Deprotonative metalation of functionalized aromatics using mixed lithium-cadmium, lithium-indium, and lithium-zinc species

Article abstract of DOI:10.1002/chem.200901432

In situ mixtures of CdCl₂TMEDA (0.5 equiv; TMEDA = N,N,N',N'-tetramethylethylenediamine) or InCl₃ (0.33 equiv) with [Li(tmp)] (tmp = 2,2,6,6-tetramethylpiperidino; 1.5 or 1.3 equiv, respectively) were compared with the previously described mixture of ZnCl₂-TMEDA (0.5 equiv) and [Li(tmp)] (1.5 equiv) for their ability to deprotonate anisole, benzothiazole, and pyrimidine. [(tmp)₃CdLi] proved to be the best base when used in tetrahydrofuran at room temperature, as demonstrated by subsequent trapping with iodine. The Cd-Li base then proved suitable for the metalation of a large range of aromatics including benzenes bearing reactive functional groups (CONEt₂, CO₂Me, CN, COPh) or heavy halogens (Br, I), and heterocycles (from the furan, thiophene, pyrrole, oxazole, thiazole, pyridine, and diazine series). Fivemembered heterocycles benefiting from doubly activated positions were similarly dideprotonated at room temperature. The aromatic lithium cadmates thus obtained were involved in palladium-catalyzed cross-coupling reactions or simply quenched with acid chlorides.

Full text of DOI:10.1002/chem.200901432

DOI: 10.1002/chem.200901432
Deprotonative Metalation of Functionalized Aromatics Using Mixed
Lithium–Cadmium, Lithium–Indium, and Lithium–Zinc Species
Katia Snꢀgaroff,[a] Jean-Martial LꢁHelgoualꢁch,[a] Ghenia Bentabed-Ababsa,[a, c]
Tan Tai Nguyen,[a] Floris Chevallier,[a] Mitsuhiro Yonehara,[b] Masanobu Uchiyama,*[b]
Aꢂcha Derdour,[c] and Florence Mongin*[a]
Abstract:
In
situ
mixtures
of
base when used in tetrahydrofuran at
room temperature, as demonstrated by
subsequent trapping with iodine. The
Cd–Li base then proved suitable for
the metalation of a large range of aro-
matics including benzenes bearing re-
active functional groups (CONEt2,
CO2Me, CN, COPh) or heavy halogens
(Br, I), and heterocycles (from the
furan, thiophene, pyrrole, oxazole, thia-
zole, pyridine, and diazine series). Five-
membered heterocycles benefiting
from doubly activated positions were
similarly dideprotonated at room tem-
perature. The aromatic lithium cad-
mates thus obtained were involved in
palladium-catalyzed cross-coupling re-
actions or simply quenched with acid
chlorides.
CdCl2·TMEDA (0.5 equiv; TMEDA=
N,N,N’,N’-tetramethylethylenediamine)
or InCl3 (0.33 equiv) with [LiACTHNUTRGNE(UNG tmp)]
(tmp=2,2,6,6-tetramethylpiperidino;
1.5 or 1.3 equiv, respectively) were
compared with the previously de-
scribed mixture of ZnCl2·TMEDA
(0.5 equiv) and [Li
for their ability to deprotonate anisole,
benzothiazole, and pyrimidine.
ACHTUNGTREN(NUGN tmp)] (1.5 equiv)
Keywords: ab initio calculations ·
cadmium · cross-coupling · lithium ·
metalation
[(tmp)3CdLi] proved to be the best
Introduction
matics bearing reactive functions (e.g., ester or cyano
groups) or sensitive p-deficient heterocycles, either extreme-
ly low reaction temperatures or in situ electrophilic trapping
are required due to the high reactivity of the corresponding
(hetero)aryllithiums.
Recourse to softer magnesium diamides can improve the
chemoselectivity of deprotonation reactions, but to the det-
riment of their efficiency.[2] In contrast, enhanced reactivities
can be attained by adding to the lithium bases neutral Lewis
bases, such as N,N,N’,N’-tetramethylethylenediamine
(TMEDA), which are able to simplify their aggregation
state.[1]
Lithium bases such as alkyllithiums or hindered lithium diACTHNUTRGNEUNGal-
ACHTUNGTRENNUNGkylamides have been largely employed for the deproto-met-
alation of aromatic rings.[1] Even if the less nucleophilic
second category is more suitable for the metalation of aro-
[a] Dr. K. Snꢁgaroff, Dr. J.-M. LꢂHelgoualꢂch, Dr. G. Bentabed-Ababsa,
T. T. Nguyen, Dr. F. Chevallier, Prof. F. Mongin
Chimie et Photonique Molꢁculaires
UMR 6510 CNRS—Universitꢁ de Rennes 1
Bꢃtiment 10A, Case 1003, Campus Scientifique de Beaulieu
35042 Rennes Cedex (France)
The use of metal additives to get more efficient or more
chemoselective bases is a challenging field. Various types of
[(R)n(R’)n’ MLi] (M=metal, R, R’=alkyl, amino, chloro,
etc.) compounds already prepared behave as superbases
since such species exhibit behaviors that cannot be repro-
duced by the monometallic compounds on their own.
Among them, LIC–KOR (LIC=butyllithium, KOR=potas-
sium tert-butoxide) first described by Schlosser[3] and Loch-
Fax : (+33)2-2323-6955
E-mail: florence.mongin@univ-rennes1.fr
[b] M. Yonehara, Prof. M. Uchiyama
The Institute of Physical and Chemical Research, RIKEN
2-1 Hirosawa, Wako-shi, Saitama 351-0198 (Japan)
Fax : (+81)48-467-2879
E-mail: uchi_yama@riken.jp
mann,[4] and BuLi–Li
ACTHNUTRGNE(NUG DMAE) (DMAE=2-dimethylami-
[c] Dr. G. Bentabed-Ababsa, Prof. A. Derdour
Laboratoire de Synthꢀse Organique Appliquꢁe
Facultꢁ des Sciences de lꢂUniversitꢁ
noethoxide) introduced by Caubꢀre[5] and developed further
by Gros and Fort in the pyridine series[6] are well-known ex-
amples of powerful [RR’MLi] mixtures of organolithiums
and M alkali-metal alkoxides.
BP 1524 Es-Senia, Oran 31000 (Algeria)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901432.
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Chem. Eur. J. 2009, 15, 10280 – 10290

FULL PAPER
More recently, [(R)n(R’)n’ MLi]-type compounds with M
different from an alkali metal have also been described for
their metalation ability.[7] These species display a large panel
of reactivities, depending on both the metal M and the
groups connected to it. By combining soft organometallic
compounds with alkali (or alkaline-earth metal) additives,
bases have been prepared and used to generate functional-
ized aromatic compounds. Ex-
erocycles, we focused on the deprotonative metalation using
the corresponding mixtures with cadmium[18] and indium[19]
instead of zinc to investigate the effect of a different size of
metal ion.
We thus attempted reactions using in situ prepared mix-
tures of CdCl2·TMEDA[20] or InCl3,[21] and [Li
ACTHUNRTGNE(GNU tmp)] (3 or
4 equiv, respectively; Table 1). Using anisole (1a), veratrole
amples
(tmeda)] (R=tBu, Bu; tmp=
2,2,6,6-tetramethylpiperidino)
are
[R2ZnACTHNGUTERNN(UG tmp)Li-
Table 1. Metalation of substrates 1a–d using different mixtures followed by trapping with I2.
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
(described by the groups of
Kondo, Uchiyama, Mulvey, and
Hevia),[8] [(tmp)2Zn]·2MgCl2·
Entry
1
Substrate 1
1a (R=H)
Product 2
Yield [%]
M=Cd[a]
M=In[b]
M=Zn[c]
84[d]
–
2LiCl,[9]
[(tmp)ZnCl]·LiCl[10]
[iBu3Al(tmp)Li]
(Knochel),
ACHTUNGTRENNUNG
2a
2b
75
79
48
52
(Uchiyama and Mulvey),[11] [Al-
1b (R=OMe)
G
(Knochel),[12]
ACHTUNGTRENNUNG(tmp)Li-
2
3
1c
1d
2c
2d
97
71
57
0
52
57
A
and
ACHTUNGTRENNUNG(tmp)(CN)Li2]
(Uchiyama and Wheatley).[14]
We recently accomplished
[a] The cadmium source was CdCl2·TMEDA (x=2). [b] The indium source was InCl3 (x=3). [c] The zinc
source was ZnCl2·TMEDA (x=2). The procedure was as previously described.[17] [d] In ref. [15a] we reported
a 30% yield for this reaction, probably due to water-contaminated ZnCl2·TMEDA.
the deproto-metalation of
large range of aromatics includ-
ing heterocycles by using
newly developed lithium–cad-
a
a
mium base, [(tmp)3CdLi].[15] Herein, the details of our inves-
tigations into the choice of the base are described. In addi-
tion, different kinds of trapping for the aromatic cadmium
species including palladium-catalyzed cross-couplings are re-
corded.
