Deprotonative metalation of aromatic compounds by using an amino-based lithium cuprate

Article abstract of DOI:10.1002/chem.201100990

Deprotonative cupration of aromatic compounds by using amino-based lithium cuprates was optimized with 2,4-dimethoxypyrimidine and 2-methoxypyridine as the substrates and benzoyl chloride as the electrophile. [(tmp)₂CuLi] (+2 LiCl) (tmp=2,2,6,6-tetramethylpiperidino) was identified as the best reagent and its use was extended to anisole, 1,4-dimethoxybenzene, other substituted pyridines, furan, thiophene and derivatives, and N-Boc-indole (Boc=tert-butyloxycarbonyl). Of the electrophiles employed to attempt the interception of the generated aryl cuprates, aroyl chlorides, iodomethane, and diphenyl disulfide efficiently reacted. In addition, different oxidative agents were identified to afford symmetrical biaryls. Finally, palladium-catalyzed coupling with aryl halides was optimized and allowed the synthesis of different aryl derivatives in medium to good yields.

Full text of DOI:10.1002/chem.201100990

FULL PAPER
DOI: 10.1002/chem.201100990
Deprotonative Metalation of Aromatic Compounds by Using an Amino-
Based Lithium Cuprate
Tan Tai Nguyen, Nada Marquise, Floris Chevallier, and Florence Mongin*[a]
Abstract: Deprotonative cupration of
aromatic compounds by using amino-
based lithium cuprates was optimized
with 2,4-dimethoxypyrimidine and 2-
methoxypyridine as the substrates and
benzoyl chloride as the electrophile.
[(tmp)2CuLi] (+2LiCl) (tmp=2,2,6,6-
tetramethylpiperidino) was identified
as the best reagent and its use was ex-
tended to anisole, 1,4-dimethoxyben-
zene, other substituted pyridines, furan,
thiophene and derivatives, and N-Boc-
aryl cuprates, aroyl chlorides, iodome-
thane, and diphenyl disulfide efficiently
reacted. In addition, different oxidative
agents were identified to afford sym-
metrical biaryls. Finally, palladium-cat-
alyzed coupling with aryl halides was
optimized and allowed the synthesis of
different aryl derivatives in medium to
good yields.
indole
(Boc=tert-butyloxycarbonyl).
Of the electrophiles employed to at-
tempt the interception of the generated
Keywords: bimetallic
bases
·
copper · deprotonation · lithium ·
synthesis design
Introduction
mixed lithium–metal bases were prepared by treating three
equivalents of [Li(tmp)] with either ZnCl2·TMEDA
AHCTUNGTRENNUNG
Lithium bases have been largely employed to functionalize
aromatic compounds.[1] Nevertheless, one limit of the
method is the low compatibility of aryllithiums generated
with reactive functions and sensitive rings, which require
very low reaction temperatures or in situ electrophilic trap-
pings. By combining lithium compounds with soft organo-
metallics, more recently bases have been designed for the
deprotonation of sensitive compounds.[2] Reactions at higher
temperatures and metal-adjustable trapping are other ad-
vantages expected from these approaches.
Because of their unique behavior, cuprates have been the
subject of many studies in organic and organometallic
chemistry.[3] For a long time, the amino ligands of cuprates
were mainly considered as nontransferable groups and al-
lowed various applications.[4] In 2007, Wheatley and Uchiya-
ma and co-workers showed that it was possible to perform
deprotonative cupration of different aromatic compounds
by amino ligand transfer from a lithium cuprate.[5] Among
the different bases tested, the authors identified the Lip-
(TMEDA=N,N,N’,N’-tetramethylethylenediamine)
CdCl2·TMEDA.
or
To
obtain
a
similar
lithium–copper(I)
base,
[(tmp)2CuLi]+2LiCl,[8] we recently documented a protocol
using air-stable CuCl2·TMEDA.[9] For this purpose, the CuII
salt was reduced to CuI by using butyllithium (1 equiv) and
the base was obtained after the addition of two equivalents
of [LiACHTNUGRTNEUNG
(tmp)] to the copper(I) species.[10] The reactivity of
this lithium–copper(I) base toward various aromatic com-
pounds was studied and was good in some cases. Herein, the
details of our investigations into the choice of base and re-
AHCTUNGTREGaNNUN ction conditions are described. In addition, different kinds
of trapping for the aromatic cuprates are recorded.
Results and Discussion
To study the reactivity of this lithium–copper(I) base as a
deprotonating agent for aromatic compounds, it is important
to have at our disposal an electrophile efficient enough to
trap the arylmetal species generated. It is acknowledged
that cuprates can be trapped by acid chlorides to provide
ketones and we thus considered this possibility.[5a,11]
To optimize the reactions conditions, we first chose 2,4-di-
methoxypyrimidine (Table 1). This substrate can be consid-
ered as a moderately sensitive one: diazines are admittedly
renowned for their ability to undergo nucleophilic attack,[12]
but the presence of the methoxy groups reduces the p defi-
ciency of the ring. As a consequence, 2,4-dimethoxypyrimi-
dine can be metalated by using hindered lithium amides
either at 08C in diethyl ether[13] or at À758C in THF[14] with
complete regioselectivity for the position adjacent to the
methoxy group.
shutz-type compound [MeCuACHTNUTRGENNG(U tmp)(CN)Li2] (tmp=2,2,6,6-
tetramethylpiperidino) as the best reagent when two equiva-
lents were employed in THF at 08C.
We recently developed tmp-based lithium–zinc[6] and lithi-
um–cadmium[7] combinations for the deprotonative metala-
tion of sensitive aromatic compounds. For this purpose, the
[a] T. T. Nguyen, N. Marquise, Dr. F. Chevallier, Prof. F. Mongin
Chimie et Photonique Molꢀculaires, UMR 6510 CNRS
Universitꢀ de Rennes 1. Bꢁtiment 10A, Case 1003
Campus Scientifique de Beaulieu, 35042 Rennes Cedex (France)
Fax : (+33)2-2323-6955
E-mail: florence.mongin@univ-rennes1.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100990.
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10405

Table 1. Deprotocupration of 2,4-dimethoxypyrimidine followed by trapping with PhCOCl or ClC6H4COCl.
1a in 70% yield after reaction
for 3 h versus 57% yield after
reaction for 2 h (Table 1,
entry 5), and deprotonation at
room temperature afforded
ketone 1a in 47% yield after
1 h versus 60% yield after 2 h
(Table 1, entry 7). Under the
best reaction conditions, ketone
1c was prepared in 58% yield
(Table 1, entry 9).
Since solvent has an impor-
tant impact on the structure
and reactivity of organometal-
lics, the effect of different
media on the course of this re-
action was studied. THF was
first chosen because it was tra-
ditionally the solvent of choice
for metalation reactions. Never-
theless, examples in the litera-
ture have shown that hexane
Entry
R, R’
Solvent
Temperature
B
Product
(Yield [%])
A
ACHTUNGTRENNUNG
1
2
3
4
5
6
7
8
TMP, TMP
Bu, TMP
Me3SiCH2, TMP
Bu, Bu
TMP, TMP
TMP, TMP
TMP, TMP
TMP, TMP
TMP, TMP
TMP, TMP
TMP, TMP
TMP, TMP
THF
THF
THF
THF
THF
THF
THF
THF
RT
RT
RT
RT
408C
608C
RT
08C
408C
RT
608C
608C
608C
608C
608C
608C
RT
RT
RT
RT
RT
1a (45) or 1b (52)
1a (33, 29[a]
)
1a (10, 9[a]
)
[b]
–
1a (57, 70[c]
1a (52)
)
1a (60, 47[d]
1a (55)
)
9[e]
10
11
12
THF
1c (58[c]
)
HexH+TMEDA (5 equiv)
PhMe+TMEDA (5 equiv)
Et2O
1a (29, 37[f])
RT
RT
1a (63[g]
1a (99)
)
RT
[a] Yield obtained if temperature B=RT. [b] Degradation was observed. [c] Metalation for 3 h instead of 2 h.
[d] Metalation for 1 h instead of 2 h. [e] Base prepared from CuCl and [Li(tmp)] (2 equiv) in the presence of
AHCTUNGTRENNUNG
TMEDA (1 equiv). [f] Conducting the reaction in hexane. [g] 6-Benzoyl-2,4-dimethoxypyrimidine (1’a) was
also formed in an estimated yield of 6%.
containing TMEDA was
better solvent than THF for
performing metalation re-
ACHTUNGTRENNUNG
actions.[15] In our case, the reactions carried out in hexane,
a
The metalation ability of [(tmp)2CuLi] (+2 LiCl)
(1 equiv) was first compared with that of amino organocup-
or in hexane containing 5 equivalents of TMEDA,[6a] led to
lower conversions, giving 1a in 37 and 29% yield, respec-
tively, after trapping (Table 1, entry 10). Using toluene con-
taining 5 equivalents of TMEDA afforded the expected
ketone 1a in 63% yield, but regioisomer 1’a, which resulted
from metalation at the 6 position next to the nitrogen ring,
was competitively formed (estimated yield: 6%; Table 1,
entry 11). Diethyl ether, which is less coordinating than
THF and often employed as a solvent in reactions involving
cuprates, was similarly tested, and surprisingly afforded 1a
in 99% yield (Table 1, entry 12). The solvent can have an
impact on the aggregation state of the base and also on its
ability to exist as contacted ion pairs or solvent-separated
ion pairs.[16] Labile Lewis bases, such as ethers and TMEDA,
could help in breaking up the aggregates and make the base
more available for interactions with substrate heteroatoms,
thus facilitating the metalation reaction. Nevertheless, THF
(more basic than diethyl ether), is known to favor cuprates
as solvent-separated ion pairs, whereas cuprates as contacted
ion pairs, which are known to favor deprotometalation,[2]
predominate in diethyl ether.[16] Thus, it seems that the sol-
vent has to be basic enough to allow the disaggregation of
the base, but not too complexing to avoid solvent-separated
ion pairs.
rates [BuCuACHTUNGTRENNUNG(tmp)Li] (+2 LiCl) and [Me3SiCH2CuACHTUNTGREN(NUGN tmp)Li]
(+2 LiCl), and of diorganocuprate [Bu2CuLi] (+2 LiCl).[8] It
is clear from the deprotonation experiments performed in
THF at room temperature for 2 h that [(tmp)2CuLi]
ACHTUNGTRENNUNG(+2 LiCl) is the best base. Under these conditions, ketones
1a and 1b were isolated in 45 and 52% yield, after trapping
of the intermediate aryl cuprates with benzoyl and 4-chloro-
benzoyl chloride, respectively, at 608C (Table 1, entry 1).
Replacing one tmp ligand with a butyl or a (trimethylsilyl)-
methyl group resulted in lower yields, as previously noted
with the corresponding lithium–zinc[6] and lithium–cadmi-
um[7] combinations, and no improvement was observed
when conducting the trapping step at room temperature in-
stead of at reflux (Table 1, entries 2 and 3). Degradation re-
actions, which took place with amino organocuprate bases,
intensified with [Bu2CuLi] (+2 LiCl) and prevented isola-
tion of the desired product (Table 1, entry 4).
