acidic methyl group unaffect-
ed (entries 8 and 9). Bromomethoxypyridines 11 and 12
were also reacted efficiently (entries 10 and 11); no side de-
protonation at the position adjacent to the methoxy group
of the pyridine ring was observed. A good chemoselectivity
was also obtained with 5-bromo-2-chloropyridine (13), since
À
the C Cl bond at C-2 was tolerated (entry 12). 3-Bromoqui-
noline (14) was also iodinated in acceptable yield (14a,
46%), but concomitant homocoupling occurred giving 3,3’-
diquinoline (16%; entry 13). Our methodology is of interest,
since very low temperatures are always needed for retention
12428
www.chemeurj.org
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 12425 – 12433

Tetraorganozincates
FULL PAPER
Table 4. Zincation-functionalization of bromopyridines.[a]
À
plings are possible avoiding the classical Li Zn transmetala-
tion.[14]
Several pyridylzincates prepared above were reacted with
various aryl and heteroaryl halides under palladium catalysis
(Table 5). As shown, the 2- and 3-zincated pyridines were
coupled efficiently. Functional arylpyridines 10d, 12c, and
BrPy
Product
Yield
[%]
Table 5. Palladium-catalyzed cross-coupling of zincated pyridines.[a]
1a: E=I[b]
75
1
2
1
1b: E=PhCH(OH)[c]
1c: 4-MeOC6H4CH(OH)[e]
2a: E=I[b]
25[d]
30[d]
78
2b: E=Me3Si[f]
2c: E=4-MeOC6H4CH(OH)[e]
2d: E=4-CF3C6H4CH(OH)[g]
3a: E=I[b]
60
2
50[d]
25[d]
84
BrPy
A
Product
A
Yield
[%][b]
3
4
3
4
3b: E=MeS
26
3c: E=D[l]
31[m]
65
2
2
2e (3-MeOC6H4)
2 f (6-MeO-2-Py)
65
58
4a: E=I[b]
4b: E=D[l]
50[m]
40
85
4c: E=PhS[k]
6a, E=I[b]
6b, 4-MeOC6H4CH(OH)[e]
20
5
6
7
3
4
5
10
12
13
13
3[c]
10d (4-MeOC6H4) 46
12c (4-MeOC6H4) 63
7a, E=I[b]
85
40
7b, E=PhS[k]
8a, E=I[b]
9a: E=I[b]
88
88
13c (4-ClC6H4)
62
8
9
9
13d (5-pyrimidyl) 50
10a: E=I[b]
88
10
10b: E=allyl[h]
25[i]
20[d]
6c (4-MeOC6H4)
41
10c: E=4-MeOC6H4CH(OH)[e]
[a] Reaction performed on 3 mmol of bromopyridine. [b] Isolated yields
after column chromatography. [c] 1 equiv of nBu4ZnLi2·TMEDA was
used.
10
11
12
13
11
12
13
14
11a: E=I[b]
60
12a: E=I[b]
80
40
12b: E=MeS[j]
13a: E=I[b]
80
20
13b: E=PhS[k]
13c, were obtained in good yields. The yield of 10d was low-
ered by steric hindering effect of the methyl group at C-3.
Bisheteroaromatic compounds were also obtained such as
2,2’-bipyridine 2 f and pyridylpyrimidine 13d. The cross-cou-
pling of 2,6-dizincated pyridine underwent the double cross-
coupling affording dianisylpyridine 6c in 41% yield. At this
stage, the aim was to show the ability of pyridylzincates to
give coupling products in a palladium catalyzed process, the
reaction conditions (solvent, catalyst, ligands) have not been
optimized yet.
14a: E=I[b]
46
[a] Reaction performed on 3 mmol of bromopyridine. All zincations con-
ducted with nBu4ZnLi2·TMEDA (1/3 equiv) for 1 h except for entries 5,
6, and 7 in which 1, 2, and 1.5 equiv of the reagent were used, respective-
ly. [b] Electrophile=I2. [c] Electrophile=PhCHO. [d] The aldehyde was
partially consumed and the alcohol (reduction) was also observed.
[e] Electrophile=4-MeOC6H4CHO. [f] Electrophile=Me3SiCl. [g] Elec-
trophile=4-F3CC6H4CHO. [h] Electrophile=allyl bromide. [i] Volatile
compound.
[j] Electrophile=MeSSMe.
[k] Electrophile=PhSSPh.
[l] Electrophile=MeOD. [m] The crude 1H NMR spectra showed exclu-
sive formation of 3c or 4b with deuterium content >98%.
Conclusion
À
of methyl side chains or C Cl bonds using nBuLi as a met-
In summary, we have shown the efficiency of
nBu4ZnLi2·TMEDA for the chemoselective zincation of bro-
mopyridines. The exchange was performed at room temper-
ature using 1/3 equivalents of the reagent. DFT calculations
clearly showed that, in the case of 2-bromopyridine, a stabi-
lized tripyridyl zincate is involved in the process. This
proved not possible with tBu4ZnLi2·TMEDA, owing to
alating agent.[13]
Palladium-catalyzed cross-coupling of pyridylzincates: As
mentioned in the introduction, besides applicability and che-
moselectivity, the direct creation of a C Zn bond on the
heteroaromatic ring is of particular interest, since cross-cou-
À
Chem. Eur. J. 2010, 16, 12425 – 12433
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12429

P. C. Gros et al.
PhCHO, 4-CF3C6H4CHO, 4-MeOC6H4CHO, TMSCl, MeOD, MeSSMe,
or PhSSPh) (4.0–8.0 mmol). The mixture was stirred for 1 h (for I2) or
18 h (for the other electrophiles) before addition of an aqueous solution
of ammonia (5 mL), aqueous saturated solution of Na2S2O3 (5 mL) (if the
electrophile was I2) and extraction with EtOAc (3ꢄ15 mL). The com-
bined organic layers were dried over MgSO4, filtered and concentrated
under reduced pressure before purification by chromatography on silica
gel.
probable consumption by tBuBr released during the ex-
change. This study also revealed a dramatic TMEDA effect
on the selectivity of dibromopyridines zincation. While
nBu4ZnLi2 gave mainly the monozincation, the use of 1–
2 equivalents of nBu4ZnLi2·TMEDA promoted a clean di-
zincation. The efficiency of the zincation was assessed by
quantitative trapping with iodine, giving useful iodopyri-
dines in high yields, and palladium-catalyzed cross-couplings.
This methodology is promising for the development of more
applicable organometallic reagents (room temperature, low
amount of reagents). Progress is still needed to optimize the
interception yields with electrophilic reagents. This will be
the subject of future work.