(1b), benzothiazole (1c), and pyrimidine (1d) as substrate,
the metalation reactions performed in tetrahydrofuran
(THF) at room temperature by combining CdCl2·TMEDA
(0.50 equiv) and [LiACTHNUTRGNE(NUG tmp)] (1.5 equiv), followed by subse-
quent trapping with elemental iodine after 2 h, proceeded in
good yields (71 to 97%). Under the same conditions, the ex-
periments carried out with InCl3 (0.33 equiv) and [LiACHTUNGTRENNUNG(tmp)]
Results and Discussion
(1.3 equiv) provided the expected iodo derivatives 2a–c in
medium yields (48 to 57%), but from pyrimidine (1d) the
corresponding 4,4’-dimer proved to be the sole product
formed.
To obtain information about the active species of the new
basic mixtures, NMR spectroscopy and DFT studies were
carried out. By recording the NMR spectrum of the mixture
Wittig and co-workers reported the synthesis of [Ph3BeLi],
[Ph3MgLi], [Ph3ZnLi], [Ph7Zn2Li3], [Ph3CdLi], and
[Ph3HgLi] and their ability to deprotonate fluorene in
diethyl ether.[16] Quenching with CO2 and subsequent acidic
workup afforded diphenyleneacetic acid in yields of 0 (after
2 weeks reaction time), 47 (after 3 d), 16 (after 10 d), 44
(after 10 d), 64 (after 3 d), and 84% (after 3 d), respectively.
In 1951 these results were analyzed as a measure of the dis-
sociation of such complexes into the original diphenylmetal
and phenyllithium. The more recent discovery of the basic
properties of lithium magnesates[7] and zincates[7,8] led us to
consider these results from another angle, and prompted us
to study the deproto-metalation of aromatic rings using lithi-
um-metal ate bases with bigger central metals.
generated from CdCl2·TMEDA and [Li
ACHTUNGTREN(NUGN tmp)] (3 equiv), it
was observed that [Li(tmp)] was not present, and the forma-
AHCTUNGTRENNUNG
tion of the lithium cadmate [(tmp)3CdLi] was inferred. This
possibility, different to what has been observed with zinc,
was supported by the B3LYP-calculated equilibrium be-
tween [LiACHTNUTRGNENU(G tmp)] and [(tmp)2Cd] on one side and
[(tmp)3CdLi] on the other.[15a]
Various attempts to get information about the structure of
the species formed from InCl3 and [Li
NMR spectroscopy were unsuccessful. DFT calculations
were performed for the equilibrium between [Li(tmp)] and
ACHTUNGTREN(NUGN tmp)] (4 equiv) by
In a recent study we showed that the in situ prepared mix-
ture of ZnCl2·TMEDA and 3 equiv of [Li
N
ACHTUNGTRENNUNG
mixture of [Li
G
[(tmp)3In] on one side and [(tmp)4InLi] on the other side.
Although the structure of [(tmp)4InLi] was obtained at the
HF/3-21G level, the re-optimization of this complex at the
higher level such as B3LYP/6-31G* led to the collapse of
the indium-ate complex. We confirmed that the tetracoordi-
ed in the form of a zincate, the combination behaves syner-
gically, allowing efficient and chemoselective deprotonation
reactions. To seek more efficient and direct methods for in-
troducing functionalities into aromatic rings including het-
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10281

F. Mongin, M. Uchiyama etal.
nated ate structure is not the global minimum by making an
artificial ideal tetrahedral geometry of [(tmp)4InLi]
(Scheme 1). Geometry optimization then caused smooth mi-
gration of one of the tmp ligands without energy barrier,
metalated at room temperature. When possible, for exam-
ACTHNUTRGNEUNG
ple, using [(tmp)2Mg][2] or [tBu2Zn(tmp)Li][8a] in THF, an
excess of base has to be used. The compatibility of the Cd–
Li base (0.5 equiv) with reactive functional groups allowed
the expected iodides 2e–g to be
formed in good yields under
the conditions optimized above
(entries 1 and 2). The ketone
function was still tolerated in
the reaction, as shown from
benzophenone (1h; entry 3).
The chemoselective accumula-
tion of the metalated deriva-
tives of 4-bromoanisole (1i), 4-
iodoanisole[25] (1j), and methyl
4-bromobenzoate (1k) also
proved feasible, with complete
regioselectivity for the position
far from the heavy halogen
atom (entries 4 and 5).
We next demonstrated that
the cadmate base was suitable
for the metalation of a large
Scheme 1. Bond lengths (in ꢅ) at B3LYP/6-31G* (SVP basis set for Zn, Cd, or In).
Table 2. Metalation of substrate 1a using different mixtures followed by
trapping with I2.
and dissociation of the ate structure into a trigonal non-ate
complex and [Li
tion indicated that the lithium indate was unlikely to form.
Similar results experimentally observed in the case of pyrim-
idine (1d) by using either the In–Li base or [Li
(tmp)][22] also
ACHTUNGTRENNUNG(tmp)]. Recourse to the theoretical calcula-
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
suggested the presence of organolithiums in the reaction
mixture.
The synergy of the reactions using [(tmp)3CdLi] was dem-
onstrated with anisole (1a) as substrate using either [Li-
Entry
Base
Yield [%]
M=Zn
M=Cd
0.5 equiv
1 equiv
0.5 equiv
1 equiv
1
2
3
4
A
75
34
7
–
57
14
–
84
–
–
–
79
20
0
ACHTUNGTRENNUNG(tmp)] (1 equiv) or [(tmp)2Cd] (1 equiv). Under the same re-
N
ACHTUNGTRENNUNG
action conditions, the iodide 2a was isolated in 9% yield
using the former, and did not form using the latter, whereas
a 75% yield was obtained using the mixed base. A possible
effect of lithium chloride[23] or TMEDA[24] on the course of
R
G
A
9
–
[a] [(tmp)3CdLi] or [LiACTHNUGTRENUNG(tmp)]+[(tmp)2Zn].
the reaction was discarded. Indeed, using [LiACTHNUGRTNEUNG(tmp)]
(1 equiv) with either LiCl (2 equiv) or TMEDA (1 equiv) or
both did not result in significant changes (14% yield in the
presence of TMEDA alone, but only traces of 2a identified
in the presence of LiCl).
range of aromatic heterocycles (Table 4). Benzo[b]thiophene
(1l) has previously been magnesated at room temperature
using [(tmp)MgCl]·LiCl,[26] and zincated using the in situ
Since lithium zincates bearing alkyl and amino groups are
efficient bases,[7,8] [(tmp)3CdLi] was compared with [BuCd-
prepared mixture of [(tmp)2Zn] and [LiACTHNUTRGNEUNG
(tmp)].[17a] Its cad-
A
E
mation was achieved in an excellent yield by using the Cd–
Li base, as demonstrated by trapping with iodine. Benzo[b]-
furan (1m) behaved similarly to extend the list of benzo[b]-
furan organometallics prepared at room temperature[27]
(entry 1). The room-temperature zincation of benzothiazole
the corresponding zinc–lithium mixtures). Using anisole
(1a) as substrate, metalation took place but in decidedly
lower yields, decreasing as the number of tmp groups also
decreased (Table 2). These results strongly suggested that
[(tmp)3CdLi] was the best species rather than other lithium
cadmates for the deprotonation reaction.