A careful study of the temperatures of both metalation
and the trapping steps was then undertaken. Yields of 45,
57, and 52% were obtained by performing the deprotona-
tion step at room temperature, 408C and 608C, respectively
(Table 1, entries 1, 5, and 6). These results indicate that the
best metalation temperature for 2,4-dimethoxypyrimidine is
40–608C. The quenching temperature also had an impact on
the yield. Indeed, after deprotonation at room temperature,
carrying out this step at 608C and room temperature led to
45 and 60% yield (55% if the deprotonation was performed
at 08C), respectively (Table 1, entries 1, 7, and 8). The
impact of the deprotonation times on the yields was also
noted, for example, deprotonation at 408C gave derivative
Nevertheless, one also has to consider LiCl, which is pres-
ent in the reaction medium (2 equiv). Wheatley and Uchiya-
ma and co-workers have shown that Lipshutz-type species,
including LiX (X=CN), were more efficient reagents than
the corresponding Gilman-type species.[5b] In our case, the
formation of Lipshutz-type species by LiX (X=Cl) inclusion
could be responsible for the good reactivity observed. The
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Deprotonative Metalation of Aromatic Compounds
FULL PAPER
moderate yield observed in hexane could in turn be related
with the lack of solubility of LiCl in hexane.
Carrying out the quenching step of the 3-metalated 2-me-
thoxypyridine at 608C instead of room temperature caused
a decrease in the yield (Table 2, entry 4), as previously ob-
served with 2,4-dimethoxypyrimidine, that could be due to a
low compatibility at this temperature between the unreacted
metal amide and the generated ketone. On the contrary,
when the trapping temperature was lowered to 08C, 3,6-di-
The reaction conditions were optimized by using 2,4-di-
methoxypyrimidine as a substrate. Depending on the sub-
stituents and the nature of the aromatic ring (presence or
absence of coordinating atoms, electron effects, etc.), these
conditions were more or less appropriate. We thus turned to
methoxypyridines to see if the results obtained with 2,4-di-
methoxypyrimidine could be extended to these substrates
(Table 2).
AHCTUNGTREGsNNNU ubstituted derivative 2’a was formed in 10% yield in addi-
tion to the expected ketone 2a. Compound 2’a could result
from metalation of 2a by unreacted amino ligands during
the trapping step (Table 2,
entry 5). Choosing reduced or
Table 2. Deprotocupration of methoxypyridines followed by trapping with PhCOCl or XC6H4COCl.
extended reaction times gave
lower yields (Table 2, entries 6
and 7). In the case of 2-
methoxyACHTNUTRGNEUNGpyridine, the use of di-
ethyl ether and toluene contain-
ing 5 equivalents of TMEDA
was less efficient than with 2,4-
dimethoxypyrimidine, giving 2a
in 71 and 49% yield, respec-
tively (Table 2, entries 8 and 9).
Dimethyl sulfide was some-
times used as cosolvent for re-
actions involving cuprates,[21]
therefore, the reaction was also
attempted with diethyl ether
containing 5 equivalents of di-
methyl sulfide, under the same
reaction conditions. Derivative
Entry
Substrate, R
Solvent
Time A [h]
Temperature B
Product (Yield [%])
1
2
2-OMe, H
2-OMe, OMe
2-OMe, OMe
2-OMe, H
2-OMe, H
2-OMe, H
2-OMe, H
2-OMe, H
2-OMe, H
2-OMe, H
2-OMe, H
2-OMe, H
2-OMe, H
4-OMe, H
THF
THF
THF
THF
THF
THF
THF
Et2O
2
2
2
2
2
0.5
6
2
2
2
0.5
2
2
2
RT
RT
RT
608C
08C
RT
RT
RT
RT
RT
RT
RT
RT
RT
2a (82, 40[a]
2b (60)
)
3[b]
4
2c (91)
2a (66)
5
6
7
8
2a (66[c]
2a (72)
)
2a (62[d]
2a (71)
2a (49)
)
9
PhMe+TMEDA (5 equiv)
Et2O+Me2S (5 equiv)
Et2O+Me2S (5 equiv)
Et2O
THF
THF
10
11
12[f]
13[f]
14
2a (81, 77[e]
)
2a (52[d]
2a (54)
2a (33)
2d (57)
)
2a was obtained in
a yield
(81%) similar to that obtained
in THF. As already observed in
[a] Using 0.5 equiv of base. [b] The base was prepared from CuCl and [LiACTHNUGTRNEUNG(tmp)] (2 equiv) in the presence of
THF, the conversion was less
complete with shorter reaction
times (Table 2, entries 10 and
TMEDA (1 equiv). [c] The 3,6-disubstituted derivative 2’a was also formed in 10% yield. [d] The 3,6-disubsti-
tuted derivative 2’a was also formed in 5% yield. [e] Metalation for 1 h instead of 2 h. [f] The base was pre-
pared from [CuBrACHTUNGTRENNUNG(Me2S)] and [LiAHCTUNGTRNEN(UGN tmp)] (2 equiv).
11).
The positive impact of di-
2-Methoxypyridine is amenable to lithiation at the 3-posi-
tion using either organolithium compounds containing a cat-
alytic amount of diisopropylamine in THF at 08C[17] or mesi-
tyllithium in THF at 08C.[18] Concerning 2,6-dimethoxypyri-
dine, butyllithium has been employed in THF at À408C.[19]
In contrast, metalation of 2-methoxypyridine occurs at C6
methyl sulfide on the course of the reaction led us to consid-
er [CuBr
methoxypyridine was treated at room temperature with a
base prepared in situ from [CuBr(Me2S)] and 2 equivalents
of [Li(tmp)] for 2 h before trapping with benzoyl chloride.
ACHTUNGTRENUN(GN Me2S)] as a copper(I) source. For this purpose, 2-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Diethyl ether and THF were tested as solvents: the former
was the best (54% yield instead of 33% with the latter,
Table 2, entries 12 and 13), but the method with
CuCl2·TMEDA remained superior.
upon treatment with BuLi–[Li
dimethyl
aminoethoxide).[20]
Treatment of 2-methoxypyridine with [(tmp)2CuLi]
ACHTUNGTREN(NGNU dmae)] (DMAE=2-
ACHTUNGTRENNUNG
A
The best conditions were finally applied to the conversion
of 4-methoxypyridine into the ketone 2d, albeit in a more
modest yield of 57% (Table 2, entry 14).
2-Fluoro-, 2-chloro-, and 2-bromopyridine were compared
with 2-methoxypyridine with regards to their behavior
toward [(tmp)2CuLi] (+2 LiCl) (1 equiv) in THF at room
temperature (Table 3). Whereas 2-fluoro- and 2-chloropyri-
dine afforded the expected benzoyl derivatives 3a and 4a in
high yields, similar to that obtained for 2-methoxypyridine,
a low 20% yield of 5a was noted for 2-bromopyridine. At-
to
a
42% drop in the yield (Table 2, entry 1). 2,6-
pyridine was similarly converted into ketones 2b
Dimethoxy
ACHTUNGTRENNUNG
and 2c, using 4-(trifluoromethyl)benzoyl chloride and 2-
chlorobenzoyl chloride, respectively, as the electrophiles
(Table 2, entries 2 and 3).
Chem. Eur. J. 2011, 17, 10405 – 10416
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10407

F. Mongin et al.
Table 3. Deprotocupration of 2-fluoro-, 2-chloro-, and 2-bromopyridine
followed by trapping with an aroyl chloride.
Table 4. Deprotocupration of anisole and 1,4-dimethoxybenzene fol-
lowed by electrophilic trapping.
Entry
R
Electrophile (E)
Product
(Yield [%])
Entry
X
Product
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
1
2
3
F
Cl
Br
)
1
2
OMe
OMe
PhCOCl (PhCO)
4-ClC6H4COCl (4-ClC6H4CO)
6a (68[a]
6b (57)
)
4a (83)
5a (20)
4
5
F
F
3b: 2-Cl (76)
3c: 4-Cl (83)
3
OMe
6c (54[b]
)
4
5
6
OMe
H
OMe
I2 (I)
I2 (I)
6d (19)
7d (20)
6e (41)
CH2=CHCH2Br (CH2=CHCH2)
6
7
F
F
3d (92)
3e (72)
[a] A more complex reaction mixture was formed when using more than
one equivalent of base. [b] By performing the deprotonation step at
408C.
these derivatives were not observed when using aroyl chlor-
ides, water, or allyl bromide as electrophiles. The 2-allylated
compound 6e was synthesized from 1,4-dimethoxybenzene
in 41% yield (Table 4, entry 6).
[a] Degradation occurs if the metalation step is performed at 408C.
tempts to perform the reaction at 08C or using diethyl ether
as the solvent did not result in any improvement (Table 3,
entries 1–3). Such a problem could be related to the instabil-
ity of 2-bromopyridine with a metal at C3.[22]
We then used five-membered heterocycles in the reaction
with [(tmp)2CuLi] (+2 LiCl). Upon treatment with 1 equiva-
lent of base at room temperature in THF for 2 h, followed
by subsequent interception with benzoyl and 4-chlorobenzo-
yl chloride at 608C, thiophene was converted into the corre-
sponding ketones 8a and 8b (Table 5, entries 1 and 2). Com-
pounds 9 and 10 were similarly prepared starting from furan
and N-Boc indole (Table 5, entries 3 and 4). When diethyl
ether was employed in the presence or absence of dimethyl
sulfide instead of THF, 2-monosubstituted thiophene 8a was
also formed after trapping with benzoyl chloride at room
temperature, together with the 2,5-disubstituted thiophene
8’a (Table 5, entries 5 and 6).
Ethyl thiophene-2-carboxylate was regioselectively depro-
tonated next to sulfur to give, after subsequent trapping at
room temperature with benzoyl chloride or iodine, function-
alized derivatives 11a and 11b in moderate to medium
yields (Table 5, entries 7 and 8). Turning to ethyl thiophene-
3-carboxylate, the reaction was more difficult at room tem-
perature; by lowering the deprotonation temperature to
08C, an improved yield of 40% of 12 resulted after intercep-
tion with benzoyl chloride at room temperature (Table 5,
entry 9).
Similar to alkynyl, cyano, and methyl groups, 2-thienyl is,
in general, considered to be a nontransferable or “dummy”
ligand of cuprates. This could partly explain the moderate
yields obtained upon reaction of such substrates.
The trapping step of the different heteroaryl cuprates was
then studied (Table 6). From 2,4-dimethoxypyrimidine, the
expected methylated and allylated derivatives 13a and 13b
were isolated in low to good yields (Table 6, entries 1 and
2). Using nitrobenzene as an oxidant resulted in homocou-
pled pyrimidine 13’ (Table 6, entry 3).
Starting from 2-fluoropyridine, the method was extended
to the synthesis of ketones 3b–e using electrophiles 2- and
4-chlorobenzoyl chloride, 4-(trifluoromethyl)benzoyl chlo-
ride, and 6-chloronicotinoyl chloride (Table 3, entries 4–7).
Attempts to deprotometalate ketone 4a were unsuccessful.
Pyridin-2-yl and -4-yl cuprates have previously been re-
ported.[23] However, the metalation of different 3-substituted
(methoxy, fluoro, chloro) pyridines was not successful, re-
gardless of the conditions used. Precomplexing the 3-substi-
tuted pyridine with BF3·Et2O before the deprotonation
step[24] did not result in isolation of an aryl ketone.
