Computed CH acidity of biaryl compounds and their deprotonative metalation by using a mixed lithium/Zinc-TMP base

Article abstract of DOI:10.1002/chem.201300552

With the aim of synthesizing biaryl compounds, several aromatic iodides were prepared by the deprotonative metalation of methoxybenzenes, 3-substituted naphthalenes, isoquinoline, and methoxypyridines by using a mixed lithium/zinc-TMP (TMP=2,2,6,6-tetramethylpiperidino) base and subsequent iodolysis. The halides thus obtained, as well as commercial compounds, were cross-coupled under palladium catalysis (e.g., Suzuki coupling with 2,4-dimethoxy-5-pyrimidylboronic acid) to afford various representative biaryl compounds. Deprotometalation of the latter compounds was performed by using the lithium/zinc-TMP base and evaluated by subsequent iodolysis. The outcome of these reactions has been discussed in light of the CH acidities of these substrates, as determined in THF solution by using the DFT B3LYP method. Except for in the presence of decidedly lower pK_a values, the regioselectivities of the deprotometalation reactions tend to be governed by nearby coordinating atoms rather than by site acidities. In particular, azine and diazine nitrogen atoms have been shown to be efficient in inducing the reactions with the lithium/zinc-TMP base at adjacent sites (e.g., by using 1-(2-methoxyphenyl)isoquinoline, 4-(2,5-dimethoxyphenyl)-3-methoxypyridine, or 5-(2,5-dimethoxyphenyl)-2,4-dimethoxypyrimidine as the substrate), a behavior that has already been observed upon treatment with lithium amides under kinetic conditions. Finally, the iodinated biaryl derivatives were involved in palladium-catalyzed reactions. Copyright

Full text of DOI:10.1002/chem.201300552

DOI: 10.1002/chem.201300552
Computed CH Acidity of Biaryl Compounds and Their Deprotonative
Metalation by Using a Mixed Lithium/Zinc-TMP Base**
Raghu Ram Kadiyala,[a] David Tilly,[a] Elisabeth Nagaradja,[a] Thierry Roisnel,[b]
Vadim E. Matulis,[c] Oleg A. Ivashkevich,[c] Yury S. Halauko,*[d] Floris Chevallier,[a]
Philippe C. Gros,[e] and Florence Mongin*[a]
Abstract: With the aim of synthesizing
biaryl compounds, several aromatic
iodides were prepared by the deproto-
native metalation of methoxybenzenes,
3-substituted naphthalenes, isoquino-
line, and methoxypyridines by using a
by using the lithium/zinc-TMP base
and evaluated by subsequent iodolysis.
The outcome of these reactions has
been discussed in light of the CH acid-
by site acidities. In particular, azine
and diazine nitrogen atoms have been
shown to be efficient in inducing the
reactions with the lithium/zinc-TMP
base at adjacent sites (e.g., by using
AHCTUNGTRENNiGUN ties of these substrates, as determined
in THF solution by using the DFT
B3LYP method. Except for in the pres-
ence of decidedly lower pKa values, the
regioselectivities of the deprotometal-
ation reactions tend to be governed by
nearby coordinating atoms rather than
1-(2-methoxyphenyl)isoquinoline,
4-
mixed
lithium/zinc-TMP
(TMP=
(2,5-dimethoxyphenyl)-3-methoxypyri-
dine, or 5-(2,5-dimethoxyphenyl)-2,4-
diACTHNUTRGNEmNUG ethoxypyrimidine as the substrate),
a behavior that has already been ob-
served upon treatment with lithium
amides under kinetic conditions. Final-
ly, the iodinated biaryl derivatives were
involved in palladium-catalyzed reac-
tions.
2,2,6,6-tetramethylpiperidino) base and
subsequent iodolysis. The halides thus
obtained, as well as commercial com-
pounds, were cross-coupled under pal-
ladium catalysis (e.g., Suzuki coupling
with 2,4-dimethoxy-5-pyrimidylboronic
acid) to afford various representative
biaryl compounds. Deprotometalation
of the latter compounds was performed
Keywords: acidity · basicity · biar-
yls · density functional calculations ·
metalation
Introduction
and analgesic properties.[1] Biaryl compounds are also pro-
spective organic semiconductors and liquid crystals,[2] as well
as materials for nonlinear optics.[3] Thus, it is of interest to
develop synthetic methods to access elaborate biaryl deriva-
tives. The development of new ligands for transition metals
is also a field in which new synthetic approaches to afford
biaryl scaffolds are appreciated.[4] If the main synthetic
Biaryl skeletons bind to numerous biological receptors and,
thus, molecules that contain them are frequently used in me-
dicinal chemistry. Among them, biphenyl compounds are,
for example, endowed with antifungal, anti-inflammatory,
antirheumatic, anti-infective, antitumor, antihypertensive,
[a] Dr. R. R. Kadiyala, Dr. D. Tilly, E. Nagaradja, Dr. F. Chevallier,
Prof. F. Mongin
[d] Dr. Y. S. Halauko
Department of Electrochemistry
Belarusian State University
14 Leningradskaya Str.
Minsk 220030 (Belarus)
Fax : (+375)17-2264696
E-mail: hys@tut.by
Equipe Chimie et Photonique Molꢀculaires
Institut des Sciences Chimiques de Rennes
UMR 6226 CNRS - Universitꢀ de Rennes 1
Bꢁtiment 10A, Case 1003, Campus Scientifique de Beaulieu
35042 Rennes (France)
Fax : (+33)2-2323-6955
E-mail: florence.mongin@univ-rennes1.fr
[e] Dr. P. C. Gros
HECRIN, SRSMC, UMR 7565 CNRS—Universitꢀ de Lorraine
Boulevard des Aiguillettes
[b] Dr. T. Roisnel
Centre de Diffractomꢀtrie X
54506 Vandoeuvre-lꢂs-Nancy (France)
Institut des Sciences Chimiques de Rennes
UMR 6226 CNRS—Universitꢀ de Rennes 1
Bꢁtiment 10B, Campus de Beaulieu
35042 Rennes (France)
[**] TMP=2,2,6,6-tetramethylpiperidino.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300552.
[c] Dr. V. E. Matulis, Prof. O. A. Ivashkevich
Research Institute for Physico-Chemical Problems
Belarusian State University
14 Leningradskaya Str.
Minsk 220030 (Belarus)
7944
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 7944 – 7960

FULL PAPER
Table 1. Synthesis of aryl iodides 1a–1j through a deprotometalation/
iodination sequence.
route to afford biaryl compounds involves the formation of
[5]
ꢀ
the aryl aryl bond, it is also possible to functionalize al-
ready formed biaryl compounds.[6]
The deprotonative metalation of biaryl compounds has
great synthetic potential. Methods that use alkyl lithium
compounds and lithium amides have largely been used to
achieve the deprotonative metalation of aromatic com-
pounds.[7] Nevertheless, owing to the low tolerance of func-
tionalized or heterocyclic substrates toward organolithium
species, organic chemists have developed more-compatible
substitutes. In particular, (R)n(R’)n’MLi-type bases, in which
the metal (M) is not an alkali metal, have been reported by
different research groups for their ability to deprotonate
sensitive substrates.[8]
ꢀ
Ar H
Entry
1
n Equiv
Product
Yield
[%][a]
0.5
1a
84[e]
2
3
0.5
1
1b
1c
82
Our group contributed to this area, notably with the de-
velopment of a room-temperature-operating lithium/zinc
combination,
ZnCl2·TMEDA (TMEDA=N,N,N’,N’-tetramethylethylene-
diamine) and Li(TMP) (TMP=2,2,6,6-tetramethylpiperi-
dino, 3 equiv), and taken to be Li(TMP)/Zn
(TMP)2 (1:1).[9]
which
was
prepared
in situ
from
79
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
4
5
6
1
1
1
1d
1e
1 f
92
Herein, we report our efforts to functionalize biaryl com-
pounds, including heterocycles, by deprotonative metalation
by using this base. In addition, the pKa values of the biaryl
compounds that were involved in these reactions were calcu-
lated within the density functional theory (DFT) framework
for their solutions in THF to evaluate the CH-acidity/regio-
selectivity relationship.
78[b]
51[c]
7
8
1
2
1g
1h
92
Results and Discussion
To access a series of biaryl compounds, various aromatic io-
dides were prepared for palladium-catalyzed coupling reac-
tions with arylmetals or related compounds (Table 1). For
this purpose, a previously reported method was employed
by using anisole as a substrate (product 1a; Table 1,
entry 1).[9e] Similarly, the use of the base that was generated
61[d]
9
1
1
1i
1j
60
71
in situ from ZnCl2·TMEDA (0.5 equiv) and LiACTHNUGRTNEUNG(TMP)
(1.5 equiv) in THF with 1,4-dimethoxybenzene for 2 h led,
after subsequent trapping with iodine, to product 1b in 82%
yield (Table 1, entry 2). In the naphthalene series, iodides
1c–1 f were furnished in satisfying yields by using
10
[a] After purification by column chromatography on silica gel. [b] From
1-chloronaphthalene, a mixture was obtained under the same reaction
conditions. [c] From 2-cyanonaphthalene, a mixture was obtained under
the same reaction conditions. [d] 2,4-Diiodo-3-methoxypyridine was also
isolated in 29% yield. [e] Ref. [9e].
ZnCl2·TMEDA (1 equiv) and LiACTHNUGRTNEUNG(TMP) (3 equiv) under the
same reaction conditions. Whereas 2,3-dimethoxynaphtha-
lene is logically functionalized at its free 1-position (Table 1,
entry 3), two different sites next to the substituent can be at-
tacked in the case of 2-substituted naphthalenes.[10] By using
methoxy, chloro, and methyl ester substituents, regioselec-
tive deprotometalation was observed in favor of the 3-posi-
tion (Table 1, entries 4–6). 1-Iodoisoquinoline, which has
previously been synthesized from isoquinoline by using Li-
methoxy group when treated in a similar manner (Table 1,
entry 10).
Next, we turned to the coupling of these iodides with aryl-
metals and related compounds under palladium catalysis.
For this purpose, we first considered the Negishi coupling[13]
of arylzinc chlorides that were prepared from their corre-
sponding lithiated compounds. In 2008, we showed the bene-
fit of a sequential deprotolithiation/transmetalation-coupling
reaction sequence by using ZnCl2·TMEDA as a transmetala-
tion agent and activated chlorides as the coupling part-
ACHTUNGTRENNUNG(TMP)/ZnACHTUNGTRENNUNG
(tBu)2,[11] was isolated herein in a similar 92%
yield (Table 1, entry 7). The reactions of 3- and 4-methoxy-
pyridine regioselectively afforded the corresponding 4- and
3-iodo derivatives, respectively (Table 1, entries 8, 9), as pre-
viously observed by using Li
2-chloro-6-methoxypyridine was functionalized next to the
(tBu)2.[12] Finally,
ACHUTGTNRNEUG(N TMP)/ZnACHTUGNTRENNUGN
Chem. Eur. J. 2013, 19, 7944 – 7960
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7945