3-Iodopyridine (1a):[16] The standard protocol was applied to 3-bromo-
pyridine (0.29 mL, 3.0 mmol) for 1 h, and
a solution of I2 (1.27 g,
5.0 mmol) in dry THF (5 mL) was used as electrophile: Yellow solid;
m.p. 50–528C (lit.[16] 52–538C); yield: 0.46 g (75%); 1H NMR (CDCl3,
200 MHz): d=8.85 (s, 1H) , 8.56 (d, J=3.8 Hz, 1H) , 8.01 (d, J=7.5 Hz,
1H), 7.07–7.13 ppm (m, 1H); 13C NMR (CDCl3, 50 MHz): d=155.8,
148.1, 144.2, 125.2, 93.6 ppm.
Phenyl(pyridin-3-yl)methanol (1b):[2a] The standard protocol was applied
to 3-bromopyridine (0.29 mL, 3.0 mmol) for 1 h, and benzaldehyde
(0.41 mL, 4.0 mmol) was used as electrophile. Beige solid; m.p. 65–678C
(lit.[2a] 67–698C); yield: 0.14 g (25%); 1H NMR (CDCl3, 200 MHz): d=
8.41 (s, 1H), 8.28 (s, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.31 (m, 5H), 7.20 (dd,
J=7.6, 5.0 Hz, 1H), 5.78 (s, 1H), 5.03 ppm (s, 1H); 13C NMR (CDCl3,
50 MHz): d=147.8, 147.6, 143.2, 139.9, 135.4, 128.6, 127.5, 126.2, 123.4,
73.4 ppm.
(4-Methoxyphenyl)(pyridin-3-yl)methanol (1c):[17] The standard protocol
was applied to 3-bromopyridine (0.29 mL, 3.0 mmol) for 1 h, and 4-me-
thoxybenzaldehyde (0.50 mL, 4.0 mmol) was used as electrophile. Beige
solid; m.p. 66–678C (lit.[17] 708C); yield: 0.19 g (30%); 1H NMR (CDCl3,
250 MHz): d=8.38 (s, 1H), 8.23 (d, J=4.1 Hz, 1H), 7.66 (dd, J=7.9,
1.7 Hz, 1H), 7.13–7.24 (m, 3H), 6.82 (d, J=8.7 Hz, 2H), 5.71 (s, 1H),
3.74 ppm (s, 3H); 13C NMR (CDCl3, 62.5 MHz): d=159.1, 147.8, 140.4,
135.8, 134.4, 127.9, 123.4, 114.0, 73.2, 55.2 ppm.
Experimental Section
Materials and methods: All reactions were performed under argon at-
mosphere. Toluene and THF were distilled over sodium/benzophenone
and stored over sodium wire. TMEDA was distilled from CaH2. Commer-
cially available starting materials were used without further purification.
Liquid chromatography separations were achieved on silica gel Merck-
Geduran Si 60 (63–200 mm). NMR spectra were acquired on Bruker
ARX-200 (200 and 50 MHz for 1H and 13C respectively), Bruker ARX-
250 (250 and 62.5 MHz for 1H and 13C respectively) and Bruker AC-400
(400 and 100 MHz for 1H and 13C respectively) spectrometers. The chemi-
cal shifts (d) are given in ppm relative to tetramethylsilane as an internal
1
standard (for H) or the central peak of the solvent signal (for 13C). Cou-
2-Iodopyridine (2a):[2a] The standard protocol was applied to 2-bromopyr-
idine (0.29 mL, 3.0 mmol) for 1 h, and a solution of I2 (1.27 g, 5.0 mmol)
in dry THF (5 mL) was used as electrophile. Yellow oil; yield: 0.47 g
pling constants are given in Hz. NMR studies of the bases were per-
1
formed on a Bruker AC-300 (300 and 75 MHz for H and 13C respective-
ly) at 208C using nBuLi (2 mL of a 2m solution in cyclohexane) with ad-
ditional C6D6 (0.5 mL).
1
(77%); H NMR (CDCl3, 200 MHz): d=8.37 (d, J=1.7 Hz, 1H), 7.73 (d,
J=7.6 Hz, 1H), 7.24–7.38 ppm (m, 2H); 13C NMR (CDCl3, 62.5 MHz):
d=150.6, 137.4, 134.8, 122.8, 118.0 ppm.
Preparation of ZnCl2·TMEDA:[15] Anhydrous ZnCl2 (20 g, 0.15 mol) was
heated under vacuum with a heating gun for 30 min. After cooling, dry
THF (400 mL) was added, and the solution was heated until complete
dissolution of the salt. TMEDA (44 mL, 0.30 mol) was then added slowly,
and the mixture was stirred for 2 h at room temperature. The solvents
were evaporated under vacuum, and the solid was recrystallized from
THF (70 mL). Crystals were collected by filtration and washed with pen-
tane. The complex was obtained in a quantitative yield (ꢀ37 g) as white
2-(Trimethylsilyl)pyridine (2b):[18] The standard protocol was applied to
2-bromopyridine (0.29 mL, 3.0 mmol) for 1 h, and trimethylsilyl chloride
(0.64 mL, 5.0 mmol) was used as electrophile. Yellow oil; yield: 0.27 g
(60%); 1H NMR (CDCl3, 200 MHz): d=8.70 (d, J=4.2 Hz, 1H), 7.25–
1
7.75 (m, 3H), 0.25 ppm (s, 9H); the H NMR data are in accordance with
those of the literature; 13C NMR (CDCl3, 62.5 MHz): d=168.2, 150.1,
133.8, 128.6, 122.6, À1.81 ppm.
1
needles. M.p. 1768C (lit.[10] 176–1778C); H NMR (CDCl3, 200 MHz): d=
(4-Methoxyphenyl)(pyridin-2-yl)methanol (2c):[19] The standard protocol
was applied to 2-bromopyridine (0.29 mL, 3.0 mmol) for 1 h, and 4-me-
thoxybenzaldehyde (0.50 mL, 4.0 mmol) was used as electrophile. Yellow-
ish solid; m.p. 124–1268C; yield: 0.32 g (50%); 1H NMR (CDCl3,
250 MHz): d=8.52 (d, J=4.5 Hz, 1H), 7.59 (td, J=7.7, 2.0 Hz, 1H), 7.24
(m, 2H), 7.13–7.18 (m, 2H), 6.85 (d, J=8.7 Hz, 2H), 5.70 (s, 1H), 5.24
(brs, 1H), 3.76 ppm (s, 3H); 13C NMR (CDCl3, 62.5 MHz): d=161.4,
159.2, 147.9, 136.8, 135.5, 128.3, 122.3, 121.3, 113.9, 74.6, 55.2 ppm.