The deprotonation–trapping sequence was then applied to
functionalized benzenes (Table 3). Due to their electrophilic
functional group, N,N-diethylbenzamide (1e),[2] methyl ben-
zoate (1 f),[2,8a] and benzonitrile (1g)[8a] have scarcely been
(1c)
[(tmp)2Zn]·2MgCl2·2LiCl[9a] or the in situ prepared mixture
of [(tmp)2Zn] and [Li
(tmp)][17a] has previously been report-
and
benzoxazole
(1n)
using
either
ACHTUNGTRENNUNG
ed. The cadmation proceeded quantitatively starting from
benzothiazole (1c), whereas a lower 63% yield was noted in
the case of benzoxazole (1n), probably in relation to the in
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Deprotonated Metalation of Functionalized Aromatics
FULL PAPER
Table 3. Metalation of substrates 1e–k using [(tmp)3CdLi] followed by trapping with I2.
sequently intercepted by iodine
(Table 4, entry 4). The situation
becomes more complex, for ex-
ample, when using 2,4-dime-
thoxypyrimidine (1q) since the
5-position can be attacked
Entry
1
Substrate 1
1e (R=NEt2)
Product 2
2e (R=NEt2)
Yield [%]
using [LiACTHUNGTRENNNUG
91
1 f (R=OMe)
2 f (R=OMe)
62 (89)[a]
and the 6-position using
[(tmp)MgCl]·LiCl at room tem-
perature.[32] The [(tmp)3CdLi]-
promoted reaction took place
in a satisfying yield using the
Cd–Li base, but with a com-
plete lack of regioselectivity,
leading to the 5- and 6-iodo de-
rivatives 2q and 2’q in a 43:57
ratio (entry 5).
N-Boc pyrrole (1r; Boc=
tert-butoxycarbonyl) was con-
verted into the iodide 2r in
68% yield.[33] As we found diio-
dide 3r among the byproducts
2
3
1g
1h
2g
2h
68
66
1i (X=Br)
1j (X=I)
2i (X=Br)
2j (X=I)
97
83
4
5
1k
2k
60
[a] Using CdCl2·TMEDA (1 equiv)+[LiACHTNUTRGNEUNG(tmp)] (3 equiv).
Table 4. Metalation of substrates 1c,l–q using [(tmp)3CdLi][a] followed by
detected in the crude, we were encouraged to attempt the
use of 1 equiv of base instead of 0.5 equiv. Under the same
reaction conditions, the dimetalation[34] was favored, and
diiodide 3r was isolated in 60% yield (Table 5, entries 1 and
trapping with I2.
Entry
Substrate 1
1l (X=S)
Product 2
2l (X=S)
Yield [%]
97
1
1m (X=O)
2m (X=O) 84
1c (X=S)
1n (X=O)
2c (X=S)
2n (X=O) 63
97
Table 5. Metalation of substrates 1r–u using [(tmp)3CdLi] followed by
trapping with I2.
2
3
4
Entry
Substrate 1
Product 2[a] or 3[b]
Yield [%]
68
1o
1p
2o
2p
52
47
1
1r
2r
3r
2
1r
60
5
1q
2q/2’q
84
3
4
1s
1t
3s
3t
50
74
[a] Conditions: CdCl2·TMEDA (0.5 equiv)+[LiACTHNUTRGNEUG(N tmp)] (1.5 equiv), THF,
RT, 2 h.
5
1u
3u
81
situ opening of the formed 2-metalated species to give 2-iso-
cyanophenolate (entry 2).[28]
[a] Metalation
conditions:
CdCl2·TMEDA
(0.5 equiv)+[LiACHTUNGTRENNUNG(tmp)]
(1.5 equiv), THF, RT, 2 h. [b] Metalation conditions: CdCl2·TMEDA
(1 equiv)+[Li(tmp)] (3 equiv), THF, RT, 2 h.
Due to easy elimination of the metal halide to give pyri-
dyne,[29] deproto-metalation of 2-chloropyridine (1o) can
barely be achieved at room temperature. Chemoselectivity
was present upon reaction with the sterically hindered cad-
mate, but not regioselectivity,[30] and the main iodide 2o re-
sulting from the metalation at the chloro-adjacent site was
only isolated in 52% yield (Table 4, entry 3).
AHCTUNGTRENNUNG
2). Since the introduction of two substituents in one step is
challenging, the behavior of other five-membered aromatic
heterocycles benefiting from doubly activated positions was
studied (Table 5, entries 3–5). Thiazole (1s)[17a,35] and thio-
phene (1t)[26,35,36] undergo monodeprotonation at room tem-
perature when exposed to DAMgCl (DA=diisopropylami-
no),[35] [Bu3MgLi]·TMEDA,[36] or [(tmp)MgCl]·LiCl.[26]
When subjected to the in situ prepared mixture of
The good chemoselectivity observed during the Cd–Li
base-mediated deprotonation prompted us to attempt to use
it for the metalation of diazines, which are prone to nucleo-
philic addition.[31] Whereas [Li
ACTHNUTRGNEUNG(tmp)] has to be used at
À758C to avoid the formation of a dimer,[31] the mixed base
can be employed at room temperature for the cadmation of
methoxypyrazine (1p), and the metalated heterocycle is sub-
[(tmp)2Zn] and [Li
(1s) was not avoided, even when using = equiv of base;
(tmp)],[17a] the dimetalation of thiazole
ACHTUNGTRENNUNG
1
3
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10283

F. Mongin, M. Uchiyama etal.
using 1 equiv of [(tmp)3CdLi] enabled diiodide 3s to be iso-
lated in 50% yield. Better yields of 74 and 81% were ob-
tained for the thiophene diiodides 3t and 3u, respectively,
under the same reaction conditions. Furan is amenable to
silyl chloride (entry 2), phenyl disulfide (entry 3), and allyl
bromide (entry 4) at the reflux temperature of THF afforded
the expected functionalized anisoles 3a–6a, but in moderate
yields ranging from 22 to 35%. The cadmate formed from
benzonitrile (1g) did not react with 4-(trifluoromethyl)benz-
aldehyde, trimethylsilyl chloride, or phenyl disulfide under
the same reaction conditions, and the allyl derivative 6g was
isolated in a low 30% yield.
To extend the synthetic applications of the aryl- and het-
eroarylcadmates, it was decided to involve them in palladi-
um-catalyzed cross-coupling reactions with aromatic bro-
mides. To our knowledge, cross-coupling reactions using
cadmium compounds have only been described starting
from organocadmium chlorides, and are known to produce,
in addition to the expected
magnesation
at
room
temperature
using
either
[Bu4MgLi2][27a] or [(tmp)MgCl]·LiCl.[26] When using
[(tmp)3CdLi], its monocadmation occurred but attempts to
dimetalate it were disappointing, in contrast to what has re-
cently been observed using the stronger [(tmeda)Na-
A
(tmp)].[37]
ACHTUNGTRENNUNG(tmp)MgACHTUGNTRENNUGN
organometallic compounds were then employed to trap the
cadmate generated from anisole (1a; Table 6). Reaction
with 4-(trifluoromethyl)benzaldehyde (entry 1), trimethyl-
products, homocoupling prod-
Table 6. Metalation of substrates 1a,g using [(tmp)3CdLi] followed by trapping using 4-(trifluoromethyl)ben-
ucts derived from both sub-
strates.[38] The first reactions of
our optimization study (Table 7)
were carried out at the reflux
temperature of THF using the
zaldehyde, trimethylsilyl chloride, phenyl disulfide, and allyl bromide.
2-metalated
thiophene
or
methyl benzoate, 2-bromopyri-
dine, and a catalytic amount of
palladium(0) tetrakis(triphenyl-
phosphine); the expected prod-
ucts 4t1,e were produced in
moderate to good yields (en-
tries 1 and 2).
Entry
1
Substrate
Electrophile
Product
Yield [%]
1a
1g
3a
3g
35
0
4-(F3C)C6H4CHO
1a
1g
4a
4g
22
0
2
3
4
Me3SiCl
Because the results of reac-
tions performed with palladi-
1a
1g
5a
5g
27
0
PhSSPh
um(0)
tetrakis(triphenylphos-
phine)[39] are dependent on the
quality of the latter, we
searched out a procedure using
in situ generated palladium(0).
Reactions were then attempted
to reproduce the result ob-
tained from 2-metalated thio-
phene and 2-bromopyridine.
1a
1g
6a
6g
35
30
BrCH2CH=CH2
Table 7. Metalation of substrates 1t,e,v using [(tmp)3CdLi] followed by cross-coupling.