To evaluate the scope of the reaction, we turned to ani-
sole, which has been the subject of many studies concerning
deprotometalation,[1–,2d] and the 4-methoxy derivative
(Table 4). These substrates do not have a complexing nitro-
gen and have less acidic hydrogen atoms. Upon treatment
with 1 equivalent of [(tmp)2CuLi] (+2 LiCl) in THF at room
temperature for 2 h and subsequent trapping with different
aroyl chlorides, the expected ketones 6a–c were obtained in
54–68% yield (Table 4, entries 1–3).
The reaction with elemental iodine instead of an aroyl
chloride to trap the metalated species resulting from 1,4-di-
methoxybenzene and anisole proceeded in low yields (com-
pounds 6d and 7d were isolated in 19–20% yield; Table 4,
entries 4 and 5). Starting from anisole, concomitant forma-
tion of 2,2’-dimethoxybiphenyl and N-(2-methoxyphenyl)-
2,2,6,6-tetramethylpiperidine was observed, probably
through reactions occurring during the trapping step with
iodine, which can behave as an oxidative agent.[25] Indeed,
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Chem. Eur. J. 2011, 17, 10405 – 10416

Deprotonative Metalation of Aromatic Compounds
FULL PAPER
Table 5. Deprotocupration of thiophene derivatives and furan followed by electrophilic trapping.
entry 4). When 2-phenyloxirane
was employed, two regioisomer-
ic alcohols resulting from attack
at the less (14b) and more
(14b’) hindered position of the
epoxide were formed in 22 and
Entry
Substrate
Solvent
Electrophile (E), T [8C]
Product (Yield [%])
12%
yield,
respectively
1
2
THF
THF
PhCOCl (PhCO), 60
4-ClC6H4COCl (4-ClC6H4CO), 60
8a (48)
8b (58)
(Table 6, entry 5), and no im-
provement was observed in the
presence of BF3·Et2O. In con-
trast, diphenyl disulfide effi-
ciently trapped pyridyl cuprate
to afford sulfide 14c (67%
yield, Table 6, entry 6).
Dimethylsulfamoyl chloride,
4-chlorobenzenesulfonyl chlo-
ride, and tetramethylthiuram
disulfide did not behave as elec-
trophiles, but as oxidative
agents, leading to homocoupled
pyridine 14’. Diarylsulfone 14d
was the only trapping product
detected, but isolated in a negli-
gible yield of 3% (Table 6,
3
4
THF
THF
PhCOCl (PhCO), 60
PhCOCl (PhCO), 60
9 (53)
10 (50[a]
)
5
6
Et2O+Me2S (5 equiv)
Et2O
PhCOCl (PhCO), RT
PhCOCl (PhCO), RT
8a (53), 8’a (18)
8a (31), 8ꢀa (29)
7
8
THF
THF
PhCOCl (PhCO), RT
I2 (I), RT
11a (49)
11b (23)
9
THF
PhCOCl (PhCO), RT
12 (26, 40[b]
)
[a] After removal of the tert-butyloxycarbonyl (Boc) group with trifluoroacetic acid (TFA) in CH2Cl2 at RT.[26]
[b] Performing the metalation step at 08C instead of RT.
From 2-methoxypyridine, the expected 3-iodo derivative
14a was isolated in a moderate yield of 28% due to the
major formation of the coupled product 14’ (Table 6,
entry 7–9). Reactions involving conjugate addition were pos-
sible by using ethyl phenylpropiolate, ethyl pentylpropiolate,
or methyl methylpropiolate as the electrophiles at room
Table 6. Deprotocupration of aromatic compounds followed by different electrophilic trapping or oxidation.
À
Ar H
Entry
Electrophile (E) or oxidative agent, T [8C]
Product (Yield [%])
1
2
3
MeI (Me), 30C
CH2=CHCH2Br (CH2=CHCH2), RT
PhNO2, RT
13a (62)
13b (19)
13ꢀ (22)
14’ (39)
4
I2 (I), RT
14a (28)
5
6
2-phenyloxirane (PhCH(OH)CH2 or HOCH2CH(Ph)), RT
ACHTUNGRTEN(NUNG PhS)2 (PhS), RT
14b (22) 14bꢀ (12)
14c (67)
7
8
9
10
11
12
Me2NSO2Cl, RT
4-ClC6H4SO2Cl (4-ClC6H4SO2), RT
ACHTUGNTREN[UNNG Me2NC(S)S]2, RT
14ꢀ (72)
14ꢀ (58)
14ꢀ (88)
14d (3)
PhC CCO2Et [(Z)-C(Ph)=CHCO2Et], RT
14e (39[a]
14 f (26)
(Z)-14g (30) (E)-14gꢀ (17)
)
ꢀ
ꢀ
PeC CCO2Et [(E)-C(Pe)=CHCO2Et], RT
ꢀ
MeC CCO2Me [(Z/E)-C(Me)=CHCO2Me], RT
13
14
15
16
I2 (I), RT
15 (31)
15’ (5[b]
)
Me3SiCl, 50
PhNO2, RT
chloranil, 60
15ꢀ (52)
15ꢀ (84, 73[c]
)
)
15ꢀ (94, 58[d]
17[e]
PhNO2, RT
16’ (10)
[a] The E isomer 14e’ was also identified in the crude (estimated yield: 10%). [b] Yield estimated from the crude mixture. [c] By using the oxidative
agent at 608C. [d] By using the oxidative agent at RT. [e] By using two equivalents of base.
Chem. Eur. J. 2011, 17, 10405 – 10416
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10409

F. Mongin et al.
temperature to afford 14e–g in moderate yields ranging
from 26 to 39% (Table 6, entries 10–12).[27]
mained moderate (Table 7, entry 1), but with dppf, it could
be improved to 64% (Table 7, entry 2); a yield that was in-
termediate between those obtained after trapping with ben-
zoyl chloride using 0.5 (40) and 1 equivalent (82%) of base
(Table 2, entry 1).
As observed with 2-methoxypyridine, the conversion of 2-
fluoropyridine into the corresponding 3-iodo derivative 14
proceeded in a moderate yield (Table 6, entry 13). The
dimer yield progressively increased when using iodine, tri-
methylsilyl chloride, nitrobenzene, and chloranil[28] as oxida-
tive agents. Whereas nitrobenzene gave the best yield at
room temperature, chloranil was more successfully em-
ployed at 608C (Table 6, entry 14–16). To perform an intra-
molecular double-deprotonation–cyclization, we treated 1,1’-
(1,2-phenylene)bis(1H-pyrazole) with 2 equivalents of
[(tmp)2CuLi] (+2 LiCl) in THF at room temperature for 2 h
before subsequent treatment with nitrobenzene. Under
these conditions, the expected cyclized derivative was isolat-
ed, albeit in a low yield of 10% (Table 6, entry 17).
It was then decided to evaluate the involvement of the
generated aryl cuprates in palladium-catalyzed cross-cou-
pling reactions. Because this possibility has not been devel-
oped to synthesize biaryl compounds, we first chose to test
the efficiency of different catalyst systems using 2-methoxy-
pyridine as the cuprate precursor and 4-iodoanisole as the
aryl halide (Table 7).
The formation of 14’ was observed in 9 and 12% yield, re-
spectively, using [PdCl
2ACHTUNGTERN(NUNG PPh3)2] without additional ligand
and [Pd(PPh3)4] (Table 7, entries 3 and 4). Palladium(II)
AHCTUNGTRENNUNG
acetate, for which mixtures with tertiary phosphines are
known to spontaneously generate palladium(0) com-
plexes,[29] was also tested as a precatalyst, combined with
dppf, but a lower yield of 43% was recorded (Table 7,
entry 5). Finally, [Pd
same bidentate ligand gave a yield comparable with that ob-
tained with [PdCl2A(PPh3)2] (Table 7, entry 6) discarding a
ACHTUNGRTEN(NUNG dba)2] as a palladium source with the
CTHUNGTRENNUNG
possible inefficient reduction of palladium(II) chloride.
With these optimized conditions in hand, different experi-
ments were conducted to evaluate the scope of this reaction
(Table 8). Starting from 2-methoxypyridine, 4-bromoanisole
Table 8. Deprotocupration of aromatic compounds followed by palladi-
um-catalyzed cross-coupling.
The first reactions of our optimization study were carried
Table 7. Optimization of the palladium-catalyzed cross-coupling reaction
of 3-metalated 2-methoxypyridine and 4-iodoanisole.
À
Ar H
À
Ar’ X
Entry
Product
(Yield [%])
AHCTUNGTRENNUNG
1
2
3
4
5
4-IC6H4OMe
4-BrC6H4OMe
4-BrC6H4F
4-BrC6H4CO2Et
2-BrPy
17a (64)
17a (46)
17b (47)
17c (64)
17d (63)
Entry
x
Catalyst[a]
Yield
[%]
equiv
6
7
4-IC6H4OMe
2-BrPy
18a (51)
18b (54)
1
2
3
4
5
6
1 (0.5)
1 (0.5)
0.5
0.5
0.5
N
(PPh3)2] (2 mol%), PPh3 (4 mol%)
40 (37)
23[b] (64)
47[c]
G
42[d]
8
9
4-IC6H4OMe
2-BrPy
19a (39[a]
)
G
43
57
19b (36[a]
)
0.5
E
10
11
4-IC6H4OMe
2-BrPy
20a (42, 46[a]
20b (44)
)
[a] dppf=1,1’-bis(diphenylphosphino)ferrocene, dba=dibenzylideneace-
tone. [b] Compound 17a’ was also isolated in 8% yield. [c] Dimer 14’ was
also isolated in 9% yield. [d] Dimer 14’ was also isolated in 12% yield.
[a] The metalation step was performed at 408C.
out after deprotocupration using one equivalent of base and
employing catalytic amounts of [PdCl
(PPh3)2] combined
was used under the conditions employed in Table 7, entry 2,
with 0.5 equivalent of base. Biaryl derivative 17a was isolat-
ed in 46% yield, versus 64% yield when employing 4-iodo-
either with triphenylphosphine (Table 7, entry 1) or with
dppf (Table 7, entry 2), at the reflux temperature of THF. A
moderate yield of 40% of the expected product 17a was ob-
tained with triphenylphosphine; in the presence of the bi-
dentate ligand, the expected coupling product 17a was pro-
duced in a low yield of 23%, partly due to the concomitant
formation of 17a’. It appeared to us that the latter was
formed by metalation of 17a during the trapping step fol-
lowed by cross-coupling, as a result of the excess base used
in the metalation step. This led us to explore the use of
0.5 equivalent of base. With triphenylphosphine the yield re-
AHCTUNGTREGaNNNU nisole (Table 8, entries 1 and 2). Biaryl 17b was similarly
prepared in 47% yield by employing 1-bromo-4-fluoroben-
zene (Table 8, entry 3). Electron-deficient aryl bromides,
such as ethyl 4-bromobenzoate and 2-bromopyridine, were
coupled with 3-metalated 2-methoxypyridine in higher
yields; a result that could be explained by a mechanism in-
volving an addition–elimination step instead of classical oxi-
dative addition.[30] Biaryls 17c and 17d were thus obtained
in satisfying yields of 64 and 63%, respectively (Table 8, en-
10410
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ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 10405 – 10416

Deprotonative Metalation of Aromatic Compounds
FULL PAPER
reduced pressure before purification by column chromatography on silica
gel (the eluent is given in the product description). When I2 was used as
the electrophile, the mixture was treated by an aqueous saturated solu-
tion of Na2S2O3 (5 mL) before extraction.
tries 4 and 5). 2,6-Dibromopyridine was converted into 3-(4-
anisyl) and -(pyridin-2-yl) derivatives 18a and 18b in 51 and
54%, respectively (Table 8, entries 6 and 7). Due to the
lower acidity or higher sensitivity to nucleophiles, respec-
tively, 1,4-dimethoxybenzene and 2,4-dimethoxypyrimidine
were similarly reacted to afford the corresponding coupling
products 19a and 19b (Table 8, entries 8 and 9) and 20a and
20b (Table 8, entries 10 and 11).