2.75 (s, 4H), 2.62 ppm (s, 12H).
Preparation of nBu3ZnLi and nBu4ZnLi2: nBuLi (1.6m hexanes solution,
0.63 mL, 1.0 mmol) (for nBu3ZnLi) or nBuLi (1.6m hexanes solution,
1.25 mL, 2.0 mmol) (for nBu4ZnLi2) was added to a stirred, cooled
(À158C) solution of nBu2Zn (1.0m heptanes solution, 1.0 mL, 1.0 mmol)
in dry toluene (3 mL). The mixture was stirred for 30 min at 08C before
introduction of the bromopyridine substrate (n equiv) at 208C.
Preparation of nBu3ZnLi·TMEDA and nBu4ZnLi2·TMEDA: nBuLi
(1.6m hexanes solution, 1.88 mL, 3.0 mmol) (for nBu3ZnLi·TMEDA) or
Pyridin-2-yl(4-(trifluoromethyl)phenyl)methanol (2d):[19] The standard
protocol was applied to 2-bromopyridine (0.29 mL, 3.0 mmol) for 1 h,
and 4-trifluromethylbenzaldehyde (0.56 mL, 4.0 mmol) was used as elec-
trophile. White solid; m.p. 66–688C; yield: 0.25 g (25%); 1H NMR
(CDCl3, 400 MHz): d=8.57 (d, J=4.5 Hz, 1H), 7.65 (td, J=7.6, 1.5 Hz,
1H), 7.59 (d, J=8.2 Hz, 2H), 7.52 (d, J=8.2 Hz, 2H), 7.23 (dd, J=7.0,
5.3 Hz, 1H), 7.15 (d, J=7.9 Hz, 1H), 5.81 ppm (s, 1H); OH not seen;
13C NMR (CDCl3, 62.5 MHz): d=160.2, 148.1, 147.2, 137.1, 130.0 (d, J=
32.2 Hz), 127.3, 126.5 (d, J=29.9 Hz), 125.5 (q, J=3.8 Hz), 122.8, 121.3,
74.5 ppm.
2-Iodo-4-methylpyridine (9a):[20] The standard protocol was applied to 2-
bromo-4-methylpyridine (0.34 mL, 3.0 mmol) for 1 h, and a solution of I2
(1.27 g, 5.0 mmol) in dry THF (5 mL) was used as electrophile. Orange
oil; yield: 0.58 g (88%); 1H NMR (CDCl3, 400 MHz): d=8.19 (d, J=
5.0 Hz, 1H), 7.56 (s, 1H), 7.07 (d, J=5.0 Hz, 1H), 2.28 ppm (s, 3H);
nBuLi
(1.6m
hexanes
solution,
2.5 mL,
4.0 mmol)
(for
nBu4ZnLi2·TMEDA) was added to a stirred, cooled (08C) solution of
ZnCl2·TMEDA (0.25 g, 1.0 mmol) in dry toluene (3 mL). The mixture
was stirred for 30 min at 08C before introduction of the bromopyridine
substrate (n equiv) at 208C.
Preparation of tBu4ZnLi2·TMEDA: tBuLi (1.7m pentanes solution,
2.35 mL, 4.0 mmol) was added to a stirred, cooled (À158C) solution of
ZnCl2·TMEDA (0.25 g, 1.0 mmol) in dry toluene (3 mL). The mixture
was stirred for 30 min at 08C before introduction of the bromopyridine
substrate (n equiv) at 208C.
Typical procedure for monozincation of bromopyridines: The bromopyri-
dine substrate (3.0 mmol) was added to
a stirred suspension of
nBu4ZnLi2·TMEDA (1.0 mmol) in toluene (3 mL) at 208C. After 0.5–3 h
at room temperature, the reaction was quenched with an electrophile (I2,
12430
www.chemeurj.org
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 12425 – 12433

Tetraorganozincates
FULL PAPER
13C NMR (CDCl3, 100 MHz): d=150.0, 149.1, 135.4, 124.0, 118.2,
20.3 ppm.
42–448C (lit.[27] 458C); yield: 0.35 g (46%); 1H NMR (CDCl3, 250 MHz):
d=9.03 (d, J=2.1 Hz, 1H), 8.54 (d, J=1.9 Hz, 1H), 8.06 (d, J=8.4 Hz,
1H), 7.69–7.77 (m, 2H), 7.53–7.59 ppm (m, 1H); 13C NMR (CDCl3,
62.5 MHz): d=155.6, 146.3, 143.7, 130.0, 129.9, 129.5, 127.4, 126.8,
89.8 ppm.
2-Iodo-3-methylpyridine (10a):[21] The standard protocol was applied to
2-bromo-3-methylpyridine (0.34 mL, 3.0 mmol) for 1 h, and a solution of
I2 (1.27 g, 5.0 mmol) in dry THF (5 mL) was used as electrophile. Yellow
oil; yield: 0.58 g (88%); 1H NMR (CDCl3, 200 MHz): d=8.15 (d, J=
2.0 Hz, 1H), 7.43 (d, J=7.3 Hz, 1H), 7.15 (dd, J=7.1, 4.7 Hz, 1H),
2.38 ppm (s, 3H); 13C NMR (CDCl3, 50 MHz): d=147.7, 139.1, 136.7,
125.4, 122.8, 26.2 ppm.
2-Bromo-6-iodopyridine (3a):[2a] The standard protocol using Bu4ZnLi2 as
reagent was applied to 2,6-dibromopyridine (0.72 g, 3.0 mmol) for 1 h,
and a solution of I2 (1.27 g, 5.0 mmol) in dry THF (5 mL) was used as
electrophile. White solid; m.p. 147–1488C (lit.[2a] 1348C); yield: 0.72 g
1
(84%); H NMR (CDCl3, 400 MHz): d=7.70 (d, J=7.7 Hz, 1H), 7.47 (d,
2-Allyl-3-methylpyridine (10b): The standard protocol was applied to 2-
bromo-3-methylpyridine (0.34 mL, 3.0 mmol) for 1 h, and allyl bromide
(0.44 mL, 5.0 mmol) was used as electrophile. Highly volatile yellow oil;
yield: 0.10 g (25%); 1H NMR (CDCl3, 250 MHz): d=8.39 (dd, J=4.7,
0.9 Hz, 1H), 7.41 (dd, J=7.6, 0.7 Hz, 1H), 7.04 (dd, J=7.6, 4.9 Hz, 1H),
6.05 (ddt, J=17, 10, 6.4 Hz, 1H), 5.01–5.13 (m, 2H), 3.57–3.60 (m, 2H),
2.30 ppm (s, 3H); 13C NMR (CDCl3, 62.5 MHz): d=158.1, 146.9, 137.7,
135.1, 131.4, 121.5, 116.1, 40.4, 18.6 ppm; HRMS: C9H12N [M+H]+:
calcd: 134.0964; found: 134.0968.