Palladium(II)
chloride
(2 mol%) was the first precata-
lyst used for this purpose, and
Entry
1
Substrate 1
Catalyst
[Pd(PPh3)4] (2 mol%)
Product 4
Yield [%]
72
monodentate
phine
triphenylphos-
Table 7,
(4 mol%;
1t
G
4t1
4e
entry 3) and bidentate 1,1’-bis-
(diphenylphosphino)ferrocene
(dppf, 2 mol%; entry 4) were
compared. The latter proved
superior, with triphenylphos-
phine only allowing the cross-
coupling when used in a larger
amount (10 mol%; entry 5). We
then turned to the cross-cou-
2
1e
[Pd
N
35
3
4
5
1t
1t
1t
PdCl2 (2 mol%), PPh3 (4 mol%)
PdCl2 (2 mol%), dppf (2 mol%)
PdCl2 (2 mol%), PPh3 (10 mol%)
4t1
4t1
4t1
0[a]
26
38
6
1v
PdCl2 (2 mol%), dppf (2 mol%)
4v1
0
7
8
9
1v
1v
1v
Pd
Pd(OAc)2 (4 mol%), dppf (2 mol%)
Pd(OAc)2 (6 mol%), dppf (2 mol%)
(OAc)2 (2 mol%), dppf (2 mol%)
4v1
4v1
4v1
10
51
83
pling
furan
between
and 4-bromoanisole.
2-metalated
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
[a] No improvement was observed using [PdCl
G
Since the reaction failed using
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Chem. Eur. J. 2009, 15, 10280 – 10290

Deprotonated Metalation of Functionalized Aromatics
FULL PAPER
palladi
um(II) chloride (2 mol%) in the presence of dppf
(1d), a lower yield (29%) was obtained, probably in relation
to the lower stability of the metalated species (entry 10).
It is acknowledged that organocadmium halides can be
trapped by acid chlorides to provide ketones.[18] This possi-
bility was attempted from the furanylcadmate using aliphat-
ic acid chlorides, and the results clearly show that nonenoliz-
able electrophiles are more suitable for the reactions
(Table 9, entries 1–3). Methyl chloroformate allowed direct
access to furan ester 5v4, albeit in a low yield that could be
due to the volatility of the product (entry 4).
(2 mol%; entry 6), we suspected an inefficient reduction of
palladium(II) chloride, and therefore decided to test the use
of another precatalyst. We chose palladium(II) acetate, for
which mixtures with tertiary phosphines are known to spon-
taneously generate palladium(0) complexes.[40] A low 10%
yield was obtained by using a 1:1 PdACTHNUTRGENUN(G OAc)2/dppf ratio
(2 mol% each; entry 7), but increasing this ratio to 2:1 and
3:1 resulted in improved yields of 51 and 83%, respectively
(entries 8 and 9).
To evaluate the scope of this reaction, experiments em-
ploying 2-metalated furan (Table 8, entries 1–4) or thio-
phene (entry 5), and different aryl bromides were first con-
ducted under the same reaction conditions. The expected 2-
arylated heterocycles 4v2–4v5 and 4t2 were isolated, albeit
in medium yields due to concomitant formation of homo-
coupling products. Similar results were noted for the depro-
tonation/cross-coupling sequences starting from the other ar-
omatic heterocycles 1l,m,w,x (entries 6–9). From pyrimidine
Gilman and Nelson reported in 1936 the reaction of di-
phenylcadmium with benzenesulfonyl chloride to give a
Table 9. Metalation of substrate 1v using [(tmp)3CdLi] followed by trap-
ping with acid chlorides.
À
Entry E Cl
Product 5
Yield [%]
0
Table 8. Metalation of substrates 1d,v,t,l,m,w,x using [(tmp)3CdLi] fol-
lowed by cross-coupling.
1
5v1
5v2
2
21
3
4
5v3
5v4
60
15
Entry
1
Substrate 1
1v
Product 4
Yield [%]
41
4v2
4v3
5v5 (R=H)
5’v5 (R=Cl)
17[a]
5
5
2
1v
42
5v6 (R=H)
5’v6 (R=Cl)
18[a]
6
3
4
5
6
7
1v
1v
4v4
4v5
4t2
4l
57
6
7
8
46
5v7
5v8
76
42
1t
63[a]
50[b]
42[c]
1l
1m
4m
9
5v9
49
51
8
9
1w
1x
4w
4x
56
59
10
5v10
11
5v11
63[b]
10
1d
4d
29
[a] 2-Chlorofuran and 2,5-dichlorofuran could form and be evaporated
[a] 2,5-Bis(4-methoxyphenyl)thiophene was isolated in 16% yield.
[b] 2,2’-Bis(benzo[b]thiophene) was isolated in 25% yield. [c] 2,2’-Bis-
ACHTUNGTRENNUNG(benzo[b]furan) was isolated in 12% yield.
under reduced pressure (b.p. 77[42a] and 1158C,[42b] respectively). [b] Bis-
ACHTUNGTRENNUNG
N
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10285

F. Mongin, M. Uchiyama etal.
added to a stirred, cooled (08C) solution of 2,2,6,6-tetramethylpiperidine
(1.0 mL, 6.0 mmol) in THF (5 mL). After the solution had been stirred
for 15 min at 08C, CdCl2·TMEDA (0.60 g, 2.0 mmol) was added, and the
mixture was stirred for 15 min at this temperature before introduction of
the substrate (4.0 mmol). After the mixture had been stirred for 2 h at
room temperature, a solution of I2 (1.5 g, 6.0 mmol) in THF (5 mL) was
added. The mixture was stirred overnight before addition of an aqueous
saturated solution of Na2S2O3 (5 mL) and extraction with CH2Cl2 (3ꢆ
20 mL). The combined organic layers were washed with brine (10 mL),
dried over Na2SO4, filtered, and concentrated under reduced pressure
before being purified by means of column chromatography on silica gel.
2-Chloro-3-iodopyridine (2o): Yellow solid; m.p. 98–1008C; 1H NMR
(CDCl3, 200 MHz): d=6.96 (dd, J=4.7, 7.7 Hz, 1H), 8.20 (dd, J=1.7,
7.7 Hz, 1H), 8.41 ppm (dd, J=1.7, 4.7 Hz, 1H). These data are consistent
with those obtained for a commercial sample.
2-Iodo-3-methoxypyrazine (2p): Pale yellow solid; m.p. 628C; 1H NMR
(CDCl3, 300 MHz): d=4.02 (s, 3H), 7.93 (d, J=2.7 Hz, 1H), 7.98 ppm (d,
J=2.7 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=55.1, 107.7, 137.4, 139.5,
159.3 ppm; elemental analysis calcd (%) for C5H5IN2O: C 25.45, H 2.14,
N 11.87; found: C 25.49, H 2.12, N 11.54.
mixture of diphenylsulfone, benzenesulfinic acid, and chlo-
ACHTUNGTRENNUNGroACHTUNGTRENNUNG
benzene.[41] The furanylcadmate was involved in similar
reactions with tosyl chloride and 4-chlorobenzenesulfonyl
chloride. The expected diarylsulfones 5v5–5v6 were isolated
in moderate yields (17–18%; Table 9, entries 5 and 6). Con-
comitant formation of 2-chlorofuran and 2,5-dichlorofuran
was suspected, even if not isolated due to their volatility.[42]
Indeed, 5-(arylsulfonyl)-2-chlorofurans 5’v5–5’v6 were also
accessed in 5–6% yield, probably through electrophilic trap-
ping of the 2,5-dimetalated species through the two different
modes. The disulfone was not detected, which suggests that
benzenesulfonyl chlorides more likely act as chlorinating
agents.
Different diarylketones were finally obtained in medium
to good yields when different benzoyl chlorides were chosen
to intercept the furanylcadmate (Table 9, entries 7–11).
5-Iodo-2,4-dimethoxypyrimidine (2q): White solid; m.p. 99–1008C;
1H NMR (CDCl3, 300 MHz): d=3.98 (s, 3H), 4.03 (s, 3H), 8.44 ppm (s,
1H); 13C NMR (CDCl3, 75 MHz): d=55.1, 55.2, 77.2, 164.8, 165.4,
Conclusion
1
168.8 ppm. The H NMR data are consistent with the literature.[43]
In summary, efficient deprotonative cadmation reactions of
functionalized aromatics including heterocycles were realiz-
ed using the newly developed (tmp)Cd-ate base. The latter
proved compatible with reactive functional groups
(CONEt2, CO2Me, CN, COPh), heavy halogens (Br, I), and
sensitive aromatic aza-heterocycles. Heterocycles benefiting
from doubly activated positions were similarly dideprotonat-
ed at room temperature.
The aromatic lithium cadmates were evidenced by using
iodine; the species were then involved in palladium-cata-
lyzed cross-coupling reactions or simply quenched with acid
chlorides to extend the synthetic applications of the method.