Y. S. Halauko, F. Mongin et al.
ners.[14] Transposition to iodides 1g, 1i, 1c, and 1g was at-
tempted by using arylzinc chlorides that were generated
from anisole and 1,4-dimethoxybenzene (Table 2). The use
of catalytic amounts of palladium(II) chloride and 1,1’-bis-
Table 3. Synthesis of biaryl compounds 2c–2x through a Suzuki-type
coupling reaction.
ACHTUNGTRENNUNG(diphenylphosphino)ferrocene (dppf) provided the expected
coupling products (2a–2d), but in low yields (9–36%).
ꢀ
ꢀ
Ar’ X
Entry
1
Ar B(OH)2
Prod- Yield
uct
[%][a]
Table 2. Synthesis of biaryl compounds 2a–2d through a deprotometala-
tion/coupling sequence.
1c
1g
2c
40
2
3
4
5
6
7
8
9
2d
2e
2 f
2g
2h
2i
80
71
81
65
50[b]
39
42
–
ꢀ
ꢀ
Entry
1
Ar H
Ar’ I
Product Yield
[%][a]
1g
1i
2a
2b
2c
36[b]
44
9
1h
1i
2
3
4
1c
1g
2d
23
1c
1c
[a] After purification by column chromatography on silica gel. [b] The
deprotometalation of isoquinoline (Table 1, entry 7), followed by treat-
ment with 4-iodoanisole in the presence of PdCl2 (2 mol.%) and dppf
(2 mol.%) in THF at reflux for 24 h, led to a complex mixture; similarly,
the deprotometalation of anisole (Table 1, entry 1), followed by treat-
ment with 1-iodoisoquinoline in the presence of PdCl2 (2 mol.%) and
dppf (2 mol.%) in THF at reflux for 24 h, did not afford compound 2a
but instead afforded a complex mixture.
2j
–
These disappointing results led us to consider Suzuki cou-
pling[15] of the synthesized iodides, as well as commercial
bromides, with commercially available arylboronic acids.
Under previously described conditions,[16] most of the at-
tempted reactions led to the expected coupling products
(Table 3). Products 2c and 2d, which had already been pre-
pared according to the method described in Table 2, en-
tries 3 and 4 in 9 and 23% yield, respectively, were isolated
by using 2,5-dimethoxyphenylboronic acid in 40 and 80%
yield, respectively (Table 3, entries 1 and 2). The same bor-
onic acid was also successfully used with 4-bromoisoquino-
line (Table 3, entry 3), 4-iodo-3-methoxypyridine (1h;
Table 3, entry 4), 3-iodo-4-methoxypyridine (1i; Table 3,
entry 5), and 2,3-dibromopyridine (Table 3, entry 6); in the
latter reaction, a major coupling product was noted in favor
of the 2-position. 3-Thienylboronic acid and 3-pyridylboron-
ic acid reacted with 1-iodo-2,3-dimethoxynaphthalene (1c)
to afford compounds 2i and 2j in moderate yields (Table 3,
10
11
12
1a
1b
2k
2l
90
88
81
2m
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Chem. Eur. J. 2013, 19, 7944 – 7960

Computed Acidity of Biaryl Compounds and their Metalation
Table 3. (Continued)
FULL PAPER
entries 7 and 8), possibly owing to more-important steric
hindrance (which could rationalize the 40% yield in Table 3,
entry 1) and no coupled product was obtained from 5-pyri-
midylboronic acid and 9-bromoanthracene (Table 3,
entry 9). The use of 2,4-dimethoxy-5-pyrimidylboronic acid
with methoxy-substituted iodobenzenes (Table 3, entries 10–
13), chloro-substituted iodo- and bromobenzenes (Table 3,
entries 14 and 15), 3-substituted 2-iodonaphthalenes
ꢀ
ꢀ
Ar’ X
Entry
Ar B(OH)2
Prod- Yield
uct
[%][a]
13
2n
37
(Table 3,
entries 16–18),
1-iodonaphthalene
(Table 3,
entry 19), 1-iodo- and 4-bromoisoquinolines (Table 3, en-
tries 20 and 21), and substituted iodopyridines (Table 3, en-
tries 22 and 23) led to a large range of biaryl compounds in
moderate-to-good yields (2k–2x).
To afford 3-methoxyphenyl-substituted compounds 2y
and 2z, Kumada coupling[17] was preferred (Table 4). The
application of catalytic amounts of palladium(II) chloride
14
15
2o
2p
78
71
Table 4. Synthesis of biaryl compounds 2y and 2z through a Kumada-
type coupling reaction.
16
17
18
1d
1e
1 f
2q
2r
2s
82
84
91
Entry
1
Ar MgBr
Ar’ X
Product
Yield [%][a]
50
ꢀ
ꢀ
2y
2
2z
52
[a] After purification by column chromatography on silica gel.
19
20
21
22
23
2t
90
68
80
38
75
and dppf[18] allowed us to isolate the corresponding coupling
products in moderate yields. Finally, 2,2’,5,5’-tetramethoxy-
biphenyl (2aa) was prepared in 64% yield through the
homocoupling of 2-iodo-1,4-dimethoxybenzene (1b) in the
presence of activated copper, according to a literature pro-
cedure.[19]
With these biaryl compounds in hands, next, we consid-
ered their deprotometalation by using the base that was gen-
erated in situ from ZnCl2·TMEDA (1 equiv) and LiACHTUNGTRENNUNG(TMP)
(3 equiv) in THF. Because the number of substances that we
investigated was rather large, we decided to present some
general trends in their computed CH acidity first. Then, the
experimental results for particular derivatives are discussed
in connection with their acidities and literature data.
1g
2u
2v
2w
2x
1h
1j
Computational aspects: Unfortunately, both experimental
and simulation data on CH acidity in biaryl compounds are
scarce. The main reasons for this lack of data are the neces-
sity of using very strong bases at low temperatures and the
possible side reactions of the generated carbanions. A brief
review of reports that were devoted to the experimental and
theoretical investigation of CH acidity in azines was present-
ed in our previous publication.[20] These works typically con-
[a] After purification by column chromatography on silica gel. [b] Major
coupling was with Br at the 2-position; competitive coupling with Br at
the 3-position was observed, but only gave the corresponding product in
a low (10%) yield.
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7947

Y. S. Halauko, F. Mongin et al.
DrGs
RT ln 10
1
cerned aromatic compounds for which side-group CH acidi-
ty was of interest; notable among these reported experimen-
tal studies are CH-acidity measurements on alkylated pyri-
dines in THF.[21]
Herein, the CH-acidity values for the biaryls were calcu-
lated within the DFT framework by using the same ap-
proach as that previously employed for substituted azoles,[22]
including arylpyrazoles[9f] and aryltriazoles,[9h] as well as
azines.[20] The gas-phase acidity of a compound was associat-
ed with its Gibbs energy (DacidG) of deprotonation, accord-
ing to Equations (1) and (2).
ð6Þ
pKaðR ꢀ HÞ ¼ 40:2 þ
The CH acidity of the (methoxy) side groups was not
taken into consideration because it was expected to be
lower and because these groups remained intact under the
employed synthetic conditions.
An investigation of gas-phase CH acidity is worthwhile
for the development of an acidity scale that is free of solvent
effects. The calculated DacidG values of the investigated com-
pounds range from 361 to 393 kcalmolꢀ1 (Scheme 1), which
are typical for weak CH acids. The corresponding pKaACHTUNGTRENNUNG(THF)
RꢀHðgÞ ! RꢀðgÞþHþ
ð1Þ
ð2Þ
values are given in Table 5 and Table 6, together with the
deprotometalation results, and are within the range 29–49.
Both series of data refer to the most-stable rotamers.
According to Alkorta and Elguero, biphenyls and biaryls
usually possess two rotational barriers, that is, planar (steric)
and perpendicular barriers (electronic).[24] In our case, the
available conformational space is limited, owing to the phys-
ical demands of bulky substituents; thus, global and local
minima could be easily found.
The global trends in the DacidG and pKa values, which
could be deduced by comparing compounds that contained
common 2,6-dimethoxypyrimidyl or mono/dimethoxyphenyl
moieties, are the same and can be summarized as follows.
First, the CH acidities of the corresponding positions corre-
late with the electron-donating or electron-withdrawing
effect of the aryl substituent. The most-prominent acidifying
effect was obtained by halogen insertion. On the contrary,
the protons a to the azine nitrogen atoms appeared to be
less prone to abstraction through an overriding base-pro-
moted mechanism.[25] Next, by considering the aromatic
rings, one can see that, in the remote parts of the systems,
the CH acidities are closer and suffer less from the influence
of substituents. Moreover, the pKa values at sites that are
adjacent to interaryl bonds are hampered, maybe by steric
factors.
ðgÞ
DacidG ¼ G0298ðRꢀÞþG0298ðHþÞꢀG0298ðRHÞ
All of the calculations were carried out by using the DFT
B3LYP method. The geometries were optimized by using
the 6-31G(d) basis set. No symmetry constraints were im-
posed. Because the biaryls included rotatable fragments, the
most-stable conformers were specified by using different ini-
tial values of the corresponding dihedral angles. To perform
stationary-point characterization and to calculate the zero-
point vibrational energies (ZPVE) and the thermal correc-
tions to the Gibbs free energy, vibrational frequencies were
calculated at the same level of theory. The single-point
energy calculations were performed by using the 6-311+G-
ACHTUNGTRENNUNG
(d,p) basis set. The gas-phase Gibbs energies (G0298) were
calculated for each species according to Equation (3) (no
scaling factors were applied).
G0298 ¼ EþZPVEþH0!298ꢀTS2098
ð3Þ
The solvent effects were evaluated by using the polarized
continuum model (PCM) with the default parameters for
THF.[23] The PCM energies were also calculated at the
B3LYP/6-311+GACHTUNGTRENNUNG(d,p) level of theory by using geometries
that were optimized for isolated structures. The cavity was
built up by using a united atom (UA) model that was ap-
plied on the atomic radii of the UFF force field. The Gibbs
energies in solution (Gs) were calculated for each species ac-
cording to Equation (4).
Deprotometalation results: By using the base that was gen-
erated in situ from ZnCl2·TMEDA (1 equiv) and LiACHTUNGTRENNUNG(TMP)
(3 equiv) in THF to perform the reaction with methoxy-sub-
stituted substrate 2aa, we found that, following subsequent
trapping with iodine, the abstraction of the most-acidic hy-
drogen atom occurred at the 4-position. This result is not
surprising, because all of the possible deprotonation sites
are adjacent to a methoxy group (Table 5, entry 1). In the
case of compound 2c, functionalization also took place at
the 4-position of the 2,5-dimethoxyphenyl group. The reason
why the most-acidic hydrogen atom next to the methoxy
group on the naphthyl ring is not attacked could be due to
steric hindrance (peri position), but it is difficult to under-
stand why the reaction does not take place at the most-
acidic 3-position of the 2,5-dimethoxyphenyl group (Table 5,
entry 2). Unfortunately, attempts to functionalize com-
pounds 2y and 2z led to complex mixtures (Table 5, en-
tries 3 and 4).
Gs ¼ G0298þEPCMꢀE
ð4Þ
To cancel out any possible errors, the pKa values were cal-
culated by means of the isodesmic reaction method. We con-
sidered the homodesmic reaction shown in Equation (5),
ꢀ
where Het H is an appropriate six-membered heterocycle
with a known pKa value.
RꢀHðsÞþHetꢀ ! RꢀðsÞþHetꢀHðsÞ
ð5Þ
ðsÞ
We chose bare pyridine as a reference compound (pKa
ACHTUNGTRENNUNG
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Computed Acidity of Biaryl Compounds and their Metalation
FULL PAPER
Scheme 1. Calculated values of the Gibbs energies (DacidG) [kcalmolꢀ1] for deprotonation of the investigated biaryl compounds at their corresponding
positions (the lowest value for each compound is given in bold).
Starting from 3-substituted thiophene 2i, double deproto-
nation at its most-acidic 2 and 5-positions was observed
under the same reaction conditions (Table 5, entry 5). This
result is not surprising, because such a base has previously
led to the double deprotonation of doubly activated five-
membered aromatic heterocycles.[9f,h,26]
Starting from the 1-substituted quinoline 2a, an attack on
a hydrogen atom that was far from being the most acidic
was noted (Table 5, entry 6), which led us to attempt to ra-
tionalize this result. In 2011, Garcꢄa-ꢅlvarez, Mulvey, and
Parkinson published a study by using DOSY NMR spectro-
scopy about the nature of the base that was generated from
ZnCl2·TMEDA and Li(TMP) (3 equiv) in THF. The authors
suggested a mixture that contained Zn(TMP)2 (as a specta-
tor species) and a Li(TMP)/LiCl (1:2) complex with the pos-
sible (reversible) coordination of TMEDA (as a possible
active lithiating base) as being the nature of the base.[9k]
Thus, it seems reasonable to consider a pathway that in-
volves an initial lithiation step; subsequent transmetalation
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
through ZnACTHNUGRTENUNG(TMP)2 could then take place, thereby leading to
more-stabilized derivatives. It is well-established that azines
can be deprotolithiated at positions that are adjacent to
Chem. Eur. J. 2013, 19, 7944 – 7960
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7949