J=7.8 Hz, 1H), 7.18 ppm (dd, J=7.8, 7.7 Hz, 1H); 13C NMR (CDCl3,
50 MHz): d=140.8, 139.2, 133.9, 127.3, 115.7 ppm.
2-Bromo-6-(methylthio)pyridine (3b):[2a] The standard protocol was ap-
plied to 2,6-dibromopyridine (0.72 g, 3 mmol) for 1 h, and dimethyl disul-
fide (0.72 mL, 8.0 mmol) was used as electrophile. Yellow oil; yield:
0.16 g (26%); 1H NMR (CDCl3, 200 MHz): d=7.31 (t, J=7.7 Hz, 1H),
7.08–7.15 (m, 2H), 2.54 ppm (s, 3H); 13C NMR (CDCl3, 62.5 MHz): d=
161.3, 141.6, 137.8, 122.9, 120.1, 13.5 ppm.
(4-Methoxyphenyl)(3-methylpyridin-2-yl)methanol (10c):[22] The standard
protocol was applied to 2-bromo-3-methylpyridine (0.34 mL, 3.0 mmol)
for 1 h, and 4-methoxybenzaldehyde (0.50 mL, 4.0 mmol) was used as
electrophile. Yellow solid; m.p. 50–528C (lit.[22] 57–588C); yield: 0.14 g
2-Bromo(6-[D])pyridine (3c):[2a] The standard protocol was applied to
2,6-dibromopyridine (0.72 g, 3.0 mmol) for 1 h, and [D1]methanol
(0.32 mL, 8.0 mmol) was used as electrophile. Yellow oil; yield: 0.15 g
1
(31%) (>98% [D]); H NMR (CDCl3, 250 MHz): d=7.46–7.60 (m, 2H),
1
(20%); H NMR (CDCl3, 250 MHz): d=8.46 (d, J=4.5 Hz, 1H), 7.42 (d,
7.26 ppm (d, J=7.0 Hz, 1H); 13C NMR (CDCl3, 62.5 MHz): d=149.9 (t,
J=27.9 Hz), 142.3 (t, J=1.9 Hz), 138.5, 128.3, 122.5 ppm.
J=7.5 Hz, 1H), 7.12–7.19 (m, 3H), 6.79–6.84 (m, 2H), 5.95 (br s, 1H),
5.69 (s, 1H), 3.76 (s, 3H), 2.07 ppm (s, 3H); 13C NMR (CDCl3,
62.5 MHz): d=159.1, 158.2, 144.9, 138.5, 134.7, 130.4, 129.0, 122.6, 113.9,
72.0, 55.2, 17.9 ppm.
2-Iodo-3-methoxypyridine (11a):[23] The standard protocol was applied to
2-bromo-3-methoxypyridine (0.58 g, 3.0 mmol) for 4 h, and a solution of
I2 (1.27 g, 5.0 mmol) in dry THF (5 mL) was used as electrophile. Beige
solid; m.p. 54–568C (lit.[23] 56–578C); yield: 0.42 g (60%); 1H NMR
(CDCl3, 400 MHz): d=7.99 (dd, J=4.6, 1.4 Hz, 1H), 7.20 (dd, J=8.1,
4.6 Hz, 1H), 7.01 (dd, J=8.1, 1.4 Hz, 1H), 3.91 ppm (s, 3H); 13C NMR
(CDCl3, 100 MHz): d=155.2, 142.5, 123.5, 116.8, 111.7, 56.3 ppm.
2-Iodo-6-methoxypyridine (12a):[24] The standard protocol was applied to
2-bromo-6-methoxypyridine (0.38 mL, 3.0 mmol) for 4 h, and a solution
of I2 (1.27 g, 5.0 mmol) in dry THF (5 mL) was used as electrophile. Yel-
lowish solid; m.p. 43–458C (lit.[24] 44–458C); yield: 0.54 g (80%);
1H NMR (CDCl3, 200 MHz): d=7.29 (dd, J=7.3, 0.7 Hz, 1H), 7.17 (dd,
J=8.1, 7.4 Hz, 1H), 6.68 (dd, J=8.1, 0.7 Hz, 1H), 3.91 ppm (s, 3H);
13C NMR (CDCl3, 62.5 MHz): d=163.4, 139.6, 127.5, 113.7, 109.8,
54.1 ppm.
2-Methoxy-6-(methylthio)pyridine (12b):[18] The standard protocol was
applied to 2-bromo-6-methoxypyridine (0.38 mL, 3.0 mmol) for 4 h, and
dimethyl disulfide (0.72 mL, 8.0 mmol) was used as electrophile. Yellow
oil; yield: 0.18 g (39%); 1H NMR (CDCl3, 250 MHz): d=7.38 (dd, J=
8.0, 7.6 Hz, 1H), 6.76 (dd, J=7.6, 0.6 Hz, 1H), 6.40 (dd, J=8.0, 0.6 Hz,
1H), 3.94 (s, 3H), 2.55 ppm (s, 3H); 13C NMR (CDCl3, 62.5 MHz): d=
163.7, 157.2, 138.5, 113.6, 105.3, 53.3, 13.2 ppm.
2-Chloro-5-iodopyridine (13a):[24] The standard protocol was applied to
5-bromo-2-chloropyridine (0.59 g, 3.0 mmol) for 4 h, and a solution of I2
(1.27 g, 5.0 mmol) in dry THF (5 mL) was used as electrophile. Yellow
solid; m.p. 97–998C (lit.[25] 978C) yield: 0.57 g (80%); 1H NMR (CDCl3,
200 MHz): d=8.60 (d, J=2.3 Hz, 1H), 7.92 (dd, J=8.3, 2.3 Hz, 1H),
7.14 ppm (dd, J=8.3, 0.5 Hz, 1H); 13C NMR (CDCl3, 62.5 MHz): d=
155.7, 151.0, 146.8, 126.1, 90.7 ppm.