Due to the toxicity of cadmium compounds we are at-
tempting to develop new mixed lithium-metal bases of ate-
type that are still efficient and chemoselective, profiting
from the present study.
6-Iodo-2,4-dimethoxypyrimidine (2’q): White solid; m.p. 728C; 1H NMR
(CDCl3, 300 MHz,): d=3.93 (s, 3H), 3.98 (s, 3H), 6.87 ppm (s, 1H);
13C NMR (CDCl3, 75 MHz): d=54.1, 55.3, 112.5, 127.8, 163.6,
170.6 ppm.[44]
General procedure for the dideprotocadmation (using [(tmp)3CdLi])–
diiodination of aromatics: BuLi (about 1.6m hexanes solution, 6.0 mmol)
was added to a stirred, cooled (08C) solution of 2,2,6,6-tetramethylpiperi-
dine (1.0 mL, 6.0 mmol) in THF (5 mL). After the solution had been
stirred for 15 min at 08C, CdCl2·TMEDA (0.60 g, 2.0 mmol) was added,
and the mixture was stirred for 15 min at this temperature before intro-
duction of the substrate (2.0 mmol). After the mixture had been stirred
for 2 h at room temperature, a solution of I2 (1.5 g, 6.0 mmol) in THF
(5 mL) was added. The mixture was stirred overnight before addition of
an aqueous saturated solution of Na2S2O3 (5 mL) and extraction with
CH2Cl2 (3ꢆ20 mL). The combined organic layers were washed with brine
(10 mL), dried over Na2SO4, filtered, and concentrated under reduced
pressure before being purified by means of column chromatography on
silica gel.
General procedure for the deprotocadmation (using [(tmp)3CdLi]) of ar-
omatics followed by trapping with different electrophiles: BuLi (about
1.6m hexanes solution, 3.0 mmol) was added to a stirred, cooled (08C) so-
lution of 2,2,6,6-tetramethylpiperidine (0.51 mL, 3.0 mmol) in THF
(3 mL). After the solution had been stirred for 15 min at 08C,
CdCl2·TMEDA (0.30 g, 1.0 mmol) was added, and the mixture was stirred
for 15 min at this temperature before introduction of the substrate
(2.0 mmol). After the mixture had been stirred for 2 h at room tempera-
ture, the electrophile (3.0 mmol) was added at 08C. The mixture was
stirred overnight at 608C before addition of brine (5 mL) and extraction
with diethyl ether (3ꢆ20 mL). The combined organic layers were washed
with brine (10 mL), dried over Na2SO4, filtered, and concentrated under
reduced pressure before being purified by means of column chromatogra-
phy on silica gel.
Experimental Section
All of the reactions occurred in Schlenk tubes under an argon atmos-
phere. THF was distilled over sodium/benzophenone, and CH2Cl2 was
distilled over CaH2. Nuclear magnetic resonance spectra were acquired
on Bruker ARX-200 (200 and 50 MHz for 1H and 13C, respectively) and
Bruker AC-300 (300 and 75 MHz for 1H and 13C, respectively) spectrom-
eters. High-resolution mass spectra measurements were performed at the
Centre Rꢁgional de Mesures Physiques de l’Ouest (CRMPO) in Rennes
using a Micromass MS/MS ZABSpec TOF instrument in EI mode.
Liquid chromatography separations were achieved on silica gel Merck
Geduran Si 60 (40–63 mesh).
CdCl2·TMEDA:[20] TMEDA (3.25 mL, 22 mmol) was added to a stirred
suspension of flame-dried CdCl2 (2.0 g, 11 mmol) in dry CH2Cl2 (50 mL).
The mixture was heated at reflux for 2 h under argon before it was
evaporated under reduced pressure. The residual solid was washed under
argon with CH2Cl2 (20 mL) and ethanol (20 mL). Solvent evaporation
(2-Methoxyphenyl)[4-(trifluoromethyl)phenyl]methanol (3a): Yellow oil;
1H NMR (CDCl3, 300 MHz): d=3.13 (d, J=5.7 Hz, 1H), 3.82 (s, 3H),
6.08 (d, J=5.4 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.97 (td, J=0.9, 7.5 Hz,
1H), 7.22 (dd, J=1.6, 7.5 Hz, 1H), 7.30 (m, 1H), 7.51 (d, J=8.2 Hz, 2H),
7.58 ppm (d, J=8.3 Hz, 2H); 13C NMR (CDCl3, 75 MHz): d=55.4, 71.8,
110.8, 120.9, 124.2 (q, JF =272 Hz), 125.1 (q, JF =3.8 Hz, 2C), 126.7,
127.8, 129.1, 129.2 (q, JF =32.3 Hz, 2C), 131.2, 147.3, 156.6 ppm. These
data are consistent with the literature.[45]
under vacuum gave CdCl2·TMEDA (2.4 g, 73%) as
a white solid.
1H NMR ([D6]DMSO, 200 MHz): d=2.29 (s, 12H), 2.45 ppm (s, 4H);
13C NMR ([D6]DMSO, 75 MHz): d=46.6 (4C), 56.0 ppm (2C).
1
2-(Trimethylsilyl)anisole (4a): Colorless oil; H NMR (CDCl3, 300 MHz):
General procedure for the deprotocadmation (using [(tmp)3CdLi])–iodi-
nation of aromatics: BuLi (about 1.6m hexanes solution, 6.0 mmol) was
d=0.27 (s, 9H), 3.81 (s, 3H), 6.84 (d, J=8.2 Hz, 1H), 6.96 (dt, J=0.9,
7.3 Hz, 1H), 7.36 ppm (m, 2H); 13C NMR (CDCl3, 75 MHz): d=À1.0
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Deprotonated Metalation of Functionalized Aromatics
FULL PAPER
(3C), 55.0, 109.5, 120.4, 127.9, 130.7, 134.9, 164.3 ppm. These data are
consistent with the literature.[46]
0.7, 3.4 Hz, 1H), 6.70 (m, 1H), 7.15 (m, 3H), 7.34 ppm (dd, J=0.7,
1.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=55.3, 105.3, 109.1, 111.6,
113.2, 116.4, 129.7, 132.2, 142.1, 153.8, 159.9 ppm. These data are consis-
tent with the literature.[53]
2-(4-Chlorophenyl)furan (4v5): Yellow solid; m.p. 65–668C; 1H NMR
(CDCl3, 300 MHz): d=6.64 (dd, J=0.7, 3.4 Hz, 1H), 6.78 (dd, J=1.8,
3.4 Hz, 1H), 7.35 (d, J=8.8 Hz, 2H), 7.47 (dd, J=0.7, 1.8 Hz, 1H),
7.60 ppm (dd, J=8.8 Hz, 2H); 13C NMR (CDCl3, 75 MHz): d=105.4,
111.8, 125.0 (2C), 128.8 (2C), 126.0, 132.9, 142.3, 152.9 ppm. These data
are consistent with the literature.[54]
2-(Phenylthio)anisole (5a): Colorless liquid; 1H NMR (CDCl3,
300 MHz): d=3.89 (s, 3H), 6.90 (m, 2H), 7.10 (dd, J=1.7, 7.7 Hz, 1H),
7.23–7.30 (m, 2H), 7.33–7.39 ppm (m, 4H); 13C NMR (CDCl3, 75 MHz):
d=55.9, 110.8, 121.2, 124.1, 127.05, 128.3, 129.1 (2C), 131.5 (2C), 131.6,
134.4, 157.3 ppm. These data are consistent with the literature.[47]
2-Allylanisole (6a): Colorless oil; 1H NMR (CDCl3, 300 MHz): d=3.40
(d, J=6.6 Hz, 2H), 3.84 (s, 3H), 5.06 (m, 2H), 6.02 (m, 1H), 6.87 (d, J=
8.2 Hz, 1H), 6.93 (dd, J=1.0, 7.4 Hz, 1H), 7.17 (m, 1H), 7.23 ppm (dd,