Y. S. Halauko, F. Mongin et al.
Table 5. Calculated pKaACHTUNGTRENNUNG(THF) values for biaryl compounds 2aa, 2a–2j, 2y, and 2z and the results of the deprotometalation/iodination sequence.
[a]
[a]
ꢀ
Ar H
ꢀ
Ar H
Entry
Prod-
uct
Yield
[%][b]
Entry
Prod-
uct
Yield
[%][b]
1
2aa
3aa
48
8
2e
3e
63
2
2c
3c
45
9
2 f
3 f
71
[c]
[d]
3
2y
–
–
10
2b
–
–
[c]
[c]
4
5
2z
–
–
11
12
2g
–
–
2i
3i
59
2h
3h
38
[e]
6
2a
3a
39
13
2j
–
–
[c]
7
2d
–
–
[a] The arrows that point toward the formula of the biaryl compounds indicate the observed deprotometalation/iodination sites, whilst the numbers are
the calculated pKa values for deprotonation at the corresponding positions (the lowest value for each compound is given in bold). [b] After purification
by column chromatography on silica gel. [c] A complex mixture was obtained. [d] Obtained in low (10%) yield, owing to degradation. [e] A mixture of
the 6-iodo- (20% yield), 2-iodo- (15% yield), and 6,4’-diiodo derivatives (12% yield) was obtained.
7950
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Chem. Eur. J. 2013, 19, 7944 – 7960

Computed Acidity of Biaryl Compounds and their Metalation
FULL PAPER
their nitrogen atoms (as atoms that are able to coordinate
the metal of the base) upon treatment under kinetic condi-
tions. It is also known that, when possible (for example, in
manner next to the nitrogen atom, thus keeping the 5-posi-
tion, which corresponded to the most-acidic hydrogen atom,
intact. Nevertheless, degradation was also observed in this
case and the iodide was formed in low yield (Table 5,
entry 10). When the 2-methoxyphenyl group was replaced
by a 2,5-dimethoxyphenyl group (substrate 2g), a mixture
was obtained from which it was not possible to unambigu-
ously identify the components (Table 5, entry 11). When the
2,5-dimethoxyphenyl group was connected to the 2-position
of 3-bromopyridine, deprotometalation occurred at the 4-
position, that is, the adjacent position to the halogen atom.
The 6-position, that is, next to the nitrogen atom, is not at-
tacked in this case, possibly owing to the decidedly lower
pKa value at the 4-position (Table 5, entry 12). The reaction
of pyridine 2j, which was 3-substituted by a 2,3-dimethoxy-
1-naphthyl group, was more complex. Indeed, under the
same reaction conditions, a mixture that contained at least
the 6-iodo- (20% yield), 2-iodo- (15% yield), and 6,4’-
diiodo derivatives (12% yield) was obtained (Table 5,
entry 13). These compounds show a nonregioselective de-
protometalation at both positions next to the pyridine nitro-
gen atom, which could be related to the similar acidities of
the hydrogen atoms at the 2- and 6-positions.
reversible reactions with LiACHTNUTRGNE(UNG TMP)), the lithiated compounds
thus formed can be converted into more-stable isomers that
contain lithium atoms at positions that are remote from the
ring nitrogen atoms (with decreased charge repulsion).[27] In
this example, a direct attack of LiACTHNUTRGNEUNG(TMP) next to the azine
nitrogen atom is likely. The reason why there is no isomeri-
zation of the thus-formed lithiated compound in this case
could be due to the absence of more-stable isomers (notably
for steric reasons). In addition, if transmetalation through
ZnACHTUNGTRENNUNG(TMP)2 rapidly takes place, a structure may be formed in
which both the lithium and zinc species synergistically con-
tribute to the stabilization. Previously, we isolated crystals
several weeks at ꢀ188C after the deprotonative metalation
of anisole[9e] and N-phenylpyrrole[9a] by using the same base
and X-ray diffraction analysis showed TMEDA-chelated di-
arylzincs as the corresponding structures. The latter species
were supposed to come from the corresponding TMP-con-
taining lithium zincates[28] through the loss of Li
ACTHUNTGRENNG(U TMP) with
time. Such a lithium zincate, if formed in the case of com-
pound 2a, could be particularly stabilized through coordina-
tion of both the azine nitrogen atom and the methoxy group
to the lithium atom (Scheme 2).
We then turned our attention to the deprotometalation of
5-substituted 2,4-dimethoxypyrimidines (Table 6). With a
methoxyphenyl group as the substituent (substrates 2k–2n),
the reaction regioselectively took place at the free position
Table 6. Calculated pKaACTHNUTRGNEUNG(THF) values for biaryl compounds 2k–2x and
the results of the deprotometalation/iodination sequence.
[a]
ꢀ
Ar H
Entry
Prod-
uct
Yield
[%][b]
Scheme 2. Proposed structure of the deprotometalated species that is ob-
tained from compound 2a.
Introducing a second methoxy group onto the phenyl sub-
stituent led to a complex mixture (Table 5, entry 7). When
the 2,5-dimethoxyphenyl group was moved from the 1-posi-
tion of isoquinoline to the 4-position, the reaction occurred
at the 1-position (Table 5, entry 8), as previously observed in
1
2k
3k
97
the case of unsubstituted isoquinoline by using Li
ACHTUNGTRENNUNG
ACHTUNGTRENN(UNG TMP)Zn-
(tBu)2.[11] Both the 1 and 3-positions next to the isoquinoline
nitrogen atom could be attacked and abstraction of the hy-
drogen atom at the 1-position, which was more acidic than
that at the 3-position, was observed.
2
2l
3l
94
With 3-methoxypyridine 2 f, which was 4-substituted by a
2,5-dimethoxyphenyl group, the reaction also took place
next to the heterocyclic nitrogen atom; in addition, the
more-acidic 2-position was favored over the 6-position
(Table 5, entry 9). Again, coordination by the nitrogen atom
overcomes its acidity and the methoxy substituents are not
capable of competing in directing the reaction. With 4-meth-
3
2m
3m
89
ACHTUNGTRENNUNG
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7951

Y. S. Halauko, F. Mongin et al.
Table 6. (Continued)
Entry
Table 6. (Continued)
Entry
[a]
[a]
ꢀ
Ar H
ꢀ
Ar H
Prod-
uct
Yield
[%][b]
Prod-
uct
Yield
[%][b]
4
5
2n
3n
82
78
11
2u
3u
85
2o
3o
12
2v
3v
60[f]
3p
3p’
70[d]
15[e]
6
2p
[g]
13
14
2w
–
–
3x
3x’
66[h]
26[i]
2x
7
2q
3q
82
[a] The arrows that point toward the formula of the biaryl compounds in-
dicate the observed deprotometalation/iodination sites, whilst the num-
bers are the calculated pKa values for deprotonation at the corresponding
positions (the lowest value for each compound is given in bold). [b] After
purification by column chromatography on silica gel. [c] Either com-
pound 2s was recovered or degradation was observed, depending on the
reaction temperature. [d] I at the 6-position. [e] I at the 6- and 3’-posi-
tion. [f] Diiodide. [g] A 1:1 mixture of the 6-iodo- and 2’-iodo derivatives
was obtained. [h] I at the 6-position. [i] I at 6- and 5’-position.
8
2r
3r
83
on the pyrimidine ring (Table 6, entries 1–4). This result was
confirmed in the case of compounds 3l–3n (Table 6, en-
tries 2–4) by X-ray diffraction from suitable crystals (see the
Supporting Information). Once again, this result demon-
strates that coordination by the nitrogen atom overcomes
the acidity issue, because the methoxy substituent(s) on the
phenyl ring make(s), in all cases, the adjacent hydrogen
atom(s) more acidic than the pyrimidine hydrogen atom.
The chloro group is a strong acidifying substituent and,
even if steric hindrance makes reaction at adjacent positions
difficult, deprotonation of the ring on which it is connected
should be favored through long-range effects.[29] Neverthe-
less, in spite of the relatively low pKa values on the chloro-
phenyl rings, 5-substituted 2,4-dimethoxypyrimidines 2o and
2p were attacked at their free pyrimidine position to afford
the corresponding monoiodides (3o and 3p) in 70–78%
yield (Table 6, entries 5 and 6). In the case of compound 2p,
[c]
9
2s
–
–
10
2t
3t
67
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Chem. Eur. J. 2013, 19, 7944 – 7960