2-Chloro-5-(phenylthio)pyridine (13b):[25] The standard protocol was ap-
plied to 5-bromo-2-chloropyridine (0.59 mL, 3.0 mmol) for 4 h, and a so-
lution of diphenyl disulfide (1.10 g, 5.0 mmol) in dry toluene (5 mL) was
used as electrophile. Yellow oil; yield: 0.13 g (20%); 1H NMR (CDCl3,
250 MHz): d=8.30 (d, J=2.5 Hz, 1H), 7.51 (dd, J=8.3, 2.5 Hz, 1H),
7.31–7.40 (m, 5H), 7.22 ppm (d, J=8.3 Hz, 1H); 13C NMR (CDCl3,
62.5 MHz): d=150.5, 149.8, 140.3, 133.3, 132.9, 132.0, 129.7, 128.2,
124.6 ppm.
5-Bromo-2-iodopyridine (5b): The standard protocol using Bu4ZnLi2 as
reagent was applied to 2,5-dibromopyridine (0.73 g, 3.0 mmol) for 1 h,
and a solution of I2 (1.27 g, 5.0 mmol) in dry THF (5 mL) was used as
electrophile. 5-Bromo-2-iodopyridine (5b; 80%) was obtained in the
non-separable mixture with 2-bromo-5-iodopyridine (5a; 8%). Data for
5b:[27] 1H NMR (CDCl3, 200 MHz): d=8.44 (s, 1H), 7.61 (d, J=8.3 Hz,
1H), 7.44 ppm (d, J=8.4 Hz, 1H); data for 5a:[28] 1H NMR (CDCl3,
200 MHz): d=8.59 (s, 1H), 7.82 (dd, J=8.3, 2.2 Hz, 1H), 7.29 ppm (d,
J=8.3 Hz, 1H);
3-Bromo-5-iodopyridine (4a):[29] The standard protocol was applied to
3,5-dibromopyridine (0.73 g, 3.0 mmol) for 1 h, and a solution of I2
(1.27 g, 5.0 mmol) in dry THF (5 mL) was used as electrophile. Yellow
solid; m.p. 114–1168C (lit.[29] 117–1188C); yield: 0.55 g (65%); 1H NMR
(CDCl3, 200 MHz): d=8.74 (d, J=1.8 Hz, 1H), 8.62 (d, J=1.6 Hz, 1H),
8.18 ppm (dd, J=1.8, 1.6 Hz, 1H); 13C NMR (CDCl3, 62.5 MHz): d=
153.9, 149.4, 146.2, 121.1, 93.2 ppm.
3-Bromo(5-[D])pyridine (4b):[2a] The standard protocol was applied to
3,5-dibromopyridine (0.73 g, 3.0 mmol) for 1 h, and [D1]methanol
(0.32 mL, 8.0 mmol) was used as electrophile. Orange oil; yield: 0.24 g
1
(50%) (>98% [D]); H NMR (CDCl3, 250 MHz): d=8.70 (d, J=2.3 Hz,
1H), 8.54 (s, 1H), 7.82 ppm (d, J=1.2 Hz, 1H); 13C NMR (CDCl3,
62.5 MHz): d=151.1, 147.8, 138.6, 124.9, 121.0 ppm.
3-Bromo-5-(phenylthio)pyridine (4c):[29] The standard protocol was ap-
plied to 3,5-dibromopyridine (0.73 g, 3.0 mmol) for 1 h, and diphenyl di-
sulfide (1.10 g, 5.0 mmol) in dry toluene (5 mL) was used as electrophile.
1
Orange liquid; yield: 0.23 g (29%); H NMR (CDCl3, 250 MHz): d=8.56
(br s, 1H), 8.46 (brs, 1H), 7.57–7.61 (m, 1H), 7.29–7.40 ppm (m, 5H);
13C NMR (CDCl3, 62.5 MHz): d=151.0, 147.8, 137.9, 134.0, 131.9, 129.5,
127.9, 123.9 ppm.
Typical procedure for dizincation of dibromopyridines: A solution of di-
bromopyridine substrate (1.0–2.0 mmol) in toluene (5 mL) was added to
a stirred suspension of Bu4ZnLi2·TMEDA (2.0 mmol) in toluene (6 mL)
at 208C. After 1–1.5 h at room temperature, the reaction was quenched
with the electrophile (I2, 4-MeOPhCHO or PhSSPh) (8 mmol). The mix-
ture was stirred for 18 h before addition of an aqueous solution of ammo-
nia (5 mL), aqueous saturated solution of Na2S2O3 (5 mL) (if electrophile
was I2) and extraction with EtOAc (3ꢄ15 mL). The combined organic
layers were dried over MgSO4, filtered and concentrated under reduced
pressure before purification by chromatography on silica gel.
2,6-Diiodopyridine (6a):[30] The standard protocol was applied to 2,6-di-
bromopyridine (0.48 g, 2.0 mmol) for 1.5 h, and a solution of I2 (2.54 g,
10 mmol) in dry THF (10 mL) was used as electrophile. Yellow solid;
m.p. 192–1948C (lit.[30] 196–1978C); yield: 0.55 g (84%); 1H NMR
3-Iodoquinoline (14a):[26] The standard protocol was applied to 3-bromo-
quinoline (0.42 mL, 3.0 mmol) for 4 h, and a solution of I2 (1.27 g,
5.0 mmol) in dry THF (5 mL) was used as electrophile. Beige solid; m.p.
Chem. Eur. J. 2010, 16, 12425 – 12433
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12431

P. C. Gros et al.
(CDCl3, 400 MHz): d=7.70 (d, J=7.70 Hz, 2H), 6.96 ppm (t, J=7.7 Hz,
1H);13C NMR (CDCl3, 62.5 MHz): d=138.4, 134.2, 116.2 ppm.
and 4-iodoanisole (0.72 g, 3.0 mmol) was used as aromatic halide. White
solid; yield: 0.42 g (63%); H NMR (CDCl3, 250 MHz): d=8.02–7.96 (m,
1
2H), 7.56 (t, J=7.9 Hz, 1H), 7.25 (d, J=7.4 Hz, 1H), 6.99–6.94 (m, 2H),
6.62 (d, J=8.2 Hz, 1H), 4.02 (s, 3H), 3.84 ppm (s, 3H); 13C NMR
(CDCl3, 62.5 MHz): d=163.6, 160.3, 154.4, 139.0, 131.7, 127.9, 113.9,
113.6, 111.8, 110.8, 108.3, 55.3, 53.1 ppm.
2-Chloro-6-(4-chlorophenyl)pyridine (13c):[37] The standard protocol was
applied to 5-bromo-2-chloropyridine (0.61 g, 3.0 mmol) for 4.5 h, and 1-
chloro-4-iodobenzene (0.78 g, 3.3 mmol) was used as aromatic halide.