2,4-Dimethoxypyrimidin-5-yl phenyl ketone (1a):[10] Eluent: heptane/
1
EtOAc (80:20); yellow oil; H NMR (CDCl3, 300 MHz): d=3.95 (s, 3H),
4.07 (s, 3H), 7.42–7.49 (m, 2H), 7.58 (tt, J=7.3, 1.3 Hz, 1H), 7.74–7.78
(m, 2H), 8.46 ppm (brs, 1H); 13C NMR (CDCl3, 75 MHz): d=54.5
(CH3), 55.5 (CH3), 114.5 (C), 128.5 (2 CH), 129.7 (2 CH), 133.3 (CH),
137.6 (C), 161.2 (CH), 166.3 (C), 169.3 (C), 192.2 ppm (C=O); HRMS
(ESI): m/z calcd for C13H13N2O3: 245.0926 [M+H]+, C13H12N2NaO3:
267.0746 [M+Na]+; found: 245.0929, 267.0746.
4-Chlorophenyl 2,4-dimethoxypyrimidin-5-yl ketone (1b):[10] Eluent: hep-
tane/EtOAc (80:20); yellow powder; m.p. 145–1468C; 1H NMR (CDCl3,
300 MHz): d=3.96 (s, 3H), 4.08 (s, 3H), 7.41–7.46 (m, 2H), 7.68–7.73 (m,
2H), 8.48 ppm (s, 1H); 13C NMR (CDCl3, 75 MHz): d=54.5 (CH3), 55.5
(CH3), 114.1 (C), 128.8 (2 CH), 130.9 (2 CH), 136.0 (C), 139.7 (C), 161.3
(CH), 166.5 (C), 169.1 (C), 190.9 ppm (C=O); HRMS (ESI): m/z calcd
for C13H1235ClN2O3: 279.05365 [M+H]+, 301.0356 [M+Na]+; found:
279.0546, 301.0354.
Conclusion
We have examined the possible use of amino-based lithium
cuprates for the deprotometalation of aromatic compounds.
As previously observed with lithium–zinc,[6e] lithium–cad-
mium,[7g] and lithium–cobalt combinations,[31] the best base
was the “all-tmp” one. In most cases, the reaction could be
performed at room temperature in THF with one equivalent
of base.
One limitation concerning the interception step of the
generated aryl cuprates with electrophiles is their easy oxi-
dation, leading to symmetrical biaryl compounds. Neverthe-
less, successful methylation, aroylation, sulfanylation, and
palladium-catalyzed coupling reactions were recorded. The
scope of the method could be considerably extended with
addition reactions to activated alkenes and alkynes; current-
ly, this possibility only led to modest yields using activated
alkynes to trap the aryl cuprates.
2-Chlorophenyl 2,4-dimethoxypyrimidin-5-yl ketone (1c): Eluent: hep-
tane/EtOAc (80:20); orange powder; m.p. 748C; 1H NMR (CDCl3,
300 MHz): d=3.91 (s, 3H), 4.06 (s, 3H), 7.31–7.44 (m, 4H), 8.62 ppm
(brs, 1H); 13C NMR (CDCl3, 75 MHz): d=54.7 (CH3), 55.7 (CH3), 114.1
(C), 127.0 (CH), 129.4 (CH), 129.9 (CH), 131.3 (C), 131.6 (CH), 139.4
(C), 163.4 (CH), 167.0 (C), 169.6 (C), 190.8 ppm (C=O); HRMS (ESI):
m/z calcd for C13H1135ClN2NaO3: 301.0356 [M+Na]+; found: 301.0356.
2-Methoxypyridin-3-yl phenyl ketone (2a): Eluent: heptane/EtOAc
(80:20); yellow powder; m.p. 85–868C (lit.[24b] 80.2–81.58C); 1H NMR
(CDCl3, 300 MHz): d=3.88 (s, 3H), 7.01 (dd, J=7.3, 5.0 Hz, 1H), 7.43–
7.48 (m, 2H), 7.59 (tt, J=7.3, 1.3 Hz, 1H), 7.72 (dd, J=7.3, 2.0 Hz, 1H),
7.78–7.81 ppm (m, 2H), 8.32 (dd, J=5.0, 1.9 Hz, 1H); 13C NMR (CDCl3,
75 MHz): d=53.8 (CH3), 116.6 (CH), 122.7 (C), 128.5 (2 CH), 129.9 (2
CH), 133.5 (CH), 137.2 (C), 139.0 (CH), 149.4 (CH), 161.3 (C),
194.9 ppm (C=O). These data are consistent with that reported in the lit-
erature.[24b]
The use of ever-efficient lithium–metal combinations,
which allow other kinds of functionalization, is currently
under investigation.
Diphenyl 2-methoxypyridine-3,6-diyl diketone (2’a): Eluent: heptane/
1
EtOAc (80:20); brown oil; H NMR (CDCl3, 300 MHz): d=3.87 (s, 3H),
7.43–7.53 (m, 4H), 7.57–7.65 (m, 2H), 7.75 (d, 1H, J=7.5 Hz), 7.79–7.85
(m, 2H), 7.88 (d, 1H, J=7.5 Hz), 8.14–8.19 ppm (m, 2H); 13C NMR
(CDCl3, 75 MHz): d=54.2 (CH3), 117.6 (CH), 125.4 (C), 128.2 (2 CH);
128.7 (2 CH), 129.9 (2 CH), 131.1 (2 CH), 133.1 (CH), 133.9 (CH), 136.3
(C), 136.7 (C), 139.6 (CH), 154.0 (C), 160.1 (C), 192.6 (C=O), 194.2 ppm
(C=O); HRMS (ESI): m/z calcd for C20H15NNaO3: 340.0950 [M+Na]+;
found: 340.0949.
Experimental Section
General: All reactions were performed in Schlenk tubes under an argon
atmosphere. THF was distilled over sodium/benzophenone. NMR spectra
were acquired on Bruker AC-300 spectrometer (300 and 75 MHz for 1H
and 13C, respectively) or Bruker Avance I500 spectrometers (500 and
125 MHz for 1H and 13C, respectively). High-resolution mass spectra
measurements were performed at the CRMPO in Rennes (Centre Rꢀ-
gional de Mesures Physiques de lꢃOuest) using a Waters Q-TOF 2 instru-
ment. Liquid chromatography separations were achieved on silica gel
Merck Geduran Si 60 (40–63 mesh). CuCl2·TMEDA was prepared ac-
cording to a described procedure.[9b]
2,6-Dimethoxypyridin-3-yl 4-(trifluoromethyl)phenyl ketone (2b):
1
Eluent: heptane/EtOAc (90:10); yellow oil; H NMR (CDCl3, 300 MHz):
d=3.84 (s, 3H), 3.99 (s, 3H), 6.41 (d, J=8.3 Hz, 1H), 7.68 (d, J=8.1 Hz,
2H), 7.81 (d, J=8.1 Hz, 2H), 7.83 ppm (d, J=8.3 Hz, 1H); 13C NMR
(CDCl3, 75 MHz): d=53.7 (CH3), 54.1 (CH3), 102.4 (CH), 112.8 (C),
123.9 (q, C,
J
N
JACTHNGUTERN(UNG C,F)=4 Hz), 129.6
(2CH), 133.5 (q, C, JAHCTUNGTRENNUNG
165.7 (C), 193.3 ppm (C=O); HRMS (ESI): m/z calcd for C15H13F3NO3:
312.0847 [M+H]+, 334.0667 [M+Na]+; found: 312.0846, 334.0670.
2-Iodo-1,4-dimethoxybenzene (6d),[31] 2-iodoanisole (7d),[7a] 3-iodo-2-me-
thoxypyridine (14a),[31] 2,2’-dimethoxy-3,3’-bipyridine (14’),[31] and 2-
fluoro-3-iodopyridine (15),[6e] have previously been described.
2-Chlorophenyl 2,6-dimethoxypyridin-3-yl ketone (2c): Eluent: heptane/
EtOAc (90:10); yellow powder; m.p. 558C; 1H NMR (CDCl3, 300 MHz):
d=3.81 (s, 3H), 3.98 (s, 3H), 6.37 (d, J=8.4 Hz, 1H), 7.31–7.37 (m, 4H),
7.98 ppm (d, 1H, J=8.4 Hz); 13C NMR (CDCl3, 75 MHz): d=54.0 (CH3),
54.2 (CH3), 102.7 (CH), 113.1 (C), 126.8 (CH), 128.7 (CH), 129.6 (CH),
130.6 (CH), 130.9 (C), 141.1 (C), 144.1 (CH), 163.0 (C), 166.3 (C),
192.1 ppm (C=O); HRMS (ESI): m/z calcd for C14H1235ClNNaO3:
300.0403 [M+Na]+; found: 300.0403.
General procedure for the deprotocupration: Electrophilic trapping of ar-
omatic compounds: BuLi (about 1.6m hexanes solution, 2.0 mmol) was
successively added to
CuCl2·TMEDA (0.5 g, 2.0 mmol) in THF (5 mL) then 15 min later, a so-
lution of [Li(tmp)] prepared in THF (2 mL) at 08C from 2,2,6,6-tetrame-
a
stirred, cooled (08C) suspension of
ACHTUNGTRENNUNG
thylpiperidine (0.68 mL, 4.0 mmol) and BuLi (about 1.6m hexanes solu-
tion, 4.0 mmol) was also added. The mixture was stirred for 15 min at
this temperature before the introduction of the substrate (2.0 mmol).
After the required reaction time at the required temperature, the electro-
phile (4.0 mmol) was added at 08C. The mixture was stirred for 16 h at
the required temperature before the addition of brine (5 mL) and extrac-
tion with Et2O (3ꢄ10 mL). The combined organic layers were washed
with brine (10 mL), dried over Na2SO4, filtered, and concentrated under
2-Chlorophenyl 4-methoxypyridin-3-yl ketone (2d): Eluent: heptane/
EtOAc (20:80); yellow powder; m.p. 1078C; 1H NMR (C6D6, 500 MHz):
d=2.96 (s, 3H), 6.26 (brs, 1H), 6.83 (m, 2H), 7.05 (m, 1H), 7.25 (m,
1H), 8.87 (brs, 1H), 9.44 ppm (brs, 1H); 13C NMR (C6D6, 125 MHz): d=
55.0 (CH3), 108.8 (C), 126.7 (CH), 128.3 (CH), 130.1 (CH), 130.1 (CH),
Chem. Eur. J. 2011, 17, 10405 – 10416
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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10411

F. Mongin et al.
131.3 (CH), 132.1 (C), 140.8 (C), 152.7 (CH), 154.5 (CH), 164.1 (C),
192.3 ppm (C=O); HRMS (ESI): m/z calcd for C13H1135ClNO2: 248.0478
[M+H]+, 270.0298 [M+Na]+; found: 248.0478, 270.0298.