Computed Acidity of Biaryl Compounds and their Metalation
FULL PAPER
diiodide 3p’, which resulted from deprotonation at both the
pyrimidine and benzene groups, was also isolated in 15%
yield (Table 6, entry 6).
Here we should briefly account for the observed results,
because, at first glance, they are at variance with what has
been reported previously in other series.[9f,20] The formation
of a particular product could be rationalized if two opposing
tendencies are taken into account, namely: 1) the most-
acidic position attracts the deprotometalation/iodination se-
The use of Li
N
strate 2p led to the formation of different iodides, depend-
ing on the reaction time. When quenching was performed
with iodine after 30 min, compound 3p was also isolated,
but in a moderate 28% yield, owing to competitive degrada-
tion. Extending the reaction time to 2 h led to the formation
of many iodides and more degradation. Iodide 3p was no
longer detected among the different products, but diiodide
3p’ (about 10% yield), as well as the monoiodide that re-
sulted from deprotonation at the 3’-position (10% yield),
were observed. Even if they were distorted owing to degra-
quence when its pKaACHTNUGRTENUNG(THF) value is low enough (less than
about 35), and 2) in the presence of an atom that is able to
coordinate a metal (methoxy oxygen atoms or, above all,
azine nitrogen atoms), the reaction is directed to a nearby
position. Similar diiodination reactions have previously been
reported for pyridylpyrazoles,[9f] but the pyrazole’s nitrogen
atom was less influenced with respect to the a orientation in
comparison with the nitrogen atoms in the pyrimidine or
pyridine groups reported herein. These results can be ex-
plained in terms of the higher pKb value of pyrazole (11.5)
dation, these results with LiACTHNUTRGENUGN(TMP) suggested the prelimina-
ry formation of a kinetic lithiated compound on the diazine
ring (at its free position, next to the nitrogen atom, as previ-
ously observed in the pyridine series)[27d] and its subsequent
isomerization into more-stable derivatives. By using the lith-
ium/zinc reagent at room temperature (reaction time: 2 h),
the diazinylmetal is formed in a more chemoselective way
and isolated compounds 3p and 3p’ are both iodinated at
the 6-position, thus showing preference for species that are
metalated next to the nitrogen atom.
as compared with pyridine (8.7), thus leading to a weaken-
[30]
ꢀ
ing of the metal ligand s interaction.
To show the value of such iodinated biaryl compounds,
we considered their further functionalization through palla-
dium-catalyzed reactions. For this purpose, we selected 5-
substituted 6-iodo-2,4-dimethoxypyrimidines 3l, 3q, 3o, and
3r and converted them through Suzuki cross-coupling[15]
with 2-chloro- or 2-aminophenylboronic acid under previ-
ously reported conditions[9i] into derivatives 4l, 4q, 4o, and
4r in high yields (Table 7).
With 3-methoxy-2-naphthyl or 3-chloro-2-naphthyl sub-
stituents, 5-substituted 2,4-dimethoxypyrimidines 2q and 2r
were only functionalized at their free pyrimidine position
(Table 6, entries 7 and 8). However, we could not react the
corresponding 3-methoxycarbonyl-2-naphthyl analogue (2s),
owing to its degradation under the required conditions for
deprotometalation (Table 6, entry 9). With a 1-naphthyl sub-
stituent (2t), the reaction logically took place next to the ni-
trogen atom, thus furnishing iodide 3t in 67% yield
(Table 6, entry 10). Next, we turned to 5-isoquinolyl-2,4-di-
methoxypyrimidine substrates 2u and 2v. With 1-isoquinolyl
as the substituent, the reaction occurred at the most-acidic
site next to the nitrogen atom and monoiodide 3u was iso-
lated in 85% yield (Table 6, entry 11). In contrast, with the
4-isoquinolyl analogue as the substituent, dimetalation took
place at two sites next to nitrogen atoms, thus giving, after
trapping, diiodide 3v in 60% yield (Table 6, entry 12). Final-
ly, we studied the behavior of 5-pyridyl-2,4-dimethoxypyri-
midine substrates 2w and 2x. With the 3-methoxy-4-pyridyl
substrate, the deprotonation was not regioselective and a 1:1
mixture of the 6-iodo- and 2’-iodo derivatives (owing to re-
actions at the most-acidic sites next to the pyrimidine and
pyridine nitrogen atoms, respectively) was obtained
(Table 6, entry 13). In the case of 6-chloro-2-methoxy-3-pyr-
idyl analogue, the reaction took place at the only free posi-
tion next to the nitrogen atom, thus affording compound 3x
in 66% yield. As already observed from compound 2p, diio-
dide 3x’, which resulted from deprotonation of both the pyr-
imidine and pyridine rings (next to the chloro group) was
also isolated in 26% yield (Table 6, entry 14). The structures
of compounds 3o, 3q, 3t–3v, and 3x’ were unambiguously
identified by X-ray diffraction (see the Supporting Informa-
tion).
[31]
ꢀ
Intramolecular C H arylation
of chlorides 4l and 4q
was considered to afford the corresponding tetracycle and
pentacycle, respectively. From compound 4q, by using differ-
ent ligands, such as tri(cyclohexyl)phosphine, tri(tert-butyl)-
phosphine, and Xantphos (4,5-bis(diphenylphosphino)-9,9-
dimethylxanthene), in the presence of palladium(II) acetate
as a transition-metal source and cesium carbonate as a base
led to degradation together with starting material after stir-
ring for 18 h in 1,4-dioxane at 1058C or o-xylene at 1508C.
In contrast, in the case of compound 4l, tri(cyclohexyl)phos-
phine was efficiently employed, thereby affording dibenzo-
AHCTUNGTREG[NNUN f,h]quinazoline 5l after purification in 68% yield
(Scheme 3).
The intramolecular N-arylation[5,32] of chlorides 4o and 4r
was attempted under various reaction conditions with re-
course to nickel-, copper-, and palladium-based catalysts.
Unfortunately, either degradation or recovery of the starting
material was obtained from both substrates. The reaction of
4-(2-aminophenyl)-3-bromo-2-(2,5-dimethoxyphenyl)pyri-
dine was easier; indeed, under the same conditions that
were used to prepare it from the corresponding 4-iodo sub-
strate (3h), both Suzuki coupling and subsequent cyclization
took place, thus furnishing azacarbazole 5h in 70% yield
(Scheme 4).
Conclusion
The results obtained herein show that the “all-TMP” mixed
lithium/zinc base is a powerful reagent for the room-temper-
ature deprotonative metalation of biaryl compounds, includ-
Chem. Eur. J. 2013, 19, 7944 – 7960
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7953