Pale yellow solid, m.p. 1128C; yield: 0.42 g (62%); 1H NMR (CDCl3,
250 MHz): d=8.57 (d, J=2.5 Hz, 1H), 7.80 (dd, J=5.7, 2.6 Hz, 1H),
7.48–7.45 (m, 4H), 7.4 ppm (d, J=7.4 Hz, 1H); 13C NMR (CDCl3,
62.5 MHz): d=150.7, 147.8, 136.9, 134.9, 134.8, 134.5, 129.4, 128.3,
124.3 ppm.
5-(6-Chloropyridin-3-yl)pyrimidine (13d):[38] The standard protocol was
applied to 5-bromo-2-chloropyridine (0.61 g, 3.0 mmol) for 4.5 h, and 5-
bromopyrimidine (0.541 g, 3.3 mmol) was used as aromatic halide. Pale
yellow solid, m.p. 1708C; yield: 0.29 g (50%); 1H NMR (CDCl3,
250 MHz): d=9.29 (s, 1H), 8.96 (s, 2H), 8.63 (d, J=2.2 Hz, 1H), 7.87
(dd, J=5.7, 2.6 Hz, 1H), 7.51 ppm (d, J=8.3 Hz, 1H); 13C NMR (CDCl3,
62.5 MHz): d=158.5, 154.8, 152.4, 147.7, 136.9, 130.4, 129.1, 124.9 ppm.
2,6-Di(4-methoxyphenyl)pyridine (6c):[39] 2,6-Dibromopyridine (0.48 g,
2.0 mmol) was added to a stirred suspension of nBu4ZnLi2·TMEDA
(2.0 mmol) in toluene (6 mL) at 208C under argon. After 1.5 h at room
Pyridine-2,6-diylbis((4-methoxyphenyl)methanol) (6b): The standard
protocol was applied to 2,6-dibromopyridine (0.48 g, 2.0 mmol) for 1.5 h,
and 4-methoxybenzaldehyde (0.99 mL, 8.0 mmol) was used as electro-
phile. Yellow oil; yield: 0.14 g (20%); 1H NMR (CDCl3, 250 MHz): d=
7.56 (t, J=7.7 Hz, 1H), 7.28 (d, J=8.7 Hz, 4H), 7.09 (d, J=7.7 Hz, 2H),
6.86 (d, J=8.7 Hz, 4H), 5.74 (s, 2H), 3.78 ppm (s, 6H); 13C NMR
(CDCl3, 62.5 MHz): d=160.3, 159.3, 137.7, 135.1, 128.3, 119.7, 114.0, 75.0,
55.3 ppm. HRMS: C21H21NO4Na [M+Na]+: calcd: 374.1363; found:
374.1359.
2,5-Diiodopyridine (8a):[31] The standard protocol was applied to 2,5-di-
bromopyridine (0.32 g, 1.3 mmol) for 2 h, and a solution of I2 (2.54 g,
10 mmol) in dry THF (10 mL) was used as electrophile. Yellow brown
1
solid; m.p. 150–1528C (lit.[31] 148–149.78C); yield: 0.38 g (88%); H NMR
(CDCl3, 200 MHz): d=8.58 (d, J=2.2 Hz, 1H), 7.60 (dd, J=8.2, 2.2 Hz,
1H), 7.50 ppm (d, J=8.2 Hz, 1H); 13C NMR (CDCl3, 62.5 MHz): d=
156.7, 145.7, 136.5, 116.4, 93.1 ppm.
3,5-Diiodopyridine (7a):[32] The standard protocol was applied to 3,5-di-
bromopyridine (0.24 g, 1.0 mmol) for 1 h, and a solution of I2 (2.54 g,
10.0 mmol) in dry THF (10 mL) was used as electrophile. Pink orange
solid; m.p. 170–1728C (lit.[32] 170–1728C); yield: 0.28 g (85%); 1H NMR
(CDCl3, 250 MHz): d=8.75 (d, J=1.8 Hz, 2H), 8.35 ppm (t, J=1.8 Hz,
1H); 13C NMR (CDCl3, 62.5 MHz): d=154.2, 151.4, 93.9 ppm.
3,5-Di(phenylthio)pyridine (7b):[33] The standard protocol was applied to
3,5-dibromopyridine (0.24 g, 1.0 mmol) for 1 h, and a solution of diphenyl
disulfide (1.76 g, 8.0 mmol) in dry toluene (10 mL) was used as electro-
phile. Yellowish solid; m.p. 50–528C (lit.[33] 558C); yield: 0.12 g (40%);
1H NMR (CDCl3, 400 MHz): d=8.30 (d, J=2.0 Hz, 2H), 7.28–7.36 ppm
(m, 11H); 13C NMR (CDCl3, 100 MHz): d=147.8, 137.4, 134.6, 132.7,
132.4, 129.6, 128.2 ppm.
temperature, [PdCl2ACHTNUTRGNE(UNG PPh3)2] (0.14 g, 0.2 mmol), PPh3 (0.11 g, 0.4 mmol),
and 4-iodoanisole (0.53 g, 2.2 mmol) were added. The mixture was re-
fluxed for 12 h before addition of an aqueous solution of ammonia
(5 mL) at room temperature. The mixture was filtered on Celite and
washed with EtOAc. The aqueous layer was extracted with EtOAc (3ꢄ
15 mL). The combined organic layers were dried over MgSO4, filtered
and concentrated under reduced pressure before purification by chroma-
tography on silica gel to give 0.24 g (41%) of 2,6-di(4-methoxyphenyl)-
pyridine. Yellowish solid; m.p. 184–1868C (lit.[40] 185–1888C). 1H NMR
(CDCl3, 250 MHz): d=8.10 (d, J=8.9 Hz, 4H), 7.69–7.75 (m, 1H), 7.56
(d, J=8.6 Hz, 2H), 7.01 (d, J=8.9 Hz, 4H), 3.87 ppm (s, 6H); 13C NMR
(CDCl3, 62.5 MHz): d=160.4, 156.3, 137.2, 132.3, 128.2, 117.1, 114.0,
55.3 ppm.
Typical procedure for the cross-coupling of pyridyl zincates: The bromo-
pyridine (3.0 mmol) at 208C under argon was added to a stirred suspen-
sion of nBu4ZnLi2·TMEDA (1.0 mmol) in toluene (3 mL). After 1 h at
room temperature, [PdCl2ACHTUNRGTNEUNG(PPh3)2] (0.15 mmol, 105 mg), PPh3 (0.30 mmol,
76 mg), and the aromatic halide (3 mmol) were added. The mixture was
refluxed for 12 h. After cooling, the mixture was treated with NH4OH
(5 mL) and filtered over a Celite pad. After extraction with EtOAc
(20 mL), the organic phase was dried (MgSO4) and evaporated. The resi-
due was then purified by column chromatography.