ACHTUNGTRENNUNG
2,5-Dimethoxyphenyl phenyl ketone (6a): Eluent: heptane/EtOAc
(90:10); 1H NMR (CDCl3, 300 MHz): d=3.66 (s, 3H), 3.78 (s, 3H), 6.92
(d, J=9.0 Hz, 1H), 6.92 (d, J=3.0 Hz, 1H), 7.01 (dd, J=9.0, 3.0 Hz, 1H),
7.39–7.47 (m, 2H), 7.55 (tt, J=7.3, 1.3 Hz, 1H), 7.79–7.85 ppm (m, 2H).
These data are consistent with those reported in the literature:[36] yellow
oil; 13C NMR (CDCl3, 75 MHz): d=55.8 (CH3), 56.2 (CH3), 112.9 (CH),
114.3 (CH), 117.2 (CH), 128.2 (2 CH), 129.4 (C), 129.8 (2 CH), 133.0
(CH), 137.5 (C), 151.4 (C), 153.4 (C), 196.1 ppm (C=O)
2-Fluoropyridin-3-yl phenyl ketone (3a): Eluent: heptane/EtOAc
(80:20); 1H NMR (CDCl3, 300 MHz): d=7.36 (ddd, J=7.4, 4.9, 1.9 Hz,
1H), 7.45–7.54 (m, 2H), 7.64 (tt, J=7.4, 1.9 Hz, 1H), 7.78–7.85 (m, 2H),
8.03 (ddd, J=9.1, 7.4, 2.0 Hz, 1H), 8.42 ppm (d, 1H, J=4.2 Hz). These
data are consistent with those reported in the literature:[32] beige oil;
13C NMR (CDCl3, 75 MHz): d=121.6 (d, C, J
CH, J(C,F)=5 Hz), 128.7 (2 CH), 129.7 (d, 2 CH, J
(CH), 136.5 (d, C, J(C,F)=1 Hz), 141.8 (d, CH, J(C,F)=3 Hz), 150.4 (d,
CH, J(C,F)=15 Hz), 160.1 (d, C, J(C,F)=243 Hz), 191.7 ppm (d, C=O, J-
(C,F)=5 Hz).
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
4-Chlorophenyl 2,5-dimethoxyphenyl ketone (6b): Eluent: heptane/
EtOAc (98:2); 1H NMR (CDCl3, 300 MHz): d=3.66 (s, 3H), 3.79 (s,
3H), 6.91 (d, J=9.0 Hz, 1H), 6.91 (d, J=3.0 Hz, 1H), 7.01 (dd, J=9.0,
3.0 Hz, 1H), 7.40 (d, J=8.7 Hz, 2H), 8.74 ppm (d, J=8.7 Hz, 2H);
13C NMR (CDCl3, 75 MHz): d=55.9 (CH3), 56.3 (CH3), 113.1 (CH),
114.5 (CH), 117.8 (CH), 128.6 (2 CH), 128.9 (2 CH), 131.2 (C), 136.2 (C),
139.4 (C), 151.5 (C), 153.6 (C), 195.0 ppm (C=O). These data are consis-
tent with those reported in the literature:[37] yellow oil.
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
2-Chloropyridin-3-yl phenyl ketone (4a): Eluent: heptane/EtOAc
(90:10); 1H NMR (CDCl3, 300 MHz): d=7.38 (dd, J=7.5, 4.9 Hz, 1H),
7.42–7.50 (m, 2H), 7.61 (tt, J=7.4, 1.3 Hz, 1H), 7.72 (dd, J=7.5, 2.0 Hz,
1H), 7.75–7.81 (m, 2H), 8.52 ppm (dd, J=4.9, 2.0 Hz, 1H). These data
are consistent with those reported in the literature:[33] yellow oil;
13C NMR (CDCl3, 75 MHz): d=122.3 (CH), 128.9 (2CH), 130.0 (2 CH),
134.3 (CH), 134.9 (C), 135.7 (C), 138.0 (CH), 147.7 (C), 150.9 (CH),
193.3 ppm (C=O)
6-Chloropyridin-3-yl 2,5-dimethoxyphenyl ketone (6c): Eluent: heptane/
EtOAc (80:20); yellow powder; m.p. 908C; 1H NMR (CDCl3, 300 MHz):
d=3.65 (s, 3H), 3.80 (s, 3H), 6.93 (d, J=9.0 Hz, 1H), 7.0 (d, J=3.1 Hz,
1H), 7.07 (dd, J=9.0, 3.1 Hz, 1H), 7.41 (dd, J=8.3, 0.6 Hz, 1H), 8.07
(dd, J=8.3, 2.4 Hz, 1H), 8.67 ppm (d, J=2.1 Hz, 1H); 13C NMR (CDCl3,
75 MHz): d=56.0 (CH3), 56.1 (CH3), 113.1 (CH), 114.5 (CH), 119.3
(CH), 124.2 (CH), 127.6 (C), 132.4 (C), 139.2 (CH), 151.6 (CH), 151.7
(C), 153.9 (C), 155.1 (C), 193.5 ppm (C=O); HRMS (ESI): m/z calcd for
C14H1335ClNO3: 278.0584 [M+H]+, 300.0403 [M+Na]+; found: 278.0581,
300.0402.
2-Bromopyridin-3-yl phenyl ketone (5a): Eluent: heptane/EtOAc
(90:10); 1H NMR (CDCl3, 300 MHz): d=7.39 (dd, J=7.5, 4.9 Hz, 1H),
7.46–7.54 (m, 2H), 7.64 (tt, J=7.4, 1.3 Hz, 1H), 7.75 (dd, J=7.5, 2.0 Hz,
1H), 7.78–7.82 (m, 2H), 8.56 ppm (dd, J=4.9, 2.0 Hz, 1H); 13C NMR
(CDCl3, 75 MHz): d=122.4 (CH), 129.0 (2CH), 130.1 (2CH), 134.3
(CH); 135.1 (C), 135.9 (C), 138.1 (CH), 147.9 (C), 151.0 (CH), 193.5 ppm
(C=O). These data are consistent with those reported in the literature:[34]
yellow oil.
N-(2-Methoxyphenyl)-2,2,6,6-tetramethylpiperidine: Eluent: CH2Cl2;
1H NMR (CDCl3, 300 MHz): d=0.78 (s, 6H), 1.23 (s, 6H), 1.49–1.64 (m,
6H), 3.75 (s, 3H), 6.82–6.88 (m, 2H), 7.13–7.19 (m, 1H), 7.29 ppm (dd,
J=8.3, 1.9 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=18.6 (CH2), 26.0 (2
CH3), 31.5 (2 CH3), 41.8 (CH2), 54.4 (2 C), 55.1 (CH3), 111.0 (CH), 119.3
(CH), 126.4 (CH), 134.2 (CH), 136.0 (C), 160.3 ppm (C); HRMS (EI): m/
z calcd for C16H25NO: 247.1936 [M]+; found: 247.1941.
2-Fluoropyridin-3-yl 2-chlorophenyl ketone (3b): Eluent: heptane/EtOAc
(80:20); yellow oil; 1H NMR (CDCl3, 300 MHz): d=7.30–7.50 (m, 5H),
8.19 (ddd, J=9.3, 7.5, 2.0 Hz, 1H), 8.36–8.42 ppm (m, 1H); 13C NMR
(CDCl3, 75 MHz): d=121.2 (d, CH, J
5 Hz), 127.2 (CH), 129.8 (CH), 130.3 (CH), 131.6 (d, C, J
132.5 (CH), 138.3 (C), 142.2 (d, CH, J(C,F)=2 Hz), 151.9 (d, CH, J-
(C,F)=15 Hz), 160.9 (d, C, J(C,F)=247 Hz), 191.0 ppm (d, C=O, J-
(C,F)=6 Hz); HRMS (ESI): m/z calcd for C12H735ClFNNaO: 258.0098
[M+Na]+; found: 258.0098.
A
ACHTUNGTRNE(NUNG C,F)=
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
2-Allyl-1,4-dimethoxybenzene (6e): Eluent: heptane/EtOAc (95:5);
1H NMR (CDCl3, 300 MHz): d=3.38 (d, J=6.6 Hz, 2H), 3.78 (s, 3H),
3.80 (s, 3H), 5.05 (t, J=1.4 Hz, 1H), 5.07–5.13 (m, 1H), 6.00 (ddt, J=
16.7, 10.4, 6.6 Hz, 1H), 6.68–6.85 ppm (m, 3H). These data are consistent
with those reported in the literature:[38] colorless oil; 13C NMR (CDCl3,
75 MHz): d=34.4 (CH2), 55.7 (CH3), 56.2 (CH3), 111.4 (CH), 111.5
(CH), 115.7 (CH2), 116.2 (CH), 129.9 (C), 136.9 (CH), 151.7 (C),
153.7 ppm (C).
2-Fluoropyridin-3-yl 4-chlorophenyl ketone (3c):[10] Eluent: heptane/
EtOAc (80:20); yellow powder; m.p. 908C; 1H NMR (CDCl3, 300 MHz):
d=7.37 (ddd, J=7.6, 4.9, 1.9 Hz, 1H), 7.44–7.50 (m, 2H), 7.73–7.79 (m,
2H), 8.04 (ddd, J=9.4, 7.5, 2.0 Hz, 1H), 8.43 ppm (ddd, J=4.9, 2.1,
1.2 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=121.3 (d, C,
30 Hz), 121.9 (d, CH, J
(C,F)=1 Hz), 135.0 (d, C, J
(C,F)=3 Hz), 150.9 (d, CH, JACHTGNURTENNUGN
JACHTUNGTRENNUNG
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
Phenyl thiophen-2-yl ketone (8a): Eluent: heptane/CH2Cl2 (70:30);
A
J
A
1
yellow oil; H NMR (CDCl3, 300 MHz): d=7.17 (dd, J=4.9, 3.8 Hz, 1H),
243 Hz), 190.7 ppm (d, C=O, JACTHUNRGTNE(NUG C,F)=5 Hz); HRMS (ESI): m/z calcd for
7.46–7.54 (m, 2H), 7.56–7.63 (m, 1H), 7.65 (dd, 1H, J=3.8 and 1.1 Hz),
7.73 (dd, 1H, J=4.9 and 1.1 Hz), 7.84–7.90 ppm (m, 2H); 13C NMR
(CDCl3, 75 MHz): d=128.0 (CH), 128.5 (2 CH), 129.2 (2 CH), 132.3
(CH), 134.3 (CH), 134.8 (CH), 138.2 (C), 143.7 (C), 188.3 ppm (C=O).
These data are consistent with those obtained from a commercial sample.
C12H835ClFNO: 236.0278 [M+H]+, 258.0098 [M+Na]+; found: 236.0281,
258.0096.