Y. S. Halauko, F. Mongin et al.
Table 7. Synthesis of biaryl compounds 4l, 4q, 4o, and 4r through a
Suzuki-type coupling reaction.
Entry
X
Product
Yield [%][a]
ꢀ
Ar I (3)
Scheme 4. Palladium-catalyzed coupling/cyclization sequence from com-
pound 3h.
1
Cl
3l
4l
92
low temperatures, favor deprotometalation at the most-
acidic sites through thermodynamic control. In particular,
deprotonation in the position a to the azine nitrogen atom
is thermodynamically unlikely, owing to destabilization of
the formed carbanion by repulsion with neighboring elec-
tron lone pairs.[22a]
On the contrary, in the majority of cases, employing the
“all-TMP” mixed lithium/zinc base drives the substitution at
the position a to the azine nitrogen atom, which is also the
favored position when using lithium amides under kinetic
control and is supposed to result from the coordination of
the nitrogen atom to lithium (Table 5, entries 1 and 2 and
Table 6). If no azine nitrogen atom is present, the reaction
can either be directed by stronger CH acidities (Table 5, en-
tries 1, 5, and 12) or by adjacent methoxy groups, which are
also able to coordinate metal atoms (Table 5, entries 1 and
2).
2
3
4
Cl
3q
3o
3r
4q
4o
4r
91
94
91
NH2
NH2
Experimental Section
Unless otherwise noted, the reactions were performed under an argon at-
mosphere. THF was distilled over sodium/benzophenone. Column chro-
matographic separations were performed on silica gel (40–63 mm). Melt-
ing points were measured on a Kofler apparatus. IR spectra were record-
ed on a Perkin–Elmer Spectrum 100 spectrometer. 1H and 13C nuclear
Magnetic Resonance (NMR) spectra were recorded on a Bruker Avance
III spectrometer at 300 and 75 MHz, respectively. 1H chemical shifts (d)
are reported in ppm relative to the residual solvent peak, 13C chemical
shifts are reported relative to the central peak of the solvent signal,[33]
and coupling constants (J) are given in Hz. High-resolution mass spectro-
scopy (HRMS) was performed at the CRMPO (Centre Rꢀgional de Me-
sures Physiques de l’Ouest) in Rennes on either a Waters Q-TOF 2 or a
Bruker micrOTOF Q II instrument in positive electrospray CI mode.
[a] After purification by column chromatography on silica gel.
2,3-Dimethoxynaphthalene[34] and methyl-2-naphthoate[35] were prepared
according to literature procedures. 1-Iodo-2,3,4-trimethoxybenzene[36] and
2-iodo-1,3-dimethoxybenzene[37] were synthesized as described previously.
1-Iodo-2-methoxynaphthalene was prepared in 93% yield by adapting a
reported procedure.[38] ZnCl2·TMEDA was prepared as described previ-
ously.[39]
General procedure A for the synthesis of aryl iodides 1:[9e] To a stirring,
cooled (08C) solution of 2,2,6,6-tetramethylpiperidine (0.82 mL,
3.0 mmol) in THF (3 mL) were successively added BuLi (3.0 mmol,
about 1.6m in hexanes) and ZnCl2·TMEDA (0.30 g, 1.0 mmol). The mix-
ture was stirred for 10 min at 08C before the introduction of the appro-
priate substrate (1.0 mmol). After 2 h at RT, a solution of I2 (1.0 g,
3.0 mmol) in THF (5 mL) was added. The mixture was stirred overnight
before the addition of a saturated aqueous solution of Na2S2O3 (10 mL)
Scheme 3. Palladium-catalyzed cyclization of compound 4l (Cy=cyclo-
hexyl).
ing sensitive heterocycles, for which lithium bases are inap-
propriate. The regioselectivities obtained during this study
are relevant because they provide information on the possi-
ble role of both the CH acidities and the substituent coordi-
nating abilities in determining the course of these reactions.
From the literature, it is known that lithium amides, when
employed in polar solvents (e.g., THF) and at moderately
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Computed Acidity of Biaryl Compounds and their Metalation
FULL PAPER
and extraction with Et2O (20 mL) and EtOAc (2ꢆ20 mL). The combined
organic layer was dried over Na2SO4 and concentrated under reduced
pressure.
6-Chloro-3-iodo-2-methoxypyridine (1j): General procedure A was em-
ployed by using 2-chloro-6-methoxypyridine. Purification by flash chro-
matography on silica gel (2:98 EtOAc/n-heptane) gave compound 1j
(71% yield) as
a
yellow powder: M.p. 648C; 1H NMR (CDCl3,
General procedure B for the synthesis of biaryls 2a–2d through a depro-
tonation/coupling sequence:[14] To a stirring, cooled (ꢀ788C) solution of
the appropriate substrate (4.0 mmol) in THF (5 mL) were added BuLi
(4.0 mmol, about 1.6m in hexanes) and, after 2 h at RT, ZnCl2·TMEDA
(1.2 g, 4.0 mmol). After a further 1 h at RT, the aryl halide (4.0 mmol),
PdCl2 (14 mg, 80 mmol, 2 mol%), and dppf (44 mg, 80 mmol, 2 mol%)
were added and the mixture was heated at reflux for 24 h. Then, the reac-
tion mixture was diluted with water and extracted with Et2O and EtOAc.
The combined organic layer was dried over Na2SO4 and concentrated
under reduced pressure.
300 MHz): d=3.97 (s, 3H), 6.66 (d, J=7.8 Hz, 1H), 7.88 ppm (d, J=
7.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=55.4, 76.8, 118.1, 148.7,
149.6, 161.7 ppm; HRMS (ESI): m/z calcd for C6H635ClINO: 269.9183
[M+H]+; found: 269.9182.
1-(2-Methoxyphenyl)isoquinoline (2a): General procedure B was em-
ployed by using anisole and 1-iodoisoquinoline. Purification by flash
chromatography on silica gel (10:90 EtOAc/n-heptane) gave compound
2a (36% yield) as a yellow oil: 1H NMR (CDCl3, 300 MHz): d=3.69 (s,
3H), 7.06 (d, J=8.3 Hz, 1H), 7.12 (td, J=7.4, 0.9 Hz, 1H), 7.39 (dd, J=
7.4, 1.7 Hz, 1H), 7.47 (m, 2H), 7.66 (m, 2H), 7.71 (br d, J=8.3 Hz, 1H),
7.86 (d, J=8.3 Hz, 1H), 8.62 ppm (d, J=5.7 Hz, 1H); 13C NMR (CDCl3,
75 MHz): d=55.6, 111.2, 120.2, 120.9, 126.8, 126.9, 127.9, 128.0, 128.8,
130.0, 130.1, 131.3, 136.3, 142.4, 157.2, 159.2 ppm; HRMS (ESI): m/z
calcd for C16H13NO: 235.0997 [M+Na]+; found: 423.0068.
General procedure C for the synthesis of biaryls 2c–2x through a Suzuki-
type coupling reaction:[16]
A degassed solution of the aryl halide
(10 mmol), the boronic acid (10 mmol), Na2CO3 (2.3 g, 22 mmol), PdCl2
(35 mg, 0.2 mmol, 2 mol%), and PPh3 (0.16 g, 0.6 mmol, 6 mol%) in
water (11 mL), EtOH (8 mL), and 1,2-dimethoxyethane (25 mL) was
heated at reflux for 24 h. Then, the reaction mixture was diluted with
water (50 mL) and extracted with CH2Cl2 (3ꢆ40 mL). The combined or-
ganic layer was dried over Na2SO4 and concentrated under reduced pres-
sure.
4-Methoxy-3-(2-methoxyphenyl)pyridine (2b): General procedure B was
employed by using anisole and 3-iodo-4-methoxypyridine. Purification by
flash chromatography on silica gel (40:60 EtOAc/n-heptane) gave com-
pound 2b (44% yield) as a yellow oil: 1H NMR (CDCl3, 300 MHz): d=
3.77 (s, 3H), 3.83 (s, 3H), 6.88 (d, J=5.7 Hz, 1H), 6.98–7.06 (m, 2H),
7.24 (dd, J=7.5, 1.8 Hz, 1H), 7.34–7.41 (m, 2H), 8.36 (s, 1H), 8.48 ppm
(d, J=5.7 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=55.5, 55.7, 106.9,
111.1, 120.4, 128.0, 124.3, 129.7, 131.3, 149.9, 150.7, 157.0, 164.0 ppm;
HRMS (ESI): m/z calcd for C13H14NO2: 216.1024 [M+H]+; found:
216.1021.
General procedure D for the synthesis of biaryls 2y and 2z through a
Kumada-type coupling reaction:[18]
A solution of the aryl halide
(3.0 mmol), the aryl Grignard reagent (3.6 mmol, about 1.0m in THF),
PdCl2 (10 mg, 60 mmol, 2 mol%), and dppf (33 mg, 60 mmol, 2 mol%) in
THF (5 mL) was heated at reflux for 8 h. Then, the reaction mixture was
diluted with water (20 mL) and extracted with Et2O (20 mL) and CH2Cl2
(2ꢆ20 mL). The combined organic layer was dried over Na2SO4 and con-
centrated under reduced pressure.
General procedure E for the synthesis of biaryl iodides 3:[9e] To a stirring,
cooled (08C) solution of 2,2,6,6-tetramethylpiperidine (0.82 mL,
3.0 mmol) in THF (3 mL) were successively added BuLi (3.0 mmol,
about 1.6m in hexanes) and ZnCl2·TMEDA (0.30 g, 1.0 mmol). The mix-
ture was stirred for 10 min at 08C before the introduction of the appro-
priate biaryl substrate (1.0 mmol). After 2 h at RT, a solution of I2 (1.0 g,
3.0 mmol) in THF (5 mL) was added. The mixture was stirred overnight
before the addition of a saturated aqueous solution of Na2S2O3 (10 mL)
and extraction with Et2O (20 mL) and EtOAc (2ꢆ20 mL). The combined
organic layer was dried over Na2SO4 and concentrated under reduced
pressure.
1-(2,5-Dimethoxyphenyl)-2,3-dimethoxynaphthalene (2c): General proce-
dure C was employed by using 2,5-dimethoxyphenylboronic acid and
1-iodo-2,3-dimethoxynaphthalene. Purification by flash chromatography
on silica gel (17:83 EtOAc/n-heptane) gave compound 2c (40% yield) as
a white solid: M.p. 898C; 1H NMR (CDCl3, 300 MHz): d=3.65 (s, 3H),
3.70 (s, 3H), 3.78 (s, 3H), 4.02 (s, 3H), 6.81–7.00 (m, 3H), 7.19–7.25 (m,
2H), 7.30–7.37 (m, 2H), 7.74 ppm (d, J=8.1 Hz, 1H); 13C NMR (CDCl3,
75 MHz): d=55.7, 55.8, 56.4, 60.9, 107.0, 112.4, 114.0, 117.6, 123.9, 125.2,
125.7, 126.1, 126.7, 128.5, 128.7, 131.2, 146.9, 152.0, 152.3, 153.5 ppm;
HRMS (ESI): m/z calcd for C20H20O4Na: 347.1259 [M+Na]+; found:
347.1257.
1-(2,5-Dimethoxyphenyl)isoquinoline (2d): General procedure
C was
employed by using 2,5-dimethoxyphenylboronic acid and 1-iodoisoquino-
line. Purification by flash chromatography on silica gel (20:80 EtOAc/
n-heptane) gave compound 2d (80% yield) as a brown solid: M.p. 128–
1298C; 1H NMR (CDCl3, 300 MHz): d=3.64 (s, 3H), 3.81 (s, 3H), 6.98
(m, 3H), 7.49 (m, 1H), 7.67 (m, 2H), 7.74 (dd, J=8.4, 0.9 Hz, 1H), 7.86
(d, J=8.2 Hz, 1H), 8.62 ppm (d, J=5.7 Hz, 1H); 13C NMR (CDCl3,
75 MHz): d=56.0, 56.5, 112.8, 115.6, 116.5, 120.4, 126.8, 127.1, 127.8,
128.1, 129.5, 130.1, 126.3, 142.3, 151.5, 153.9, 158.9 ppm; HRMS (ESI): m/
z calcd for C17H15NO2Na: 288.1000 [M+Na]+; found: 288.0999.
General procedure F for the synthesis of biaryls 4:[9i] To a degassed solu-
tion of the aryl iodide (1.0 mmol), the boronic acid (4.0 mmol), and CsF
(0.30 g, 2.0 mmol) in 1,4-dioxane (10 mL) were added [PdACTHUNRGTNEUNG(dba)2] (28 mg,
50 mmol, 5 mol%, dba=dibenzylideneacetone) and PPh3 (52 mg,
0.20 mmol, 10 mol%). The resulting mixture was heated for 18 h at
1058C before cooling and diluting with Et2O (50 mL), washing with
water (20 mL), and extracting with CH2Cl2 (3ꢆ30 mL). After drying over
Na2SO4, the solvent was evaporated under reduced pressure and the cou-
pled compound was isolated by flash chromatography on silica gel (10:90
EtOAc/n-heptane).
4-(2,5-Dimethoxyphenyl)isoquinoline (2e): General procedure C was em-
ployed by using 2,5-dimethoxyphenylboronic acid and 4-bromoisoquino-
line. Purification by flash chromatography on silica gel (20:80 EtOAc/
n-heptane) gave compound 2e (71% yield) as a white solid: M.p. 110–
1118C; 1H NMR (CDCl3, 300 MHz): d=3.64 (s, 3H), 3.80 (s, 3H), 6.89
(t, J=1.7 Hz, 1H), 6.99 (d, J=1.7 Hz, 2H), 7.61 (m, 3H), 8.01 (m, 1H),
8.47 (s, 1H), 9.26 ppm (s, 1H); 13C NMR (CDCl3, 75 MHz): d=55.9, 56.3,
112.4, 114.4, 117.8, 125.6, 126.8, 127.1, 127.8, 128.3, 130.2, 130.3, 134.8,
143.3, 151.7, 152.1, 153.7 ppm; HRMS (ESI): m/z calcd for C17H15NO2Na:
288.1000 [M+Na]+; found: 288.1002.
1-Iodo-2,3-dimethoxynaphthalene (1c): General procedure A was em-
ployed by using 2,3-dimethoxynaphthalene. Purification by flash chroma-
tography on silica gel (14:86 EtOAc/n-heptane) gave compound 1c (79%
yield) as a white powder: M.p. 518C; 1H NMR (CDCl3, 300 MHz): d=
3.93 (s, 3H), 3.99 (s, 3H), 7.17 (s, 1H), 7.39–7.44 (m, 2H), 7.64–7.68 (m,
1H), 8.04–8.08 ppm (s, 1H); 13C NMR (CDCl3, 75 MHz): d=55.8, 60.5,
96.0, 108.1, 125.5, 125.9, 126.9, 130.1, 131.6, 131.7, 150.1, 151.6 ppm;
HRMS (ESI): m/z calcd for C12H11IO2Na: 336.9701 [M+Na]+; found:
336.9703.
4-(2,5-Dimethoxyphenyl)-3-methoxypyridine (2 f): General procedure C
was employed by using 2,5-dimethoxyphenylboronic acid and 4-iodo-3-
methoxypyridine. Purification by flash chromatography on silica gel
(40:60 EtOAc/n-heptane) gave compound 2 f (81% yield) as a yellow
solid: M.p. 1038C; 1H NMR (CDCl3, 300 MHz): d=3.69 (s, 3H), 3.75 (s,
3H), 3.84 (s, 3H), 6.80 (m, 1H), 6.88 (m, 2H), 7.17 (br d, J=4.7 Hz, 1H),
8.26 (br d, J=4.7 Hz, 1H), 8.34 ppm (br s, 1H); 13C NMR (CDCl3,
75 MHz): d=55.6, 56.2, 56.3, 112.4, 114.2, 116.6, 125.6, 125.7, 134.0, 135.2,
2-Chloro-3-iodonaphthalene (1e): General procedure A was employed
by using 2-chloronaphthalene. Purification by flash chromatography on
silica gel (5:95 EtOAc/n-heptane) gave compound 1e (78% yield) as a
white powder: M.p. 101–1028C; 1H NMR (CDCl3, 300 MHz): d=7.44–
7.54 (m, 2H), 7.65–7.74 (m, 2H), 7.88 (s, 1H), 8.35 ppm (s, 1H);
13C NMR (CDCl3, 75 MHz): d=95.5, 126.5, 126.8, 126.8, 127.1, 127.3,
133.1, 133.4, 134.5, 139.6 ppm; HRMS (ESI/ASAP): m/z calcd for
C10H635ClI: 287.9203 [M]+; found: 287.9203.
Chem. Eur. J. 2013, 19, 7944 – 7960
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7955