2-(3-Methoxyphenyl)pyridine (2e):[34] The standard protocol was applied
to 2-bromopyridine (0.29 mL, 3.0 mmol) for 1 h and 3-iodoanisole
(0.37 mL, 3.0 mmol) was used as aromatic halide. Pale yellow oil; yield:
0.36 g (65%); 1H NMR (CDCl3, 250 MHz): d=8.66 (dt, J=4.8, 1.3 Hz,
1H), 7.67 (dd, J=4.9, 1.5 Hz, 2H), 7.60–7.59 (m, 1H), 7.53 (dt, J=7.5,
1.5 Hz, 1H), 7.35 (t, J=7.9 Hz, 1H), 7.21–7.12 (m, 1H), 6.94 (dd, , J=
8.2, 2.6, 0.9 Hz, 1H), 3.84 ppm (s, 3H); 13C NMR (CDCl3, 62.5 MHz): d=
160.1, 157.1, 149.5, 140.8, 136.7, 129.7, 122.2, 120.6, 119.3, 115.0, 112.0,
55.3 ppm.
Acknowledgements
The authors gratefully acknowledge the financial support of the Agence
Nationale de la Recherche (ACTIVATE program). The calculations were
performed by using the RIKEN Integrated Cluster of Clusters (RICC)
facility.
[1] a) H. Gilman, S. M. Spatz, J. Org. Chem. 1951, 16, 1485–1494;
b) G. R. Newkome, J. M. Roper, J. Organomet. Chem. 1980, 186,
147–153; c) D. Cai, D. L. Hughes, T. R. Verhoeven, Tetrahedron
Lett. 1996, 37, 2537–2540; d) W. E. Parham, R. M. Piccirilli, J. Org.
Chem. 1977, 42, 257–260; e) X. Wang, P. Rabbat, P. OꢅShea, R. Till-
yer, E. J. J. Grabowski, P. J. Reider, Tetrahedron Lett. 2000, 41,
4335–4338.
[2] a) F. Trꢀcourt, G. Breton, V. Bonnet, F. Mongin, F. Marsais, G. Quꢀ-
guiner, Tetrahedron 2000, 56, 1349–1360; b) T. Iida, T. Wada, K. To-
mimoto, T. Mase, Tetrahedron Lett. 2001, 42, 4841–4844; c) P. C.
Gros, F. Elaachbouni, Chem. Commun. 2008, 4813–4815; d) A.
Doudouh, C. Woltermann, P. C. Gros, J. Org. Chem. 2007, 72, 4978–
4980.
[3] D. R. Gauthier, R. H. Szumigala, P. G. Dormer, J. D. Armstrong,
R. P. Volante, P. J. Reider, Org. Lett. 2002, 4, 375–378.
[4] a) M. Uchiyama, T. Furuyama, M. Kobayashi, Y. Matsumoto, K.
Tanaka, J. Am. Chem. Soc. 2006, 128, 8404–8405; b) T. Furuyama,
M. Yonehara, S. Arimoto, M. Kobayashi, Y. Matsumoto, M. Uchiya-
ma, Chem. Eur. J. 2008, 14, 10348–10356.
6-Methoxy-2,2’-bipyridine (2 f):[35] The standard protocol was applied to
2-bromopyridine (0.29 mL, 3.0 mmol) for 1 h and 2-bromo-6-methoxypyr-
idine (0.38 mL, 3.0 mmol) was used as aromatic halide. Yield : 0.33 g
1
(58%); H NMR (CDCl3, 250 MHz): d=8.66 (d, J=5.6 Hz, 1H), 8.40 (d,
J=8.0 Hz, 1H), 8.02 (d, J=7.4 Hz, 1H), 7.79 (td, J=7.6, 1.8 Hz, 1H),
7.70 (t, J=8.1 Hz, 1H), 7.30–7.25 (m, 1H), 6.77 (d, J=8.7 Hz, 1H),
4.04 ppm (s, 3H); 13C NMR (CDCl3, 62.5 MHz): d=168.5, 156.1, 153.4,
149.0, 139.3, 136.7, 123.4, 120.9, 113.7, 111.0, 53.2 ppm.
2-(4-Methoxyphenyl)-3-methylpyridine (10d): The standard protocol was
applied to 2-bromo-3-methylpyridine (0.34 mL, 3.0 mmol) for 1 h, and 4-
iodoanisole (0.72 g, 3.0 mmol) was used as aromatic halide.Pale yellow
oil; yield: 0.23 g (46%); 1H NMR (CDCl3, 250 MHz): d=8.50 (dd, J=
3.6, 1.2 Hz, 1H), 7.55–7.45 (m, 3H), 7.12 (dd, J=7.6, 4.7 Hz, 1H), 7.0–6.9
(m, 2H), 3.84 (s, 3H), 2.35 ppm (s, 3H); 13C NMR (CDCl3, 62.5 MHz):
d=159.3, 158.2, 146.8, 138.3, 133.1, 130.5, 130.2, 121.6 , 113.4, 55.2,
20.1 ppm. HRMS: C13H14NO [M+H]+: calcd: 200.1070; found: 200.1073.
2-Methoxy-6-(4-methoxyphenyl)pyridine (12c):[36] The standard protocol
was applied to 2-bromo-6-methoxypyridine (0.38 mL, 3.0 mmol) for 1 h,
12432
www.chemeurj.org
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 12425 – 12433

Tetraorganozincates
FULL PAPER
[5] Y. Kondo, M. Fujinami, M. Uchiyama, T. Sakamoto, J. Chem. Soc.
Perkin Trans. 1 1997, 799–800.
183; b) A. Seggio, G. Priem, F. Chevallier, F. Mongin, Synthesis
2009, 21, 3617–3632.
[15] M. Isobe, S. Kondo, N. Nagasawa, T. Goto, Chem. Lett. 1977, 6,
679–682.
[16] E. A. Krasnokutskaya, N. I. Semenischeva, V. D. Filimonov, P. Kno-
chel, Synthesis 2007, 81–89.
[17] G. Panda, M. K. Parai, S. K. Das, Shagufta, M. Sinha, V. Chaturvedi,
A. K. Srivastava, Y. S. Manju, A. N. Gaikwad, S. Sinha, Eur. J. Med.
Chem. 2007, 42, 410–419.
[18] E. Lukevics, E. Leipins, I. Segal, M. Fleisher, J. Organomet. Chem.