2-Fluoropyridin-3-yl 4-(trifluoromethyl)phenyl ketone (3d): Eluent: hep-
tane/EtOAc (80:20); 1H NMR (CDCl3, 300 MHz): d=7.40 (ddd, J=7.4,
4.9, 1.9 Hz, 1H), 7.75 (d, J=8.2 Hz, 2H), 7.90 (d, J=8.2 Hz, 2H), 8.09
(ddd, J=9.0, 7.4, 2.0 Hz, 1H), 8.45 ppm (ddd, J=4.9, 2.0, 1.1 Hz, 1H);
Furan-2-yl phenyl ketone (9): Eluent: heptane/Et2O (80:20); yellow oil;
1H NMR (CDCl3, 300 MHz): d=6.59 (dd, J=3.6, 1.7 Hz, 1H), 7.23 (dd,
J=3.6, 0.8 Hz, 1H), 7.45–7.53 (m, 2H), 7.55–7.63 (m, 1H), 7.71 (dd, J=
1.7, 0.8 Hz, 1H), 7.93–8.00 ppm (m, 2H); 13C NMR (CDCl3, 75 MHz):
d=112.3 (CH), 120.8 (CH), 128.5 (2 CH), 129.4 (2 CH), 132.7 (CH),
137.3 (C), 147.3 (CH), 152.3 (C), 182.7 ppm (C=O). These data are con-
sistent with those reported the literature.[39]
13C NMR (CDCl3, 75 MHz): d=120.6 (d, C, J
CH, J(C,F)=5 Hz), 123.7 (q, C, J
(C,F)=4 Hz), 129.8 (d, CH, (C,F)=1 Hz), 134.8 (q, C,
33 Hz), 139.5 (C), 142.1 (d, CH, J(C,F)=3 Hz), 151.2 (d, CH, J
15 Hz), 160.1 (d, C, J
ACHTUNGTRENNUNG
N
ACHTUNGTRENNUNG
N
2
J
A
JACHTUNGTRENNUNG
E
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG(C,F)=243 Hz), 190.8 ppm (d, C=O, JCAHTUNGTRENNUNG
These data are consistent with those reported in the literature:[35] beige
oil.
Indol-2-yl phenyl ketone (10): Eluent: heptane/CH2Cl2 (50:50); pale
yellow solid; m.p. 1538C (lit.[40] 149–1508C); 1H NMR (CDCl3,
300 MHz): d=7.14–7.22 (m, 2H), 7.39 (td, J=8.2, 1.1 Hz, 1H), 7.49–7.59
(m, 3H), 7.64 (tt, J=7.3, 1.4 Hz, 1H), 7.73 (dd, J=8.1, 0.8 Hz, 1H), 7.99–
8.05 (m, 2H), 9.68 ppm (s, 1H); 13C NMR (CDCl3, 75 MHz): d=112.4
(CH), 113.0 (CH), 121.2 (CH), 123.3 (CH), 126.7 (CH), 127.8 (C), 128.6
(2 CH), 129.4 (2 CH), 132.5 (CH), 134.5 (C), 137.8 (C), 138.1 (C),
187.4 ppm (C=O). These data are consistent with those reported in the
literature.[40]
2-Chloropyridin-5-yl 2-fluoropyridin-3-yl ketone (3e): Eluent: heptane/
EtOAc (70:30); orange solid; m.p. 948C; 1H NMR (CDCl3, 300 MHz):
d=7.40 (ddd, J=7.4, 4.9, 1.9 Hz, 1H), 7.46 (d, 1H, J=8.3 Hz), 8.04–8.12
(m, 2H), 8.43–8.45 (m, 1H), 8.72 ppm (s, 1H); 13C NMR (CDCl3,
75 MHz): d=119.9 (d, C, J
124.5 (CH), 131.0 (C), 139.1 (d, CH, J
(C,F)=3 Hz), 150.8 (d, CH, (C,F)=2 Hz), 151.5 (d, CH,
15 Hz), 156.0 (C), 159.8 (d, C, J(C,F)=243 Hz), 189.0 ppm (d, C=O, J-
A
ACHTUNGTRENUN(NG C,F)=5 Hz),
AHCTUNGTRENNUNG
A
J
A
JACHTUNGTRENNUNG
AHCTUNGTRENNUNG
10412
www.chemeurj.org
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 10405 – 10416

Deprotonative Metalation of Aromatic Compounds
FULL PAPER
4-Chlorophenyl thiophen-2-yl ketone (8b): Eluent: heptane/CH2Cl2
(70:30); 1H NMR (CDCl3, 300 MHz): d=7.17 (dd, J=5.0, 3.8 Hz, 1H),
7.48 (d, J=8.7 Hz, 2H), 7.62 (dd, J=3.8, 1.1 Hz, 1H), 7.74 (dd, J=5.0,
1.1 Hz, 1H), 7.82 ppm (d, J=8.7 Hz, 2H); 13C NMR (CDCl3, 75 MHz):
d=128.2 (CH), 128.9 (2 CH), 130.7 (2 CH), 134.7 (CH), 134.9 (CH),
136.5 (C), 138.8 (C), 143.3 (C), 187.0 ppm (C=O). These data are consis-
tent with the literature:[39] pale yellow solid; m.p. 998C.
2-(2-Methoxypyridin-3-yl)-2-phenylethanol (14b’): Eluent: heptane/
EtOAc (80:20); yellow oil; H NMR (CDCl3, 300 MHz): d=1.92 (s, 1H),
1
3.91 (s, 3H), 4.06–4.20 (m, 2H), 4.50 (t, J=7.0 Hz, 1H), 6.84 (dd, J=7.3,
5.0 Hz, 1H), 7.19–7.38 (m, 5H), 7.45 (dd, J=7.3, 1.8 Hz, 1H), 8.03 ppm
(dd, J=5.0, 1.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=46.8 (CH), 53.6
(CH3), 64.9 (CH2), 116.9 (CH), 124.4 (C), 126.9 (CH), 128.6 (2CH), 128.7
(2CH), 136.9 (CH), 140.5 (C), 145.0 (CH), 161.9 ppm (C); HRMS (ESI):
m/z calcd for C14H16NO2: 230.1181 [M+H], 252.1000 [M+Na]+; found:
230.1182, 252.1000.
Diphenyl thiophene-2,5-diyl diketone (8’a): Eluent: heptane/CH2Cl2
(70:30); beige powder; m.p. 1078C (lit.[41] 114.5–1158C); 1H NMR
(CDCl3, 300 MHz): d=7.49–7.56 (m, 4H), 7.64 (tt, J=7.5, 1.4 Hz, 2H),
7.68 (s, 2H), 7.89–7.94 ppm (m, 4H). These data are consistent with
those reported in the literature:[41] 13C NMR (CDCl3, 75 MHz): d=128.8
(4CH), 129.5 (4CH), 133.1 (2CH), 133.9 (2CH), 137.4 (2C), 148.6 (2C),
188.2 ppm (2C=O); HRMS (ESI): m/z calcd for C18H13O2S: 293.0636
[M+H]+, 315.0456 [M+Na]+; found: 236.0281, 315.0454.
2-Methoxy-3-(phenylthio)pyridine
(14c):
Eluent:
heptane/EtOAc
(90:10); orange oil; 1H NMR (CDCl3, 300 MHz): d=4.01 (s, 3H), 6.75
(dd, J=7.5, 4.9 Hz, 1H), 7.16 (dd, J=7.5, 1.8 Hz, 1H), 7.32–7.45 (m,
5H), 7.99 ppm (dd, J=4.9, 1.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=
54.0 (CH3), 117.4 (CH), 121.2 (C), 128.3 (CH), 129.6 (2CH), 132.2 (C),
133.2 (2CH), 137.6 (CH), 144.3 (CH), 160.4 ppm (C); HRMS (ESI): m/z
calcd for C12H12NOS: 218.0640 [M+H]+, 240.0459 [M+Na]+; found:
218.0641, 240.0460.
Ethyl 5-benzoylthiophene-2-carboxylate (11a): Eluent: heptane/EtOAc
(80:20); yellow oil; 1H NMR (CDCl3, 300 MHz): d=1.40 (t, J=7.1 Hz,
3H), 4.40 (q, J=7.1 Hz, 2H), 7.48–7.56 (m, 2H), 7.59–7.67 (m, 1H), 7.61
(d, J=4.0 Hz, 1H), 7.79 (d, J=4.0 Hz, 1H), 7.85–7.90 ppm (m, 2H);
13C NMR (CDCl3, 75 MHz): d=14.4 (CH3), 62.0 (CH2), 128.7 (2 CH),
129.5 (2 CH), 133.0 (CH), 133.1 (CH), 134.0 (CH), 137.5 (C), 140.5 (C),
147.8 (C), 161.8 (C), 188.2 ppm (C=O); HRMS (ESI): m/z calcd for
C14H13O3S: 261.0585 [M+H]+, 283.0404 [M+Na]+; found: 261.0583,
283.0403.
4-Chlorophenyl 2-methoxypyridin-3-yl sulfone (14d): Eluent: heptane/
EtOAc (80:20); yellow powder; m.p. 1178C; 1H NMR (CDCl3,
300 MHz): d=3.94 (s, 3H), 7.07 (dd, J=7.6, 5.0 Hz, 1H), 7.48 (d, J=
8.8 Hz, 2H), 7.93 (d, J=8.8 Hz, 2H), 8.34 (dd, J=5.0, 1.9 Hz, 1H),
8.39 ppm (dd, J=7.6, 1.9 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=54.4
(CH3), 117.1 (CH), 123.8 (C), 129.2 (2CH), 130.4 (2CH), 138.9 (C), 139,4
(CH), 140.3 (C), 152.7 (CH), 159.9 (C); HRMS (ESI): m/z calcd for
C12H1135ClNO3S: 284.0148 [M+H]+, 305.9968 [M+Na]+; found: 284.0149,
305.9968.
Ethyl 5-iodothiophene-2-carboxylate (11b): Eluent: heptane/CH2Cl2
(80:20); yellow oil; 1H NMR (CDCl3, 300 MHz): d=1.36 (t, J=7.1 Hz,
3H), 4.33 (q, J=7.1 Hz, 2H), 7.25 (d, J=3.9 Hz, 1H), 7.42 ppm (d, J=
3.9 Hz, 1H). These data are consistent with those reported in the litera-
ture:[42] 13C NMR (CDCl3, 75 MHz): d=14.4 (CH3), 61.5 (CH2), 82.6 (C),
134.4 (CH), 137.8 (CH), 139.8 (C), 161.0 ppm (C=O).
(Z)-Ethyl 3-(2-methoxypyridin-3-yl)-3-phenylpropenoate (14e): Eluent:
1
heptane/EtOAc (80:20); orange oil; H NMR (CDCl3, 300 MHz): d=1.12
(t, J=7.1 Hz, 3H), 3.85 (s, 3H), 4.05 (q, J=7.1 Hz, 2H), 6.47 (s, 1H),
6.93 (dd, J=7.3, 5.0 Hz, 1H), 7.29–7.37 (m, 6H), 8.21 ppm (dd, J=5.0,
1.9 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=14.0 (CH3), 53.5 (CH3), 60.0
(CH2), 116.3 (CH), 119.1 (CH), 122.5 (C), 127.4 (2CH), 128.5 (2CH),
129.5 (CH), 138.5 (CH), 139.4 (C), 146.5 (CH), 151.0 (C), 160.8 (C),
165.6 ppm (C=O); HRMS (ESI): m/z calcd for C17H18NO3: 284.1287
[M+H]+, 306.1106 [M+Na]+; found: 284.1288, 306.1106.