J=1.5, 7.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=34.2, 55.3, 110.3,
115.3, 120.5, 127.3, 128.6, 129.7, 137.0, 157.2 ppm. These data are consis-
tent with the literature.[48]
2-Allylbenzonitrile (6g): Colorless oil; 1H NMR (CDCl3, 300 MHz): d=
3.62 (d, J=6.7 Hz, 2H), 5.11–5.17 (m, 2H), 5.91–6.00 (m, 1H), 7.30–7.35
(m, 2H), 7.52–7.55 (m, 1H), 7.63 ppm (d, J=7.6 Hz, 1H); 13C NMR
(CDCl3, 75 MHz): d=38.5, 112.5, 117.4, 117.9, 126.8, 129.7, 132.8, 132.9,
134.9, 143.8 ppm. These data are consistent with the literature.[49]
1
2-(4-Methoxyphenyl)thiophene (4t2): Brown solid; m.p. 1048C; H NMR
(CDCl3, 300 MHz): d=3.84 (s, 3H), 6.92 (d, J=8.8 Hz, 2H), 7.05 (dd, J=
3.6, 5.0 Hz, 1H), 7.21 (m, 2H), 7.54 ppm (d, J=8.8 Hz, 2H); 13C NMR
(CDCl3, 75 MHz): d=55.1, 114.4 (2C), 122.2, 124.0, 127.4, 127.4, 128.0
(2C), 144.5, 159.3 ppm. These data are consistent with the literature.[55]
2-(4-Methoxyphenyl)benzo[b]thiophene (4l): White solid; m.p. 2008C;
1H NMR ([D6]DMSO, 300 MHz): d=3.81 (s, 3H), 7.04 (d, J=8.7 Hz,
2H), 7.34 (m, 2H), 7.76 (m, 4H), 7.94 ppm (m, 1H); 13C NMR
([D6]DMSO, 75 MHz): d=55.2, 114.5 (2C), 118.5, 122.3, 123.3, 124.1,
124.2, 124.6, 127.3 (2C), 138.1, 140.6, 143.1, 159.5 ppm. These data are
consistent with the literature.[56]
General procedure for the deprotocadmation (using [(tmp)3CdLi])–cross-
coupling ([PdACHTUNGTRENNUNG(PPh3)4]) of aromatics: BuLi (about 1.6m hexanes solution,
6.0 mmol) was added to a stirred, cooled (08C) solution of 2,2,6,6-tetra-
methylpiperidine (1.0 mL, 6.0 mmol) in THF (5 mL). After the solution
had been stirred for 15 min at 08C, CdCl2·TMEDA (0.60 g, 2.0 mmol)
was added, and the mixture was stirred for 15 min at this temperature
before introduction of the substrate (4.0 mmol). After the mixture had
been stirred for 2 h at room temperature, the heterocyclic bromide
2-(4-Methoxyphenyl)benzo[b]furan (4m): White solid; m.p. 1538C;
1H NMR ([D6]DMSO, 300 MHz): d=3.82 (s, 3H), 7.06 (d, J=9.0 Hz,
2H), 7.26 (m, 3H), 7.60 (m, 2H), 7.85 ppm (d, J=9.0 Hz, 2H); 13C NMR
([D6]DMSO, 75 MHz): d=55.2, 100.1, 110.8, 114.4 (2C), 120.7, 122.3,
123.3, 123.9, 126.2 (2C), 129.0, 153.9, 155.3, 159.7 ppm. These data are
consistent with the literature.[57]
(6.0 mmol) and [PdACHTUNGTRENNUNG(PPh3)4] were added to the reaction mixture, which
was stirred for 18 h at reflux. The solution was cooled before addition of
water (0.5 mL) and filtration over Celite. The mixture was dried over
MgSO4, filtered, concentrated under reduced pressure, and purified by
means of flash chromatography on silica gel.
N-Boc-2-(4-methoxyphenyl)indole (4w): Beige solid; m.p. 87–888C;
1H NMR (CDCl3, 300 MHz): d=1.26 (s, 9H), 3.73 (s, 3H), 6.41 (brs,
1H), 6.83 (d, J=8.8 Hz, 2H), 7.10–7.27 (m, 4H), 7.43 (m, 1H), 8.11 ppm
(m, 1H); 13C NMR (CDCl3, 75 MHz): d=27.7 (3C), 55.4, 83.4, 109.6,
113.3 (2C), 115.3, 120.4, 122.9, 124.1, 127.5, 129.4 (2C), 130.0, 137.4,
140.5, 150.4, 159.3 ppm. These data are consistent with the literature.[58]
(4-Methoxyphenyl)pyrazine (4x): Beige solid; m.p. 958C; 1H NMR
(CDCl3, 300 MHz): d=3.85 (s, 3H), 7.01 (d, J=8.9 Hz, 2H), 7.96 (d, J=
8.9 Hz, 2H), 8.42 (d, J=2.4 Hz, 1H), 8.56 (brm, 1H), 8.60 ppm (brs,
1H); 13C NMR (CDCl3, 75 MHz): d=55.5, 114.6 (2C), 128.4 (2C), 128.9,
141.7, 142.2, 144.0, 152.6, 161.3 ppm. These data are consistent with the
literature.[59]
2-(Thiophen-2-yl)pyridine (4t1): White solid; m.p. 61–638C. The physical
and spectroscopic data are consistent with those obtained for a commer-
cial sample.
Methyl 2-(pyridin-2-yl)benzoate (4e): Colorless oil; 1H NMR (CDCl3,
200 MHz): d=3.64 (s, 3H), 7.20 (ddd, J=1.2, 5.0, 7.6 Hz, 1H), 7.48 (m,
4H), 7.70 (td, J=1.8, 7.7 Hz, 1H), 7.78 (d, J=7.6 Hz, 1H), 8.60 ppm (dd,
J=1.0, 5.0 Hz, 1H). These data are consistent with the literature.[50]
13C NMR (CDCl3, 50 MHz): d=51.9, 122.0, 122.6, 128.2, 129.6, 129.7,
131.0, 131.5, 136.2, 140.8, 148.9, 158.4, 169.2 ppm.
4-(4-Methoxyphenyl)pyrimidine (4d): Yellow liquid; 1H NMR (CDCl3,
300 MHz): d=3.84 (s, 3H), 7.10 (d, J=8.4 Hz, 2H), 8.02 (d, J=5.0 Hz,
1H), 8.19 (d, J=8.4 Hz, 2H), 8.78 (d, J=5.0 Hz, 1H), 9.17 ppm (s, 1H);
13C NMR (CDCl3, 75 MHz): d=55.3, 114.4 (2C), 116.1, 128.1, 128.6 (2C),
157.6, 158.6, 161.8, 162.1 ppm. These data are consistent with the litera-
ture.[60]
General procedure for the deprotocadmation (using [(tmp)3CdLi])–cross-
coupling (PdACHTUNGTRENNUNG(OAc)2 +dppf) of aromatics: BuLi (about 1.6m hexanes so-
lution, 6.0 mmol) was added to a stirred, cooled (08C) solution of 2,2,6,6-
tetramethylpiperidine (1.0 mL, 6.0 mmol) in THF (5 mL). After the solu-
tion had been stirred for 15 min at 08C, CdCl2·TMEDA (0.60 g,
2.0 mmol) was added and the mixture was stirred for 15 min at this tem-
perature before introduction of the substrate (4.0 mmol). After the mix-
ture had been stirred for 2 h at room temperature, the heterocyclic bro-
General procedure for the deprotocadmation (using [(tmp)3CdLi])–trap-
ping of aromatics with RCOCl, ArSO2Cl, and ArCOCl: BuLi (about
1.6m hexanes solution, 6.0 mmol) was added to a stirred, cooled (08C) so-
lution of 2,2,6,6-tetramethylpiperidine (1.0 mL, 6.0 mmol) in THF
(5 mL). After the solution had been stirred for 15 min at 08C,
CdCl2·TMEDA (0.60 g, 2.0 mmol) was added and the mixture was stirred
for 15 min at this temperature before introduction of furan (0.29 mL,
4.0 mmol). After the mixture had been stirred for 2 h at room tempera-
ture, the electrophile (RCOCl, ArSO2Cl, or ArCOCl) (8.0 mmol) was
added at 08C. The mixture was stirred overnight at room temperature
before addition of an aqueous saturated brine solution (20 mL) and ex-
traction with Et2O (3ꢆ20 mL). The combined organic layers were
washed with brine (2ꢆ10 mL), dried over Na2SO4, filtered, and concen-
trated under reduced pressure before being purified by column chroma-
tography on silica gel.