Y. S. Halauko, F. Mongin et al.
142.2, 150.8, 153.1, 153.3 ppm; HRMS (ESI): m/z calcd for C14H15NO3Na:
268.0950 [M+Na]+; found: 268.0946.
1H), 6.92 (d, J=8.5 Hz, 1H), 8.14 ppm (s, 1H); 13C NMR (CDCl3,
75 MHz): d=54.2, 54.9, 56.1, 60.9, 61.0, 107.1, 113.1, 120.0, 125.5, 142.3,
152.0, 154.0, 158.2, 164.6, 168.8 ppm; HRMS (ESI): m/z calcd for
C15H18N2O5Na: 329.1113 [M+Na]+; found: 329.1112.
3-(2,5-Dimethoxyphenyl)-4-methoxypyridine (2g): General procedure C
was employed by using 2,5-dimethoxyphenylboronic acid and 3-iodo-4-
methoxypyridine. Purification by flash chromatography on silica gel
(40:60 EtOAc/n-heptane) gave compound 2g (65% yield) as a white
solid: M.p. 103–1048C; 1H NMR (CDCl3, 300 MHz): d=3.72 (s, 3H),
3.79 (s, 3H), 3.84 (s, 3H), 6.82 (dd, J=2.6, 0.9 Hz, 1H), 6.91 (m, 2H),
8.36 (s, 1H), 8.48 ppm (d, J=5.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz):
d=55.4, 55.8, 56.4, 106.4, 112.5, 113.9, 117.4, 123.6, 124.9, 150.5, 151.4,
151.5, 153.4, 163.0 ppm; HRMS (ESI): m/z calcd for C14H15NO3Na:
268.0950 [M+Na]+; found: 268.0951.
5-(2,6-Dimethoxyphenyl)-2,4-dimethoxy-pyrimidine (2n): General proce-
dure C was employed by using 2,4-dimethoxypyrimidine-5-boronic acid
and 2-iodo-1,3-dimethoxybenzene. Purification by flash chromatography
on silica gel (10:90 EtOAc/n-heptane) gave compound 2n (37% yield) as
a white solid: M.p. 1248C; 1H NMR (CDCl3, 300 MHz): d=3.74 (s, 6H),
3.93 (s, 3H), 4.03 (s, 3H), 6.63 (d, J=8.4 Hz, 2H), 7.31 (t, J=8.4 Hz,
1H), 8.08 ppm (s, 1H); 13C NMR (CDCl3, 75 MHz): d=54.1, 54.8, 56.0
(2C), 104.1 (2C), 109.0, 110.8, 129.8, 158.4, 159.3 (2C), 164.7, 169.1 ppm;
HRMS (ESI): m/z calcd for C14H16N2O4Na: 299.1008 [M+Na]+; found:
299.1019.
3-Bromo-2-(2,5-dimethoxyphenyl)pyridine (2h): General procedure
C
was employed by using 2,5-dimethoxyphenylboronic acid and 2,3-dibro-
mopyridine. Purification by flash chromatography on silica gel (20:80
EtOAc/n-heptane) gave compound 2h (60% yield) as a yellow solid:
M.p. 1118C; 1H NMR (CDCl3, 300 MHz): d=3.75 (s, 3H), 3.79 (s, 3H),
6.85 (dd, J=2.8, 0.4 Hz, 1H), 6.92 (d, J=0.4 Hz, 1H), 6.94 (d, J=2.8 Hz,
1H), 7.15 (dd, J=8.1, 4.7 Hz, 1H), 7.95 (dd, J=8.1, 1.4 Hz, 1H),
8.61 ppm (dd, J=4.7, 1.4 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=55.9,
56.3, 112.4, 115.5, 115.6, 122.2, 123.5, 129.9, 140.3, 147.9, 150.9, 153.5,
157.1 ppm; HRMS (ESI): m/z calcd for C13H1279BrNO2Na: [M+Na]+
315.9949; found: 315.9951.
5-(2-Chlorophenyl)-2,4-dimethoxypyrimidine (2o): General procedure C
was employed by using 2,4-dimethoxypyrimidine-5-boronic acid and
1-chloro-2-iodobenzene. Purification by flash chromatography on silica
gel (10:90 EtOAc/n-heptane) gave compound 2o (78% yield) as a white
solid: M.p. 988C; 1H NMR (CDCl3, 300 MHz): d=3.97 (s, 3H), 4.04 (s,
3H), 7.30 (m, 3H), 4.46 (m, 1H), 8.14 ppm (s, 1H); 13C NMR (CDCl3,
75 MHz): d=54.2, 55.0, 114.4, 126.8, 129.6, 129.8, 131.9, 132.6, 134.5,
158.3, 165.2, 168.4 ppm; HRMS (ESI): m/z calcd for C12H1135ClN2O2Na:
273.0407 [M+Na]+; found: 273.0405.
3-(2,3-Dimethoxy-1-naphthyl)thiophene (2i): General procedure C was
employed by using thiophene-3-boronic acid and 1-iodo-2,3-dimethoxy-
naphthalene. Purification by flash chromatography on silica gel (10:90
EtOAc/n-heptane) gave compound 2i (39% yield) as a white solid: M.p.
1168C; 1H NMR (CDCl3, 300 MHz): d=3.63 (s, 3H), 4.02 (s, 3H), 7.21
(m, 2H), 7.27 (m, 1H), 7.36 (dd, J=3.0, 1.2 Hz, 1H), 7.40 (m, 1H), 7.47
(dd, J=4.9, 3.0 Hz, 1H), 7.62 (br d, J=8.4 Hz, 1H), 7.74 ppm (br d, J=
8.1 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=55.8, 61.1, 107.0, 124.1,
124.7, 124.8, 125.4, 125.7, 126.7, 127.1, 128.9, 130.3, 131.3, 135.4, 147.2,
152.3 ppm; HRMS (ESI): m/z calcd for C16H14O2SNa: 293.0612
[M+Na]+; found: 293.0611.
5-(2,4-Dichlorophenyl)-2,4-dimethoxypyrimidine (2p): General proce-
dure C was employed by using 2,4-dimethoxypyrimidine-5-boronic acid
and 1-bromo-2,4-dichlorobenzene. Purification by flash chromatography
on silica gel (5:95 EtOAc/n-heptane) gave compound 2p (71% yield) as
a white solid: M.p. 1148C; 1H NMR (CDCl3, 300 MHz): d=3.94 (s, 3H),
4.01 (s, 3H), 7.18 (d, J=8.2 Hz, 1H), 7.27 (dd, J=2.0, 8.2 Hz, 1H), 7.45
(d, J=2.0 Hz, 1H), 8.10 ppm (s, 1H); 13C NMR (CDCl3, 75 MHz): d=
54.2, 55.0, 113.3, 127.1, 129.6, 131.1, 132.6, 134.7, 135.1, 158.4, 165.3,
168.3 ppm; HRMS (ESI): m/z calcd for C12H1035Cl2N2O2Na: 307.0017
[M+Na]+; found: 307.0019.
2,4-Dimethoxy-5-(3-methoxy-2-naphthyl)pyrimidine (2q): General proce-
dure C was employed by using 2,4-dimethoxypyrimidine-5-boronic acid
and 2-iodo-3-methoxynaphthalene. Purification by flash chromatography
on silica gel (15:85 EtOAc/n-heptane) gave compound 2q (82% yield) as
a white solid: M.p. 108–1098C; 1H NMR (CDCl3, 300 MHz): d=3.89 (s,
3H), 3.97 (s, 3H), 4.06 (s, 3H), 7.21 (s, 1H), 7.33–7.49 (m, 2H), 7.69 (s,
1H), 7.77 (m, 2H), 8.25 ppm (s, 1H); 13C NMR (CDCl3, 75 MHz): d=
54.2, 54.9, 55.7, 105.7, 113.3, 124.1, 124.3, 126.6, 126.8, 127.8, 128.5, 130.8,
134.6, 155.7, 158.4, 164.8, 169.0; ppm HRMS (ESI): m/z calcd for
C17H16N2O3Na: 319.1059 [M+Na]+; found: 319.1056.
3-(2,3-Dimethoxy-1-naphthyl)pyridine (2j): General procedure
C was
employed by using pyridine-3-boronic acid and 1-iodo-2,3-dimethoxy-
naphthalene. Purification by flash chromatography on silica gel (25:75
EtOAc/n-heptane) gave compound 2j (42% yield) as a yellow solid:
M.p. 104–1058C; 1H NMR (CDCl3, 300 MHz): d=3.64 (s, 3H), 4.03 (s,
3H), 7.24–7.30 (m, 2H), 7.37–7.47 (m, 3H), 7.73–7.79 (m, 2H), 8.66–
8.70 ppm (m, 2H); 13C NMR (CDCl3, 75 MHz): d=55.7, 61.0, 107.7,
123.2, 124.4, 125.1, 125.5, 126.8, 128.1, 128.2, 131.3, 131.9, 138.3, 147.0,
148.5, 151.1, 152.1 ppm; HRMS (ESI): m/z calcd for C17H15NO2Na:
288.1000 [M+Na]+; found: 288.1003.
5-(3-Chloro-2-naphthyl)-2,4-dimethoxypyrimidine (2r): General proce-
dure C was employed by using 2,4-dimethoxypyrimidine-5-boronic acid
and 2-chloro-3-iodonaphthalene. Purification by flash chromatography on
silica gel (7:93 EtOAc/n-heptane) gave compound 2r (84% yield) as a
yellow solid: M.p. 108–1108C; 1H NMR (CDCl3, 300 MHz): d=3.98 (s,
3H), 4.07 (s, 3H), 7.51 (m, 2H), 7.55–7.83 (m, 3H), 7.95 (s, 1H),
8.21 ppm (s, 1H); 13C NMR (CDCl3, 75 MHz): d=54.2, 55.1, 114.7, 126.7,
126.9, 127.3, 127.8, 127.9, 130.6, 131.0, 131.8, 132.1, 133.7, 158.3, 165.3,
168.8 ppm; HRMS (ESI): m/z calcd for C16H1335ClN2O2Na: 323.0563
[M+Na]+; found: 323.0560.
2,4-Dimethoxy-5-(2-methoxyphenyl)pyrimidine (2k): General procedure
C was employed by using 2,4-dimethoxypyrimidine-5-boronic acid and
2-iodoanisole. Purification by flash chromatography on silica gel (10:90
EtOAc/n-heptane) gave compound 2k (90% yield) as a brown solid:
M.p. 968C; 1H NMR (CDCl3, 300 MHz): d=3.77 (s, 3H), 3.95 (s, 3H),
4.03 (s, 3H), 6.99 (m, 2H), 7.23 (dd, J=7.5, 1.7 Hz, 1H), 7.35 (m, 1H),
8.18 ppm (s, 1H); 13C NMR (CDCl3, 75 MHz): d=54.1, 54.8, 55.6, 111.2,
113.1, 120.5, 122.4, 129.5, 131.4, 157.2, 158.6, 164.6, 168.6 ppm; HRMS
(ESI): m/z calcd for C13H14N2O3Na: 269.0902 [M+Na]+; found: 269.0904.
5-(2,5-Dimethoxyphenyl)-2,4-dimethoxypyrimidine (2l): General proce-
dure C was employed by using 2,4-dimethoxypyrimidine-5-boronic acid
and 2-iodo-1,4-dimethoxybenzene. Purification by flash chromatography
on silica gel (10:90 EtOAc/n-heptane) gave compound 2l (88% yield) as
a yellow solid: M.p. 74–768C; 1H NMR (CDCl3, 300 MHz): d=3.73 (s,
3H), 3.78 (s, 3H), 3.96 (s, 3H), 4.03 (s, 3H), 6.85 (m, 3H), 8.19 ppm (s,
1H); 13C NMR (CDCl3, 75 MHz): d=54.2, 54.9, 55.9, 56.4, 112.4, 113.0,
113.9, 117.5, 123.3, 151.5, 153.5, 158.6, 164.7, 168.6 ppm; HRMS (ESI): m/
z calcd for C14H16N2O4Na: 299.1008 [M+Na]+; found: 299.1009.
Methyl-3-(2,4-dimethoxy-5-pyrimidyl)-2-naphthoate (2s): General proce-
dure C was employed by using 2,4-dimethoxypyrimidine-5-boronic acid
and methyl-3-iodonaphthalene-2-carboxylate. Purification by flash chro-
matography on silica gel (20:80 EtOAc/n-heptane) gave compound 2s
(91% yield) as
a
yellow solid: M.p. 130–1328C; 1H NMR (CDCl3,
300 MHz): d=3.79 (s, 3H), 3.92 (s, 3H), 4.06 (s, 3H), 7.58 (m, 2H), 7.73
(br s, 1H), 7.87 (br d, J=7.5 Hz, 1H), 7.94 (dd, J=7.9, 1.4 Hz, 1H), 8.27
(br s, 1H), 8.51 ppm (s, 1H); 13C NMR (CDCl3, 75 MHz): d=52.2, 54.0,
55.1, 117.2, 127.2, 127.9, 128.6, 128.7, 128.9, 130.3, 130.5, 131.7, 132.1,
134.8, 156.2, 164.9, 167.9, 168.5 ppm; HRMS (ESI): m/z calcd for
C18H16N2O4Na: 347.1008 [M+Na]+; found: 347.1010.
2,4-Dimethoxy-5-(2,3,4-trimethoxyphenyl)pyrimidine (2m): General pro-
cedure C was employed by using 2,4-dimethoxypyrimidine-5-boronic acid
and 1-iodo-2,3,4-trimethoxybenzene. Purification by flash chromatogra-
phy on silica gel (20:80 EtOAc/n-heptane) gave compound 2m (81%
yield) as a yellow solid: M.p. 1408C; 1H NMR (CDCl3, 300 MHz): d=
3.77 (s, 3H), 3.89 (s, 6H), 3.97 (s, 3H), 4.03 (s, 3H), 6.71 (d, J=8.5 Hz,
2,4-Dimethoxy-5-(1-naphthyl)pyrimidine (2t): General procedure C was
employed by using 2,4-dimethoxypyrimidine-5-boronic acid and 1-iodo-
naphthalene. Purification by flash chromatography on silica gel (5:95
EtOAc/n-heptane) gave compound 2t (90% yield) as a white solid: M.p.
7956
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Chem. Eur. J. 2013, 19, 7944 – 7960