Ethyl 2-benzoylthiophene-3-carboxylate (12): Eluent: heptane/EtOAc
(80:20); beige oil; 1H NMR (CDCl3, 300 MHz): d=0.89 (t, J=7.2 Hz,
3H), 3.92 (q, J=7.2 Hz, 2H), 7.41–7.53 (m, 4H), 7.58 (tt, J=7.4, 1.3 Hz,
1H), 7.78–7.84 ppm (m, 2H); 13C NMR (CDCl3, 75 MHz): d=13.6
(CH3), 61.3 (CH2), 127.9 (CH), 128.7 (2CH), 129.1 (CH), 129.5 (2CH),
133.5 (CH), 134.0 (C), 137.8 (C), 145.3 (C), 162.6 (C=O), 189.9 ppm (C=
O); HRMS (ESI): m/z calcd for C14H12NaO3S: 283.0405 [M+Na]+;
found: 283.0407.
(E)-Ethyl 3-(2-methoxypyridin-3-yl)-3-phenylpropenoate (14e’): Com-
pound 14e’ was identified by the NMR spectrum: 1H NMR (CDCl3,
300 MHz): d=1.10 (t, J=7.1 Hz, 3H), 3.89 (s, 3H), 4.05 (q, J=7.1 Hz,
2H), 6.51 (s, 1H), 6.83 (dd, J=7.4, 5.0 Hz, 1H), 7.15–7.23 (m, 2H), 7.28–
7.37 (m, 4H), 8.11 (dd, J=5.0, 1.9 Hz, 1H).
2,4-Dimethoxy-5-methylpyrimidine (13a): Eluent: heptane/EtOAc
(80:20); white powder; m.p. 64–658C (lit.[43] 61.9–63.28C); 1H NMR
(CDCl3, 300 MHz): d=2.01 (s, 3H), 3.92 (s, 3H), 3.95 (s, 3H), 7.94 ppm
(s, 1H); 13C NMR (CDCl3, 75 MHz): d=12.0 (CH3), 53.9 (CH3), 54.7
(CH3), 111.2 (C), 156.9 (CH), 164.2 (C), 169.7 ppm (C). These data are
consistent with those reported in the literature.[43]
5-Allyl-2,4-dimethoxypyrimidine (13b):[10] Eluent: heptane/EtOAc
(80:20); yellow oil; 1H NMR (CDCl3, 300 MHz): d=3.22 (m, 2H), 3.96
(s, 3H), 3.97 (s, 3H), 5.00–5.08 (m, 2H), 5.82–5.97 (m, 1H), 7.98 ppm
(brs, 1H); 13C NMR (CDCl3, 75 MHz): d=29.8 (CH2), 54.0 (CH3), 54.8
(CH3), 113.6 (C), 116.5 (CH2), 135.2 (CH), 157.0 (CH), 164.4 (C),
169.4 ppm (C); HRMS (ESI): m/z calcd for C9H12N2NaO2: 203.0796
[M+Na]+; found: 203.0800.
2,2’,4,4’-Tetramethoxy-5,5’-bipyrimidine (13’):[10] Eluent: heptane/EtOAc
(80:20); red powder; m.p. 2098C; 1H NMR (CDCl3, 300 MHz): d=3.97
(s, 6H), 4.03 (s, 6H), 8.20 ppm (s, 2H); 13C NMR (CDCl3, 75 MHz): d=
54.3 (2CH3), 55.0 (2CH3), 108.3 (2C), 158.8 (2CH), 165.1 (2C),
168.7 ppm (2C); HRMS (ESI): m/z calcd for C12H15N4O4: 279.1093
[M+H]+, 301.0913 [M+Na]+; found: 279.1095, 301.0916.
(E)-Ethyl 3-(2-methoxypyridin-3-yl)octenoate (14 f): Eluent: heptane/
EtOAc (80:20); orange oil; 1H NMR (CDCl3, 300 MHz): d=0.76–0.86
(m, 3H), 1.20–1.36 (m, 6H), 1.29 (t, J=7.1 Hz, 3H), 2.98–3.06 (m, 2H),
3.94 (s, 3H), 4.19 (q, J=7.1 Hz, 2H), 5.82 (s, 1H), 6.89 (dd, J=7.2,
5.0 Hz, 1H), 7.39 (dd, J=7.2, 1.9 Hz, 1H), 8.12 ppm (dd, J=5.0, 1.9 Hz,
1H); 13C NMR (CDCl3, 75 MHz): d=14.1 (CH3), 14.4 (CH3), 22.6 (CH2),
28.2 (CH2), 31.3 (CH2), 31.9 (CH2), 53.6 (CH3), 60.0 (CH2), 116.7 (CH),
120.1 (CH), 125.9 (C), 137.8 (CH), 146.6 (CH), 159.1 (C), 160.1 (C),
166.3 ppm (C=O); HRMS (ESI): m/z calcd for C16H24NO3: 278.1756
[M+H]+, 300.1576 [M+Na]+; found: 278.1758, 300.1579.
(Z)-Methyl 3-(2-methoxypyridin-3-yl)butenoate (14g): Eluent: heptane/
EtOAc (80:20); orange oil; 1H NMR (CDCl3, 300 MHz): d=2.12 (d, J=
1.5 Hz, 3H), 3.52 (s, 3H), 3.91 (s, 3H), 5.96 (q, J=1.5 Hz, 1H), 6.86 (dd,
J=7.2, 5.1 Hz, 1H), 7.31 (dd, J=7.2, 1.9 Hz, 1H), 8.10 ppm (dd, J=5.1,
1.9 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=25.6 (CH3), 51.1 (CH3), 53.5
(CH3), 116.4 (CH), 119.2 (CH), 124.1 (C), 136.6 (CH), 146.1 (CH), 151.7
(C), 159.7 (C), 165.8 ppm (C=O); HRMS (ESI): m/z calcd for
C11H13NNaO3: 230.0793 [M+Na]+; found: 230.0795.
2-(2-Methoxypyridin-3-yl)-1-phenylethanol (14b): Eluent: heptane/
1
(E)-Methyl 3-(2-methoxypyridin-3-yl)butenoate (14g’): Eluent: heptane/
EtOAc (80:20); orange oil; 1H NMR (CDCl3, 300 MHz): d=2.47 (d, J=
1.4 Hz, 3H), 3.72 (s, 3H), 3.95 (s, 3H), 5.95 (q, J=1.4 Hz, 1H), 6.87 (dd,
J=7.3, 5.0 Hz, 1H), 7.42 (dd, J=7.3, 1.9 Hz, 1H), 8.12 ppm (dd, J=5.0,
1.9 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=19.2 (CH3), 51.2 (CH3), 53.6
(CH3), 116.8 (CH), 119.7 (CH), 126.8 (C), 137.1 (CH), 146.8 (CH), 154.4
(C), 160.6 (C), 167.0 ppm (C=O); HRMS (ESI): m/z calcd for
C11H13NNaO3: 230.0793 [M+Na]+; found: 230.0792.
EtOAc (80:20); yellow oil; H NMR (CDCl3, 300 MHz): d=2.49 (s, 1H),
2.88–3.10 (m, 2H), 3.95 (s, 3H), 4.98 (dd, J=7.4, 5.0 Hz, 1H), 6.78 (dd,
J=7.2, 5.0 Hz, 1H), 7.20–7.40 (m, 6H), 8.04 ppm (dd, J=5.0, 1.9 Hz,
1H); 13C NMR (CDCl3, 75 MHz): d=40.6 (CH2), 53.6 (CH3), 73.6 (CH),
116.9 (CH), 121.1 (C), 125.9 (2CH), 127.6 (CH), 128.4 (2CH), 139.7
(CH), 144.2 (C), 145.2 (CH), 162.4 ppm (C); HRMS (ESI): m/z calcd for
C14H16NO2: 230.1181 [M+H]+, 252.1000 [M+Na]; found: 230.1182,
252.1000.
Chem. Eur. J. 2011, 17, 10405 – 10416
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10413

F. Mongin et al.
2,2’-Difluoro-3,3’-bipyridine (15’):[10] Eluent: heptane/EtOAc (80:20);
beige powder; m.p. 1538C; 1H NMR (CDCl3, 300 MHz): d=7.31–7.36
(m, 2H), 7.88–7.96 (m, 2H), 8.30 ppm (dd, J=4.9, 1.9 Hz, 2H); 13C NMR
(CDCl3, 75 MHz): d=116.7 (m, 2C), 121.7 (m, 2CH), 142.0 (t, 2CH, J-
8.68 ppm (ddd, J=4.8, 1.8, 0.9 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=
53.6 (CH3), 117.5 (CH), 122.3 (CH), 123.1 (C), 124.7 (CH), 136.1 (CH),
139.5 (CH), 147.1 (CH), 149.6 (CH), 154.2 (C), 161.1 ppm (C); HRMS
(ESI): m/z calcd for C11H11N2O: 187.0871 [M+H]+ and 209.0691
[M+Na]+; found: 187.0872, 209.0691.
ACHTUNGTRENNUNG(C,F)=3 Hz), 148.1 (m, 2CH), 160.4 (d, 2C, JHCATUNGTRENN(UGN C,F)=241 Hz); HRMS
(ESI): m/z calcd for C10H7F2N2: 193.0577 [M+H]+, 215.0397 [M+Na]+;
2,6-Dimethoxy-3-(4-methoxyphenyl)pyridine (18a): Eluent: heptane/
Et2O (90:10); white powder; 1H NMR (CDCl3, 300 MHz): d=3.84 (s,
3H), 3.96 (s, 3H), 3.97 (s, 3H), 6.38 (d, J=8.0 Hz, 1H), 6.95 (d, J=
8.9 Hz, 2H), 7.47 (d, J=8.9 Hz, 2H), 7.54 ppm (d, J=8.0 Hz, 1H);
13C NMR (CDCl3, 75 MHz): d=53.5 (CH3), 53.7 (CH3), 55.4 (CH3), 101.0
(CH), 113.8 (2 CH), 115.5 (C), 129.4 (C), 130.1 (2 CH), 141.3 (CH), 158.6
(C), 159.3 (C), 162.0 ppm (C). These data are consistent with those re-
ported in the literature.[44]
found: 193.0583, 215.0397.
1,1’-(Benzene-1,2-diyl)-2,2’-bi(1H-pyrazole) (16’): Eluent: heptane/
EtOAc (80:20); yellow powder; m.p. 1898C; 1H NMR (CDCl3,
300 MHz): d=6.80 (d, J=2.0 Hz, 2H), 7.50 (dd, J=6.2, 3.4 Hz, 2H), 7.95
(d, J=2.0 Hz, 2H), 8.41 ppm (dd, J=6.2, 3.4 Hz, 2H); 13C NMR (CDCl3,
75 MHz): d=101.1 (2CH), 116.5 (2CH), 126.0 (2C), 126.6 (2CH), 130.5
(2C), 141.9 ppm (2CH); HRMS (ESI): m/z calcd for C12H9N4: 209.0827
[M+H]+; found: 209.0829.