Cyclohexyl furan-2-yl ketone (5v2): Colorless liquid; 1H NMR (CDCl3,
300 MHz): d=1.14–1.52 (m, 5H), 1.69 (m, 1H), 1.77–1.85 (m, 4H), 3.02
(tt, J=3.3, 12 Hz, 1H), 6.48 (dd, J=1.7, 3.6 Hz, 1H), 7.14 (dd, J=0.8,
3.6 Hz, 1H), 7.54 ppm (dd, J=0.8, 1.7 Hz, 1H); 13C NMR (CDCl3,
75 MHz): d=25.7 (2C), 25.8, 28.9 (2C), 46.3, 112.1, 117.0, 146.2, 152.3,
192.9 ppm. These data are consistent with the literature.[61]
mide (6.0 mmol), PdACHTUNGTRENNUNG(OAc)2 and dppf were added to the reaction mixture,
which was stirred for 18 h at reflux. The solution was cooled before addi-
tion of water (0.5 mL) and filtration over Celite. The mixture was dried
over MgSO4, filtered, concentrated under reduced pressure, and purified
by means of flash chromatography on silica gel.
1
Methyl 4-(furan-2-yl)benzoate (4v2): Orange solid; m.p. 1148C; H NMR
(CDCl3, 300 MHz): d=3.92 (s, 3H), 6.50 (dd, J=1.5, 3.4 Hz, 1H), 6.78
(brd, J=3.4 Hz, 1H), 7.51 (brd, J=1.5 Hz, 1H), 7.72 (d, J=8.7 Hz, 2H),
8.05 ppm (d, J=8.7 Hz, 2H); 13C NMR (CDCl3, 75 MHz): d=52.2, 107.4,
112.1, 123.5 (2C), 128.7, 130.2 (2C), 134.9, 143.3, 153.0, 166.9 ppm. These
data are consistent with the literature.[51]
2-(2-Methoxyphenyl)furan (4v3): Brown liquid; 1H NMR (CDCl3,
300 MHz): d=3.95 (s, 3H), 6.49 (dd, J=1.8, 3.3 Hz, 1H), 6.94–7.05 (m,
3H), 7.24 (m, 1H), 7.46 (dd, J=0.6, 1.7 Hz, 1H), 7.85 ppm (dd, J=1.7,
7.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=55.5, 109.9, 111.1, 111.7,
120.1, 120.9, 126.1, 128.1, 141.2, 150.4, 155.4 ppm. These data are consis-
tent with the literature.[52]
2-(3-Methoxyphenyl)furan (4v4): Brown liquid; 1H NMR (CDCl3,
300 MHz): d=3.72 (s, 3H), 6.34 (dd, J=1.8, 3.4 Hz, 1H), 6.53 (dd, J=
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F. Mongin, M. Uchiyama etal.
2-Pivaloylfuran (5v3): Colorless oil; 1H NMR (CDCl3, 300 MHz): d=
1.34 (s, 9H), 6.49 (dd, J=1.7, 3.6 Hz, 1H), 7.20 (dd, J=0.8, 3.6 Hz, 1H),
7.52 ppm (dd, J=0.8, 1.7 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=27.0
(3C), 43.0, 111.7, 118.0, 145.0, 152.5, 194.9 ppm. These data are consistent
with the literature.[62]
Methyl furan-2-carboxylate (5v4): Yellow liquid; 1H NMR (CDCl3,
300 MHz): d=3.87 (s, 3H), 6.48 (dd, J=1.8, 3.5 Hz, 1H), 7.15 (dd, J=
0.8, 3.5 Hz, 1H), 7.55 ppm (dd, J=0.8, 1.7 Hz, 1H); 13C NMR (CDCl3,
75 MHz): d=51.9, 111.8, 117.9, 144.6, 146.3, 159.1 ppm. These data are
consistent with the literature.[63]
2-[(4-Tolyl)sulfonyl]furan (5v5): Pale yellow solid; m.p. 1098C; 1H NMR
(CDCl3, 300 MHz): d=2.42 (s, 3H), 6.48 (dd, J=1.8, 3.5 Hz, 1H), 7.17
(dd, J=0.9, 3.5 Hz, 1H), 7.33 (dd, J=0.6, 8.6 Hz, 2H), 7.52 (dd, J=0.9,
1.8 Hz, 1H), 7.87 ppm (dd, J=1.8, 8.4 Hz, 2H); 13C NMR (CDCl3,
75 MHz): d=21.7, 77.3, 111.6, 117.0, 127.9 (2C), 130.0 (2C), 144.9, 147.3,
150.2 ppm. The spectroscopic data are consistent with the literature.[64]
179.1 ppm (2C). X-ray diffraction quality crystals of 5’v11 were obtained
from CHCl3.[65]
General procedure for the deprotometalation (using an in situ prepared
mixture of InCl3 and 4 equiv of LiACHTNUTRGNE(NUG TMP))–iodination of aromatics: BuLi
(about 1.6m hexanes solution, 5.3 mmol) was added to a stirred, cooled
(08C) solution of 2,2,6,6-tetramethylpiperidine (0.97 mL, 5.3 mmol) in
THF (2 mL). The solution was transferred at 08C to anhydrous InCl3
(0.30 g, 1.3 mmol) in THF (3 mL), and the mixture was stirred for 15 min
at this temperature before introduction of the substrate (4.0 mmol).
After the mixture had been stirred for 2 h at room temperature, a solu-
tion of I2 (1.3 g, 5.3 mmol) in THF (5 mL) was added. The mixture was
stirred overnight before addition of an aqueous saturated solution of
Na2S2O3 (5 mL) and extraction with Et2O (3ꢆ20 mL). The combined or-
ganic layers were dried over MgSO4, filtered, and concentrated under re-
duced pressure before being purified by means of column chromatogra-
phy on silica gel.
2-Chloro-5-[(4-tolyl)sulfonyl]furan (5’v5): Yellow solid; m.p. 89–928C;
1H NMR (CDCl3, 300 MHz): d=2.46 (s, 3H), 6.28 (d, J=3.6 Hz, 1H),
7.14 (d, J=3.6 Hz, 1H), 7.34 (dd, J=0.6, 8.6 Hz, 2H), 7.86 ppm (d, J=
8.3 Hz, 2H); 13C NMR (CDCl3, 75 MHz): d=21.7, 108.6, 119.0, 128.1
(2C), 130.1 (2C), 136.4, 142.3, 145.2, 149.2 ppm. X-ray diffraction quality
crystals of 5 f were obtained from CHCl3.[65]
ACHUTNERGN[NUG BuMACHTUNGTRNE(NUGN tmp)2Li]: BuLi (about 1.6m hexanes solution, 4.0 mmol) was
added to a stirred, cooled (08C) solution of 2,2,6,6-tetramethylpiperidine
(0.68 mL, 4.0 mmol) in THF (5 mL). After the solution had been stirred
for 15 min at 08C, MCl2·TMEDA (2.0 mmol) was added, and the mixture
was stirred for 15 min at this temperature before addition of BuLi
(2.0 mmol). After the mixture had been stirred for 15 min at 08C, the
substrate (4.0 mmol) was introduced. After the mixture had been stirred
for 2 h at room temperature, a solution of I2 (1.5 g, 6.0 mmol) in THF
(5 mL) was added. The mixture was stirred overnight before addition of
an aqueous saturated solution of Na2S2O3 (5 mL) and extraction with
CH2Cl2 (3ꢆ20 mL). The combined organic layers were washed with brine
(10 mL), dried over Na2SO4, filtered, and concentrated under reduced
pressure before being purified by means of column chromatography on
silica gel.
2-[(4-Chlorophenyl)sulfonyl]furan (5v6): Pale yellow solid; m.p. 1048C;
1H NMR (CDCl3, 300 MHz): d=6.51 (dd, J=1.8, 3.6 Hz, 1H), 7.21 (dd,
J=0.9, 3.6 Hz, 1H), 7.51 (dd, J=2.0, 8.8 Hz, 2H), 7.56 (dd, J=0.9,
1.8 Hz, 1H), 7.93 ppm (dd, J=2.0, 8.8 Hz, 2H); 13C NMR (CDCl3,
75 MHz): d=111.8, 117.7, 129.4 (2C), 129.7 (2C), 138.4, 140.5, 147.7,
149.5 ppm; HRMS (EI): m/z calcd for C10H735ClO3S: 241.9804; found:
241.9814.
2-Chloro-5-[(4-chlorophenyl)sulfonyl]furan (5’v6): Pale yellow solid; m.p.