1991, 406, 283–298.
[19] F. Shibahara, R. Sugiura, E. Yamaguchi, A. Kitagawa, T. Murai, J.
Org. Chem. 2009, 74, 3566–3568.
[20] Y. Yamamoto, A. Yanagi, Heterocycles 1981, 16, 1161–1164.
[21] K. M. Maloney, E. Nwakpuda, J. T. Kuethe, J. Yin, J. Org. Chem.
2009, 74, 5111–5114.
[6] R. A. Kjonaas, R. K. Hoffer, J. Org. Chem. 1988, 53, 4133–4135.
[7] NMR studies of TMEDA-free trialkyl and tetralkylzincates have
been reported; see: M. Uchiyama, M. Kameda, O. Mishima, N. Yo-
koyama, M. Koike, Y. Kondo, T. Sakamoto, J. Am. Chem. Soc. 1998,
120, 4934–4946.
[8] a) J. F. McGarrity, C. A. Ogle, J. Am. Chem. Soc. 1985, 107, 1805–
1810; b) J. F. McGarrity, C. A. Ogle, Z. Brich, H.-R. Loosli, J. Am.
Chem. Soc. 1985, 107, 1810–1815; c) W. Bauer, P. v. R. Schleyer, J.
Am. Chem. Soc. 1989, 111, 7191–7198; d) R. A. Rennels, A. J. Ma-
liakal, D. B. Collum, J. Am. Chem. Soc. 1998, 120, 421–422; e) V. H.
Gessner, C. Dꢆschlein, C. Strohmann, Chem. Eur. J. 2009, 15, 3320–
3334.
[9] These chemical shifts are in agreement with those reported for
Et3ZnLi·TMEDA; see: C. A. Musser, H. G. Richey, J. Org. Chem.
2000, 65, 7750–7756.
[22] R. F. Knott, J. Ciric, J. G. Breckenridge, Can. J. Chem. 1953, 31,
615–616.
[10] Such use of 1/3 equiv of ate complex was reported in case of lithium
trialkylmagnesates and magnesium trialkylzincates; see: a) T. Iida,
T. Wada, K. Tomimoto, T. Mase, Tetrahedron Lett. 2001, 42, 4841–
4844; b) E. Hevia, J. Z. Chua, P. Garcꢇa-ꢈlvarez, A. R. Kennedy,
M. D. McCall, Proc. Natl. Acad. Sci. USA 2010, 107, 5294–5299.
[11] The B3LYP calculations were performed by using Ahlrichsꢅ SVP all-
electron basis set for Zn and Br atoms and 6–31G* basis set for
other atoms (denoted as B3LYP/631SVPs). All calculations were
carried with the Gaussian 09 program package: Gaussian 09, Revi-
sion A.02, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci,
G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian,
A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M.
Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima,
Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr.,
J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N.
Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K. Raghava-
chari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N.
Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C.
Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J.
Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Mo-
rokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannen-
berg, S. Dapprich, A. D. Daniels, ꢉ. Farkas, J. B. Foresman, J. V.
Ortiz, J. Cioslowski, D. J. Fox, Gaussian, Inc., Wallingford CT, 2009..
Computational details are given in the Supporting Information.
[12] For reduction of aldehydes with lithium alkoxides in apolar solvents,
see: C. G. Screttas, B. R. Steele, J. Organomet. Chem. 1986, 317,
137–144.
[23] B. R. Baker, F. J. McEvoy, J. Org. Chem. 1955, 20, 118–135.
[24] D. P. Curran, H. Liu, H. Josien, S.-B. Ko, Tetrahedron 1996, 52,
11385–11404.
[25] P. Pierrat, P. C. Gros, Y. Fort, J. Comb. Chem. 2005, 7, 879–886.
[26] R. J. Bochis, US 4092321, 1978.
[27] K. T. J. Loones, B. U. W. Maes, R. A. Dommisse, Tetrahedron 2007,
63, 8954–8961.
[28] J. J. Song, N. K. Yee, Z. Tan, J. Xu, S. R. Kapadia, C. H. Senanayake,
Org. Lett. 2004, 6, 4905–4907.
[29] A. G. M. Barrett, B. Bibal, B. T. Hopkins, J. Kçbberling, A. C. Love,
L. Tedeschi, Tetrahedron 2005, 61, 12033–12041.
[30] F. Cottet, M. Schlosser, Eur. J. Org. Chem. 2002, 327–330.
[31] T. Miura, K. Kanemoto, S. Natsume, N. Ohkura, Y. Fujihira, T. Wa-
tanabe, H. Fushimi, K. Atsumi, K. Ajito PCT Int. Appl. , WO-
2005019238 A1 20050303, 2005.
[32] Y. Hama, Y. Nobuhara, Y. Aso, T. Otsubo, F. Ogura, Bull. Chem.
Soc. Jpn. 1988, 61, 1683–1686.
[33] Y. Yamamoto, A. Yanagi, Chem. Pharm. Bull. 1982, 30, 1731–1737.
[34] C. Amatore, C. Combellas, N.-E. Lebbar, A. Thiebault, J.-N. Ver-
peaux, J. Org. Chem. 1995, 60, 18–26.
[35] M. Parmentier, P. Gros, Y. Fort, Tetrahedron 2005, 61, 3261–3269.
[36] S.-H. Kim, R. D. Rieke, Tetrahedron Lett. 2009, 50, 5329–5331.
[37] C. Gosmini, C. Bassene-ernst, M. Durandetti, Tetrahedron 2009, 65,
6141–6146.
[38] R. Church, R. Trust, J. D. Albright, D. W. Powell, J. Org. Chem.
1995, 60, 3750–3758.
[39] R. Parry, C. Wang, A. S. Batsanov, M. R. Bryce, B. Tarbit, J. Org.
Chem. 2002, 67, 7541–7543.
[13] a) U. S. Schubert, C. Eschbaumer, M. Heller, Org. Lett. 2000, 2,
3373–3376; b) P. Pierrat, P. Gros, Y. Fort, Synlett 2004, 2319–2322.
[14] a) J.-M. LꢅHelgoualꢅch, A. Seggio, F. Chevallier, M. Yonehara, E.
Jeanneau, M. Uchiyama, F. Mongin, J. Org. Chem. 2008, 73, 177–
[40] J. Xu, G. Cheng, D. Su, Y. Liu, X. Wang, Y. Hu, Chem. Eur. J. 2009,
15, 13105–13110.
Received: June 11, 2010
Published online: September 17, 2010
Chem. Eur. J. 2010, 16, 12425 – 12433
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12433