2,6-Dimethoxy-3-(pyridin-2-yl)pyridine (18b): Eluent: heptane/EtOAc
(80:20); pale yellow oil; 1H NMR (CDCl3, 300 MHz): d=4.96 (s, 3H),
4.02 (s, 3H), 6.44 (d, J=8.2 Hz, 1H), 7.13 (ddd, J=7.4, 4.9, 1.1 Hz, 1H),
7.67 (ddd, J=8.0, 7.5, 1.9 Hz, 1H), 7.94 (dt, J=8.0, 1.0 Hz, 1H), 8.24 (d,
J=8.2 Hz, 1H), 8.63 ppm (ddd, J=4.9, 1.9, 1.0 Hz, 1H); 13C NMR
(CDCl3, 75 MHz): d=53.4 (CH3), 53.6 (CH3), 101.8 (CH), 114.2 (C),
121.2 (CH), 123.9 (CH), 135.9 (CH), 142.2 (CH), 149.2 (CH), 154.3 (C),
159.8 (C), 162.9 ppm (C); HRMS (ESI): m/z calcd for C12H13N2O2:
217.0977 [M+H]+, 239.0796 [M+Na]+; found: 217.0983, 239.0797.
General procedure for the deprotocupration: Cross-coupling: BuLi
(about 1.6m hexanes solution, 2.0 mmol) was successively added to a
stirred, cooled (08C) suspension of CuCl2·TMEDA (0.5 g, 2.0 mmol) in
THF (5 mL) then 15 min later a solution of [LiACTHNUTRGNEUNG(tmp)] prepared in THF
(2 mL) at 08C from 2,2,6,6-tetramethylpiperidine (0.68 mL, 4.0 mmol)
and BuLi (about 1.6m hexanes solution, 4.0 mmol) was added. The mix-
ture was stirred for 15 min at this temperature before the introduction of
the substrate (4.0 mmol). After 2 h at RT, the halide (4.0 mmol) was
2,4’,5-Trimethoxybiphenyl (19a):[45] Eluent: heptane/EtOAc (90:10); pale
yellow oil; 1H NMR (CDCl3, 300 MHz): d=3.77 (s, 3H), 3.82 (s, 3H),
3.86 (s, 3H), 6.81–6.87 (m, 1H), 6.89–6.95 (m, 2H), 6.97 (d, J=8.8 Hz,
2H), 7.50 ppm (d, J=8.8 Hz, 2H); 13C NMR (CDCl3, 75 MHz): d=55.4
(CH3), 55.9 (CH3), 56.4 (CH3), 112.6 (CH), 112.7 (CH), 113.6 (2CH),
116.7 (CH), 130.6 (2CH), 130.9 (C), 131.5 (C), 150.9 (C), 153.9 (C),
158.9 ppm (C).
added, as well as [PdCl2ACHTNUTRGNEUNG(PPh3)2] (55 mg, 80 mmol) and dppf (44 mg,
80 mmol), and the mixture was heated at reflux for 16 h. After cooling,
water (0.5 mL) and EtOAc (20 mL) were added, the solution was filtered
through Celite, the mixture was dried over Na2SO4, filtered, and concen-
trated under reduced pressure before purification by column chromatog-
raphy on silica gel (the eluent is given in the product description).
2-Methoxy-3-(4-methoxyphenyl)pyridine (17a): Eluent: heptane/EtOAc
1
(80:20); white powder; m.p. 112–1138C; H NMR (CDCl3, 300 MHz): d=
2-(2,5-Dimethoxyphenyl)pyridine (19b): Eluent: heptane/EtOAc (80:20);
brown oil; 1H NMR (CDCl3, 300 MHz): d=3.77 (s, 3H), 3.81 (s, 3H),
6.87–6.95 (m, 2H), 7.18 (ddd, J=7.3, 4.9, 0.9 Hz, 1H), 7.39 (dd, J=2.2,
1.2 Hz, 1H), 7.67 (td, J=7.9, 1.8 Hz, 1H), 7.84 (d, J=7.9 Hz, 1H),
8.69 ppm (d, J=4.9 Hz, 1H). These data are consistent with those report-
ed in the literature:[46] 13C NMR (CDCl3, 75 MHz): d=55.8 (CH3), 56.4
(CH3), 113.1 (CH), 115.7 (CH), 115.8 (C), 121.8 (CH), 125.1 (CH), 129.8
(C), 135.7 (CH), 149.4 (CH), 151.3 (C), 154.0 (C), 155.8 ppm (C).
3.85 (s, 3H), 3.98 (s, 3H), 6.92–7.00 (m, 3H), 7.51 (d, J=8.9 Hz, 2H),
7.59 (dd, J=7.3, 1.9 Hz, 1H), 8.14 (dd, J=5.0, 1.9 Hz, 1H); 13C NMR
(CDCl3, 75 MHz): d=53.6 (CH3), 55.4 (CH3), 113.8 (2CH), 117.2 (CH),
124.4 (C), 129.2 (C), 130.4 (2CH), 138.3 (CH), 145.3 (CH), 159.2 (C),
161.0 ppm (C); HRMS (ESI): m/z calcd for C13H14NO2: 216.1024 [M+H],
238.0844 [M+Na]; found: 216.1026, 238.0845.
2-Methoxy-3-[4-methoxy-3-(4-methoxyphenyl)phenyl]pyridine
(17a’):
Eluent: heptane/EtOAc (80:20); white powder; m.p. 828C; 1H NMR
(CDCl3, 300 MHz): d=3.85 (s, 3H), 3.86 (s, 3H), 4.0 (s, 3H), 6.94–7.01
(m, 3H), 7.04 (d, J=8.3 Hz, 1H), 7.49–7.56 (m, 4H), 7.63 (dd, J=7.3,
1.9 Hz, 1H), 8.15 ppm (dd, J=5.0, 1.9 Hz, 1H); 13C NMR (CDCl3,
75 MHz): d=53.7 (CH3), 55.4 (CH3), 55.8 (CH3), 111.1 (CH), 113.6
(2CH), 117.2 (CH), 124.4 (C), 129.0 (CH), 129.3 (C), 130.3 (C), 130.7
(2CH), 130.8 (C), 131.6 (CH), 138.3 (CH), 145.3 (CH), 156.1 (C), 158.9
(C), 161.0 (C); HRMS (ESI): m/z calcd for C20H20NO3: 322.1443
[M+H]+, 344.1263 [M+Na], 360.1002 [M+K]+; found: 322.1443,
344.1266, 360.1010.
2,4-Dimethoxy-5-(4-methoxyphenyl)pyrimidine (20a): Eluent: heptane/
EtOAc (80:20); white powder; m.p. 1048C; 1H NMR (CDCl3, 300 MHz):
d=3.83 (s, 3H), 4.00 (s, 3H), 4.02 (s, 3H), 6.95 (d, J=8.9 Hz, 2H), 7.41
(d, J=8.9 Hz, 2H), 8.21 ppm (s, 1H); 13C NMR (CDCl3, 75 MHz): d=
54.2 (CH3), 54.9 (CH3), 55.4 (CH3), 114.0 (2CH), 116.0 (C), 125.6 (C),
130.0 (2CH), 157.2 (CH), 159.3 (C), 164.3 (C), 168.2 ppm (C); HRMS
(ESI): m/z calcd for C13H15N2O3: 247.1083 [M+H], 269.0902 [M+Na]+;
found: 247.1085, 269.0900.
2,4-Dimethoxy-5-(pyridin-2-yl)pyrimidine (20b): Eluent: heptane/EtOAc
(80:20); white powder; m.p. 838C; 1H NMR (CDCl3, 300 MHz): d=4.02
(s, 3H), 4.05 (s, 3H), 7.19 (ddd, J=7.4, 4.9, 1.2 Hz, 1H), 7.69 (td, J=7.5,
1.9 Hz, 1H), 7.80 (dt, J=8.0, 1.0 Hz, 1H), 8.64 (ddd, J=4.8, 1.8, 1.0 Hz,
1H), 8.87 ppm (s, 1H); 13C NMR (CDCl3, 75 MHz): d=54.3 (CH3), 55.1
(CH3), 114.7 (C), 122.3 (CH), 124.1 (CH), 136.4 (CH), 149.6 (CH), 151.9
(C), 159.9 (CH), 165.1 (C), 168.3 ppm (C); HRMS (ESI): m/z calcd for
C11H12N3O2: 218.0929 [M+H]+, 240.0749 [M+Na]+; found: 218.0943,
240.0749.
3-(4-Fluorophenyl)-2-methoxypyridine (17b): Eluent: heptane/EtOAc
(90:10); pale yellow oil; 1H NMR (CDCl3, 300 MHz): d=3.98 (s, 3H),
6.96 (dd, J=7.3, 5.0 Hz, 1H), 7.11 (t, J=8.8 Hz, 2H), 7.48–7.60 (m, 3H),
8.17 ppm (dd, J=5.0, 1.9 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=53.6
(CH3), 115.2 (d, 2CH, J
2CH, J(C,F)=8 Hz), 132.8 (d, C, J
160.9 (C), 162.4 ppm (d, C, J(C,F)=247 Hz); HRMS (ESI): m/z calcd for
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
C12H12N2NaO2: 239.0796 [M+Na]; found: 239.0795.
Ethyl 4-(2-methoxypyridin-3-yl)benzoate (17c): Eluent: heptane/EtOAc
1
(80:20); yellow powder; m.p. 828C; H NMR (CDCl3, 300 MHz): d=1.40
(t, J=7.1 Hz, 3H), 3.97 (s, 3H), 4.40 (q, J=7.1 Hz, 2H), 6.99 (dd, J=7.3,
5.0 Hz, 1H), 7.60–7.66 (m, 3H), 8.09 (d, J=8.5 Hz, 2H), 8.19 ppm (dd,
J=5.0, 1.9 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=14.5 (CH3), 53.7
(CH3), 61.1 (CH2), 117.2 (CH), 123.7 (C), 129.2 (2CH), 129.5 (2CH),
138.7 (CH), 141.5 (C), 146.6 (CH), 160.9 (C), 166.5 ppm (C=O); HRMS
(ESI): m/z calcd for C15H16NO3: 258.1130 [M+H]+, 280.0950 [M+Na]+;
found: 258.1133, 280.0950.
Acknowledgements
We gratefully acknowledge financial support from MESR of France (to
T.T.N.), the Agence Nationale de la Recherche (ACTIVATE program, to
N.M.), the Institut Universitaire de France (to F.M.), and Rennes Mꢀtro-
pole (to F.M.).
2-Methoxy-3-(pyridin-2-yl)pyridine (17d): Eluent: heptane/EtOAc
(80:20); yellow oil; 1H NMR (CDCl3, 300 MHz): d=4.02 (s, 3H), 7.02
(dd, J=7.1, 5.3 Hz, 1H), 7.21 (ddd, J=7.5, 4.8, 1.2 Hz, 1H), 7.71 (ddd,
J=8.0, 7.6, 1.9 Hz, 1H), 8.0 (dt, J=8.0, 1.0 Hz, 1H), 8.17–8.23 (m, 2H),
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10414
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ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 10405 – 10416

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Received: March 31, 2011
Published online: August 3, 2011
10416
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Chem. Eur. J. 2011, 17, 10405 – 10416