124–1258C; 1H NMR (CDCl3, 300 MHz): d=6.32 (d, J=3.6 Hz, 1H),
7.19 (d, J=3.6 Hz, 1H), 7.53 (dd, J=2.0, 8.8 Hz, 2H), 7.93 ppm (dd, J=
2.0, 8.8 Hz, 2H); 13C NMR (CDCl3, 75 MHz): d=108.8, 119.7, 129.6
(2C), 129.8 (2C), 137.9, 140.9, 142.9, 148.5 ppm. X-ray diffraction quality
crystals of 5’f were obtained from CHCl3.[65]
Furan-2-yl 4-tolyl ketone (5v8): Orange solid; m.p. 708C; 1H NMR
(CDCl3, 300 MHz): d=2.42 (s, 3H), 6.58 (dd, J=1.8, 3.6 Hz, 1H), 7.22
(dd, J=0.6, 3.6 Hz, 1H), 7.28 (d, J=7.9 Hz, 2H), 7.69 (dd, J=0.6, 1.8 Hz,
1H), 7.87 ppm (d, J=7.9 Hz, 2H); 13C NMR (CDCl3, 75 MHz): d=21.7,
112.3, 120.2, 129.2 (2C), 129.6 (2C), 134.5, 143.6, 147.2, 152.3, 182.6 ppm.
These data are consistent with the literature.[66]
ACHUTNGERN[NUG Bu2MAHCTUNGTRENN(UGN tmp)Li]: BuLi (about 1.6m hexanes solution, 2.0 mmol) was
added to a stirred, cooled (08C) solution of 2,2,6,6-tetramethylpiperidine
(0.34 mL, 2.0 mmol) in THF (5 mL). After the solution had been stirred
for 15 min at 08C, MCl2·TMEDA (2.0 mmol) was added, and the mixture
was stirred for 15 min at this temperature before addition of BuLi
(4.0 mmol). After the mixture had been stirred for 15 min at 08C, the
substrate (4.0 mmol) was introduced. After the mixture had been stirred
for 2 h at room temperature, a solution of I2 (1.5 g, 6.0 mmol) in THF
(5 mL) was added. The mixture was stirred overnight before addition of
an aqueous saturated solution of Na2S2O3 (5 mL) and extraction with
CH2Cl2 (3ꢆ20 mL). The combined organic layers were washed with brine
(10 mL), dried over Na2SO4, filtered, and concentrated under reduced
pressure before being purified by means of column chromatography on
silica gel.
4-Chlorophenyl furan-2-yl ketone (5v9): Pale brown solid; m.p. 96–988C;
1H NMR (CDCl3, 300 MHz): d=6.57 (dd, J=1.7, 3.6 Hz, 1H), 7.22 (dd,
J=0.8, 3.6 Hz, 1H), 7.43 (d, J=8.8 Hz, 2H), 7.68 (dd, J=0.8, 1.7 Hz,
1H), 7.91 ppm (d, J=8.7 Hz, 2H); 13C NMR (CDCl3, 75 MHz): d=112.4,
120.6, 128.7 (2C), 130.8 (2C), 135.4, 139.0, 147.2, 152.1, 181.0 ppm. These
data are consistent with the literature.[62]
AHCTUNGTRENNG[UN Bu3MLi]: MCl2·TMEDA (2.0 mmol) was added to a stirred, cooled
(08C) solution of BuLi (about 1.6m hexanes solution, 6.0 mmol) in THF
(5 mL), and the mixture was stirred for 15 min at this temperature before
introduction of the substrate (4.0 mmol). After the mixture had been
stirred for 2 h at room temperature, a solution of I2 (1.5 g, 6.0 mmol) in
THF (5 mL) was added. The mixture was stirred overnight before addi-
tion of an aqueous saturated solution of Na2S2O3 (5 mL) and extraction
with CH2Cl2 (3ꢆ20 mL). The combined organic layers were washed with
brine (10 mL), dried over Na2SO4, filtered, and concentrated under re-
duced pressure before being purified by means of column chromatogra-
phy on silica gel.
3-Chlorophenyl furan-2-yl ketone (5v10): Pale yellow solid; m.p. <408C;
1H NMR (CDCl3, 300 MHz): d=6.61 (dd, J=1.7, 3.6 Hz, 1H), 7.27 (dd,
J=0.7, 3.6 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.55 (ddd, J=1.2, 2.1,
8.0 Hz, 1H), 7.70 (dd, J=0.8, 1.7 Hz, 1H), 7.86 (ddd, J=1.2, 1.5, 7.7 Hz,
1H), 7.95 ppm (t, J=1.7 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=112.4,
120.9, 127.4, 129.3, 129.8, 132.5, 134.6, 138.7, 147.4, 152.0, 180.9 ppm.
These data are consistent with the literature.[62]
3,5-Bis(trifluoromethyl)phenyl furan-2-yl ketone (5v11): Red oil;
1H NMR (CDCl3, 300 MHz): d=6.68 (dd, J=1.7, 3.6 Hz, 1H), 7.38 (dd,
J=0.8, 3.6 Hz, 1H), 7.77 (dd, J=0.8, 1.7 Hz, 1H), 8.09 (m, 1H),
8.47 ppm (dd, J=0.5, 1.0 Hz, 2H); 13C NMR (CDCl3, 75 MHz): d=113.0,
121.5, 122.9 (q, JF =273 Hz, 2C), 125.8 (septuplet, JF =4.0 Hz), 129.5 (m,
2C), 132.1 (q, JF =34 Hz, 2C), 138.5, 147.9, 151.7, 178.9 ppm; HRMS
(EI): m/z calcd for C13H6F6O2: 308.0272; found: 308.0261.
2-Iodoanisole (2a), 1-iodo-2,3-dimethoxybenzene (2b), 2-iodobenzothia-
zole (2c), 4-iodopyrimidine (2d), N,N-diethyl-2-iodobenzamide (2e),
methyl 2-iodobenzoate (2 f), 2-iodobenzonitrile (2g), 2-iodobenzophe-
none (2h), 4-bromo-2-iodoanisole (2i), 2,4-diiodoanisole (2j), methyl 4-
bromo-2-iodobenzoate (2k), 2-iodobenzo[b]thiophene (2l), 2-iodoben-
zo[b]furan (2m), 2-iodobenzoxazole (2n), N-Boc-2-iodopyrrole (2r), N-
Boc-2,5-diiodopyrrole (3r), 2,5-diiodothiazole (3s), 2,5-diiodothiophene
(3t), 2,5-diiodo-3,4-ethylenedioxythiophene (3u), 2-(4-methoxyphenyl)-
furan (4v1), and furan-2-yl phenyl ketone (5v7) have been previously de-
scribed.[15a]
BisACHTUNGTRENNUNG[3,5-bis(trifluoromethyl)phenyl]furan-2,5-diyl diketone (5’v11): Red
1
solid; m.p. 173–1748C; H NMR (CDCl3, 300 MHz): d=7.57 (s, 2H), 8.14
(m, 2H), 8.49 ppm (dd, J=1.5 Hz, 4H); 13C NMR (CDCl3, 75 MHz): d=
121.0 (2C), 122.7 (q, JF =273 Hz, 4C), 126.6 (septuplet, JF =3.6 Hz, 2C),
129.5 (m, 4C), 132.5 (q, JF =34 Hz, 4C), 137.3 (2C), 153.3 (2C),
10288
www.chemeurj.org
ꢄ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 10280 – 10290

Deprotonated Metalation of Functionalized Aromatics
FULL PAPER
Ababsa, F. Chevallier, A. Derdour, F. Mongin, Synthesis 2008,
4033–4035; c) G. Bentabed-Ababsa, F. Blanco, A. Derdour, F.
Mongin, F. Trꢁcourt, G. Quꢁguiner, R. Ballesteros, B. Abarca, J.
Org. Chem. 2009, 74, 163–169.
Acknowledgements
We gratefully acknowledge the financial support of Rꢁgion Bretagne (to
K.S. and J.M.L.), MESRS of Algeria (to G.B.A.), MESR of France (to
T.T.N.). We thank Mathieu Pucheault for helpful discussion.
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ACHTUNGTRNE(NUNG tmp)], see ref. [17a]; c) For the
alumination using [iBu3A(tmp)AlLi], see ref. [11a,e].
CTHUNGTRENNUNG
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[30] A similar result has previously been observed, even if to a lesser
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[33] The same yield had previously been obtained using the in situ pre-
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Received: May 28, 2009
Published online: August 17, 2009
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Chem. Eur. J. 2009, 15, 10280 – 10290