Computed Acidity of Biaryl Compounds and their Metalation
FULL PAPER
968C; 1H NMR (CDCl3, 300 MHz): d=3.92 (s, 3H), 4.10 (s, 3H), 7.37–
7.59 (m, 5H), 7.89 (d, J=8.2 Hz, 2H), 8.26 ppm (s, 1H); 13C NMR
(CDCl3, 75 MHz): d=54.0, 54.9, 115.0, 125.3, 125.5, 125.9, 126.2, 128.0,
128.4, 128.7, 131.2, 132.1, 133.6, 158.8, 165.1, 168.9 ppm; HRMS (ESI): m/
z calcd for C16H14N2O2Na: 289.0953 [M+Na]+; found: 289.0952.
7.03 (d, J=8.3 Hz, 1H), 7.10 (td, J=7.4, 0.9 Hz, 1H), 7.38 (dd, J=
7.4,1.7 Hz, 1H), 7.47 (m, 2H), 7.65 (m, 2H), 7.73 (br d, J=8.3 Hz, 1H),
8.16 ppm (s, 1H); 13C NMR (CDCl3, 75 MHz): d=55.6, 109.5, 111.2,
121.0, 125.5, 127.0, 127.5, 128.3, 128.4, 130.6, 130.7, 130.8, 131.5, 137.9,
157.2, 160.2 ppm; HRMS (ESI): m/z calcd for C16H13INO: 362.0042
[M+H]+; found: 362.0042.
1-(2,4-Dimethoxy-5-pyrimidyl)isoquinoline (2u): General procedure
C
was employed by using 2,4-dimethoxypyrimidine-5-boronic acid and
1-iodoisoquinoline. Purification by flash chromatography on silica gel
(40:60 EtOAc/n-heptane) gave compound 2u (68% yield) as a white
solid: M.p. 132–1348C; 1H NMR (CDCl3, 300 MHz): d=3.92 (s, 3H),
4.08 (s, 3H), 7.52 (m, 1H), 7.69 (m, 3H), 7.87 (m, 1H), 8.38 (s, 1H),
8.61 ppm (d, J=5.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=54.3, 55.2,
114.8, 120.9, 126.9, 127.1, 127.5, 127.9, 130.4, 136.5, 142.5, 154.2, 159.6,
165.6, 168.9 ppm; HRMS (ESI): m/z calcd for C15H13N3O2Na: 290.0905
[M+Na]+; found: 290.0904.
1-(4-Iodo-2,5-dimethoxyphenyl)-2,3-dimethoxynaphthalene (3c): General
procedure E was employed by using compound 2c. Purification by flash
chromatography on silica gel (10:90 EtOAc/n-heptane) gave compound
3c (45% yield) as a colorless oil: 1H NMR (CDCl3, 300 MHz): d=3.65
(s, 3H), 3.69 (s, 3H), 3.79 (s, 3H), 4.02 (s, 3H), 6.73 (s, 1H), 7.23–7.31
(m, 3H), 7.38 (m, 1H), 7.46 (s, 1H), 7.74 ppm (br d, J=8.1 Hz, 1H);
13C NMR (CDCl3, 75 MHz): d=55.8, 56.5, 57.1, 61.0, 84.9, 107.2, 114.9,
122.6, 124.1, 125.3, 125.5, 126.3, 126.8, 127.9, 128.4, 131.2, 146.9, 152.3,
152.4, 152.6 ppm; HRMS (ESI): m/z calcd for C20H19IO4Na: 473.0226
[M+Na]+; found: 473.0230.
2,4-Dimethoxy-5-(3-methoxy-4-pyridyl)pyrimidine (2w): General proce-
dure C was employed by using 2,4-dimethoxypyrimidine-5-boronic acid
and 4-iodo-3-methoxypyridine. Purification by flash chromatography on
silica gel (70:30 EtOAc/n-heptane) gave compound 2w (38% yield) as a
yellow solid: M.p. 1708C; 1H NMR (CDCl3, 300 MHz): d=3.88 (s, 3H),
3.97 (s, 3H), 4.03 (s, 3H), 7.21 (d, J=4.5 Hz, 1H), 8.25 (s, 1H), 8.29 (d,
J=4.8 Hz, 1H), 8.36 ppm (s, 1H); 13C NMR (CDCl3, 75 MHz): d=54.3,
55.1, 56.4, 110.5, 125.4, 130.2, 134.2, 142.6, 153.1, 158.9, 165.3, 168.3 ppm;
HRMS (ESI): m/z calcd for C12H13N3O3Na: 270.0855 [M+Na]+; found:
270.0870.
4-(2,5-Dimethoxyphenyl)-1-iodoisoquinoline (3e): General procedure E
was employed by using compound 2e. Purification by flash chromatogra-
phy on silica gel (5:95 EtOAc/n-heptane) gave compound 3e (63%
1
yield) as a white solid: M.p. 1218C; H NMR (CDCl3, 300 MHz): d=3.63
(s, 3H), 3.80 (s, 3H), 6.85 (dd, J=2.3, 1.2 Hz, 1H), 6.99 (m, 2H), 7.53 (m,
1H), 7.64 (m, 2H), 8.16 (m, 1H), 8.19 ppm (s, 1H); 13C NMR (CDCl3,
75 MHz): d=55.9, 56.2, 112.4, 114.6, 117.7, 125.6, 126.4, 127.0, 128.9,
131.0, 131.2, 131.3, 133.0, 135.4, 143.3, 151.6, 153.7 ppm; HRMS (ESI): m/
z calcd for C17H14INO2: 413.9967 [M+Na]+; found: 413.9965.
5-(6-Chloro-2-methoxy-3-pyridyl)-2,4-dimethoxypyrimidine (2x): General
procedure C was employed by using 2,4-dimethoxypyrimidine-5-boronic
acid and 6-chloro-3-iodo-2-methoxypyridine. Purification by flash chro-
matography on silica gel (20:80 EtOAc/n-heptane) gave compound 2x
(75% yield) as a white solid: M.p. 1668C; 1H NMR (CDCl3, 300 MHz):
d=3.93 (s, 3H), 3.97 (s, 3H), 4.04 (s, 3H), 6.97 (d, J=7.7 Hz, 1H), 7.52
(d, J=7.7 Hz, 1H), 8.23 ppm (s, 1H); 13C NMR (CDCl3, 75 MHz): d=
54.3, 54.5, 55.1, 110.4, 114.9, 116.4, 141.9, 148.0, 158.7, 161.0, 164.9,
168.5 ppm; HRMS (ESI): m/z calcd for C12H1235ClN3O3Na: 304.0465
[M+Na]+; found: 304.0466.
4-(2,5-Dimethoxyphenyl)-2-iodo-3-methoxypyridine (3 f): General proce-
dure E was employed by using compound 2 f. Purification by flash chro-
matography on silica gel (10:90 EtOAc/n-heptane) gave compound 3 f
(71% yield) as a yellow solid: M.p. 1108C; 1H NMR (CDCl3, 300 MHz):
d=3.49 (s, 3H), 3.75 (s, 3H), 3.78 (s, 3H), 6.87 (m, 1H), 6.94 (m, 2H),
7.19 (d, J=4.8 Hz, 1H), 8.15 ppm (d, J=4.8 Hz, 1H); 13C NMR (CDCl3,
75 MHz): d=56.0, 56.4, 61.0, 112.6, 115.6, 116.0, 117.4, 124.9, 126.7, 139.6,
145.4, 150.6, 153.6, 154.6 ppm; HRMS (ESI): m/z calcd for
C14H14INO3Na: 393.9916 [M+Na]+; found: 393.9918.
3-Bromo-2-(2,5-dimethoxyphenyl)-4-iodopyridine (3h): General proce-
dure E was employed by using compound 2h. Purification by flash chro-
matography on silica gel (15:85 EtOAc/n-heptane) gave compound 3h
2-Methoxy-1-(3-methoxyphenyl)naphthalene (2y): General procedure D
was employed by using 3-methoxyphenylmagnesium bromide and 1-iodo-
2-methoxynaphthalene. Purification by flash chromatography on silica
gel (n-heptane) gave compound 2y (50% yield) as a white solid: M.p.
1128C; 1H NMR (CDCl3, 300 MHz): d=3.86 (s, 3H), 3.87 (s, 3H), 6.98
(m, 3H), 7.34–7.47 (m, 4H), 7.55 (m, 1H), 7.84 (m, 1H), 7.90 ppm (br d,
J=8.9 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=55.3, 56.9, 112.9, 113.9,
116.5, 123.5, 123.6, 125.3, 125.4, 126.5, 127.9, 129.1, 129.2, 129.3, 133.7,
137.9, 153.8, 159.5 ppm; HRMS (ESI): m/z calcd for C18H16O2Na:
287.1048 [M+Na]+; found: 287.1049.
(38% yield) as
a
yellow solid: M.p. 168–1708C; 1H NMR (CDCl3,
300 MHz): d=3.75 (s, 3H), 3.78 (s, 3H), 6.80 (d, J=2.5 Hz, 1H), 6.90 (d,
J=9.0 Hz, 1H), 6.95 (dd, J=9.0, 2.5 Hz, 1H), 7.78 (br d, J=4.0 Hz, 1H),
8.18 ppm (br d, J=4.0 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=55.9,
56.3, 112.4, 114.1, 115.1, 115.7, 130.0, 131.2, 134.2, 147.4, 150.6, 153.5,
158.0 ppm; HRMS (ESI): m/z calcd for C13H1179BrINO2Na: 441.8916
[M+Na]+; found: 441.8914.
3-(2,3-Dimethoxy-1-naphthyl)-2,5-diiodothiophene (3i): General proce-
dure E was employed by using compound 2i. Purification by flash chro-
matography on silica gel (15:85 EtOAc/n-heptane) gave compound 3i
9-(3-Methoxyphenyl)anthracene (2z): General procedure
D was em-
ployed by using 3-methoxyphenylmagnesium bromide and 9-iodoanthra-
cene. Purification by flash chromatography on silica gel (n-heptane) gave
compound 2z (52% yield) as a yellow solid: M.p. 1108C; 1H NMR
(CDCl3, 300 MHz): d=3.88 (s, 3H), 7.10 (m, 3H), 7.41 (m, 2H), 7.53 (m,
3H), 7.80 (d, J=8.7 Hz, 2H), 8.08 (d, J=8.4 Hz, 2H), 8.53 ppm (s, 1H);
13C NMR (CDCl3, 75 MHz): d=55.3, 113.4, 116.7, 123.8, 125.2 (2C),
125.5 (2C), 126.7, 127.0 (2C), 128.4 (2C), 129.5 (2C), 130.2, 131.5 (2C),
137.0, 140.3, 159.7 ppm; HRMS (ESI): m/z calcd for C21H16ONa:
307.1099 [M+Na]+; found: 307.1099.
(59% yield) as
a
yellow solid: M.p. 130–1328C; 1H NMR (CDCl3,
300 MHz): d=3.73 (s, 3H), 4.02 (s, 3H), 7.04 (s, 1H), 7.30 (m, 3H), 7.41
(m, 1H), 7.76 ppm (br d, J=8.1 Hz, 1H); 13C NMR (CDCl3, 75 MHz):
d=55.8, 61.3, 76.4, 81.2, 108.0, 124.5, 125.2, 125.6, 125.7, 126.8, 127.8,
131.1, 139.8, 144.9, 147.5, 152.0 ppm; HRMS (ESI): m/z calcd for
C16H12I2O2SNa: 544.8545 [M+Na]+; found: 544.8549.
5-(2,3-Dimethoxy-1-naphthyl)-2-iodopyridine: General procedure E was
employed to afford the product (20% yield), which was identified by its
NMR data: 1H NMR (CDCl3, 300 MHz): d=3.66 (s, 3H), 4.03 (s, 3H),
7.26–7.31 (m, 2H), 7.35–7.44 (m, 3H), 7.77 (d, J=8.1 Hz, 1H), 7.88 (d,
J=8.1 Hz, 1H), 8.42 ppm (d, J=1.8 Hz, 1H); 13C NMR (CDCl3,
75 MHz): d=55.7, 61.1, 108.0, 116.0, 124.6, 124.7, 125.6, 126.6, 126.9,
127.7, 131.3, 131.7, 134.5, 140.3, 146.9, 151.8, 151.9 ppm.
4-Iodo-2,2’,5,5’-tetramethoxybiphenyl (3aa): General procedure E was
employed by using 2aa. Purification by flash chromatography on silica
gel (10:90 EtOAc/n-heptane) gave compound 3aa (48% yield) as a white
solid: M.p. 112–1138C; 1H NMR (CDCl3, 300 MHz): d=3.73 (s, 6H),
3.79 (s, 3H), 3.83 (s, 3H), 6.76 (s, 1H), 6.81–6.93 (m, 3H), 7.36 ppm (s,
1H); 13C NMR (CDCl3, 75 MHz): d=55.9, 56.6, 56.8, 57.1, 84.6, 112.6,
113.6, 114.3, 117.3, 122.8, 128.1, 128.8, 151.3, 151.8, 152.5, 153.5 ppm;
HRMS (ESI): m/z calcd for C16H17IO4Na: 423.0069 [M+Na]+; found:
423.0068.
3-(2,3-Dimethoxy-1-naphthyl)-2-iodopyridine: General procedure E was
employed to afford the product (15% yield), which was identified by its
NMR data: 1H NMR (CDCl3, 300 MHz): d=3.77 (s, 3H), 4.05 (s, 3H),
7.12 (d, J=8.4 Hz, 1H), 7.32 (m, 1H), 7.43 (m, 2H), 7.56 (m, 1H), 7.79
(d, J=8.0 Hz, 1H), 8.48 ppm (m, 1H).
3-Iodo-1-(2-methoxyphenyl)isoquinoline (3a): General procedure E was
employed by using 2a. Purification by flash chromatography on silica gel
(15:85 EtOAc/n-heptane) gave compound 3a (39% yield) as a brown
solid: M.p. 120–1228C; 1H NMR (CDCl3, 300 MHz): d=3.69 (s, 3H),
2-Iodo-5-(4-iodo-2,3-dimethoxy-1-naphthyl)pyridine: General procedure
E was employed to afford the product (12% yield), which was identified
Chem. Eur. J. 2013, 19, 7944 – 7960
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7957

Y. S. Halauko, F. Mongin et al.
by its NMR data: 1H NMR (CDCl3, 300 MHz): d=3.72 (s, 3H), 4.00 (s,
3H), 7.36–7.40 (m, 3H), 7.52 (ddd, J=8.2, 4.8, 3.4 Hz, 1H), 7.89 (d, J=
8.1 Hz, 1H), 8.20 (dt, J=8.5, 0.8 Hz, 1H), 8.40 ppm (d, J=2.2 Hz, 1H);
13C NMR (CDCl3, 75 MHz): d=60.8, 61.4, 97.3, 117.0, 125.6, 126.6, 127.3,
128.2, 130.5, 131.2, 132.5, 132.6, 134.6, 140.0, 149.4, 152.1, 153.2 ppm.
4-Iodo-2,6-dimethoxy-5-(3-methoxy-2-naphthyl)pyrimidine (3q): General
procedure E was employed by using compound 2q. Purification by flash
chromatography on silica gel (10:90 EtOAc/n-heptane) gave compound
3q (82% yield) as
a
white solid: M.p. 1948C; 1H NMR (CDCl3,
300 MHz): d=3.88 (s, 6H), 4.05 (s, 3H), 7.22 (s, 1H), 7.64–7.51 (m, 2H),
7.59 (s, 1H), 7.79 ppm (m, 2H); 13C NMR (CDCl3, 75 MHz): d=54.8,
55.4, 55.8, 105.9, 119.5, 124.0, 126.7, 126.9, 127.3, 128.0, 128.6, 131.4,
134.6, 134.9, 155.3, 163.0, 167.6 ppm; HRMS (ESI): m/z calcd for
C17H15IN2O3Na: 445.0025 [M+Na]+; found: 445.0027.
4-Iodo-2,6-dimethoxy-5-(2-methoxyphenyl)pyrimidine (3k): General pro-
cedure E was employed by using compound 2k. Purification by flash
chromatography on silica gel (15:85 EtOAc/n-heptane) gave compound
3k (97% yield) as
a
brown solid: M.p. 1308C; 1H NMR (CDCl3,
300 MHz): d=3.77 (s, 3H), 3.88 (s, 3H), 4.02 (s, 3H), 7.03 (m, 3H),
7.42 ppm (m, 1H); 13C NMR (CDCl3, 75 MHz): d=54.8, 55.4, 55.8, 111.3,
119.7, 120.6, 125.7, 130.3, 131.7, 134.7, 157.1, 163.0, 167.5 ppm; HRMS
(ESI): m/z calcd for C13H13IN2O3Na: 394.9869 [M+Na]+; found:
394.9869.
5-(3-Chloro-2-naphthyl)-4-iodo-2,6-dimethoxypyrimidine (3r): General
procedure E was employed by using compound 2r. Purification by flash
chromatography on silica gel (5:95 EtOAc/n-heptane) gave compound 3r
(83% yield) as
a
white solid: M.p. 188–1908C; 1H NMR (CDCl3,
300 MHz): d=3.90 (s, 3H), 4.07 (s, 3H), 7.53 (m, 2H), 7.70 (s, 1H), 7.83
(m, 2H), 7.99 ppm (s, 1H); 13C NMR (CDCl3, 75 MHz): d=54.9, 55.6,
120.7, 126.6, 127.1, 127.6, 127.8, 128.1, 131.7, 131.8, 131.9, 133.6, 134.0,
134.4, 163.4, 167.5 ppm; HRMS (ESI): m/z calcd for C16H1235ClIN2O2Na:
448.9530 [M+Na]+; found: 448.9532.
5-(2,5-Dimethoxyphenyl)-4-iodo-2,6-dimethoxypyrimidine (3l): General
procedure E was employed by using compound 2l. Purification by flash
chromatography on silica gel (20:80 EtOAc/n-heptane) gave compound
3l (94% yield) as
a
white solid: M.p. 1328C; 1H NMR (CDCl3,
300 MHz): d=3.72 (s, 3H), 3.78 (s, 3H), 3.87 (s, 3H), 4.01 (s, 3H), 6.65
(d, J=2.8 Hz, 1H), 6.91 ppm (m, 2H); 13C NMR (CDCl3, 75 MHz): d=
54.8, 55.4, 55.8, 56.4, 112.5, 114.7, 117.5, 119.5, 126.4, 134.5, 151.3, 153.4,
162.9, 167.3 ppm; HRMS (ESI): m/z calcd for C14H15IN2O4Na: 424.9974
[M+Na]+; found: 424.9977.
4-Iodo-2,6-dimethoxy-5-(1-naphthyl)pyrimidine (3t): General procedure
E was employed by using compound 2t. Purification by flash chromatog-
raphy on silica gel (10:90 EtOAc/n-heptane) gave compound 3t (67%
yield) as a white solid: M.p. 968C; 1H NMR (CDCl3, 300 MHz): d=3.83
(s, 3H), 4.09 (s, 3H), 7.33 (dd, J=7.1, 1.1 Hz, 1H), 7.43–7.58 (m, 4H),
7.94 ppm (m, 2H); 13C NMR (CDCl3, 75 MHz): d=54.9, 55.6, 120.9,
124.9, 125.6, 126.2, 126.6, 128.5, 128.6, 129.1, 131.7, 133.7, 134.4, 135.1,
163.4, 167.8 ppm; HRMS (ESI): m/z calcd for C16H13IN2O2Na: 414.9919
[M+Na]+; found: 414.9917.
4-Iodo-2,6-dimethoxy-5-(2,3,4-trimethoxyphenyl)pyrimidine (3m): Gener-
al procedure E was employed by using compound 2m. Purification by
flash chromatography on silica gel (20:80 EtOAc/n-heptane) gave com-
pound 3m (89% yield) as a yellow solid: M.p. 1108C; 1H NMR (CDCl3,
300 MHz): d=3.77 (s, 3H), 3.89 (s, 3H), 3.90 (s, 6H), 4.02 (s, 3H), 6.73
(s, J=8.5 Hz, 1H), 6.77 ppm (s, J=8.5 Hz, 1H); 13C NMR (CDCl3,
75 MHz): d=54.8, 55.4, 56.0, 61.0, 61.1, 107.1, 119.6, 123.6, 125.8, 135.1,
142.2, 151.8, 154.4, 163.0, 167.5 ppm; HRMS (ESI): m/z calcd for
C15H17IN2O5Na: 455.0080 [M+Na]+; found: 455.0073.
1-(4-Iodo-2,6-dimethoxy-5-pyrimidyl)isoquinoline (3u): General proce-
dure E was employed by using compound 2u. Purification by flash chro-
matography on silica gel (30:70 EtOAc/n-heptane) gave compound 3u
(85% yield) as
a
white solid: M.p. 179–1808C; 1H NMR (CDCl3,
300 MHz): d=3.84 (s, 3H), 4.08 (s, 3H), 7.58 (m, 2H), 7.73 (m, 2H), 7.92
(d, J=8.3 Hz, 1H), 8.66 ppm (d, J=5.7 Hz, 1H); 13C NMR (CDCl3,
75 MHz): d=54.9, 55.6, 120.2, 121.3, 126.1, 127.3, 127.6, 127.8, 130.5,
132.7, 136.5, 142.6, 156.3, 163.5, 168.0 ppm; HRMS (ESI): m/z calcd for
C15H12IN3O2Na: 415.9872 [M+Na]+; found: 415.9868.
5-(2,6-Dimethoxyphenyl)-4-iodo-2,6-dimethoxypyrimidine (3n): General
procedure E was employed by using compound 2n. Purification by flash
chromatography on silica gel (15:85 EtOAc/n-heptane) gave compound
3n (82% yield) as a white solid: M.p. 166–1688C; 1H NMR (CDCl3,
300 MHz): d=3.75 (s, 6H), 3.87 (s, 3H), 4.02 (s, 3H), 6.63 (d, J=8.4 Hz,
2H), 7.38 ppm (t, J=8.4 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=54.7,
55.3, 56.1 (2C), 104.2 (2C), 114.5, 116.5, 130.5, 135.7, 158.1 (2C), 163.0,
167.8 ppm; HRMS (ESI): m/z calcd for C14H15IN2O4Na: 424.9974
[M+Na]+; found: 424.9971.
1-Iodo-4-(4-iodo-2,6-dimethoxy-5-pyrimidyl)isoquinoline (3v): General
procedure E was employed by using compound 2v. Purification by flash
chromatography on silica gel (20:80 EtOAc/n-heptane) gave compound
3v (60% yield) as
a
white solid: M.p. 2488C; 1H NMR (CDCl3,
300 MHz): d=3.82 (s, 3H), 4.07 (s, 3H), 7.34 (m, 1H), 7.70 (m, 2H), 8.10
(s, 1H), 8.20 ppm (m, 1H); 13C NMR (CDCl3, 75 MHz): d=55.0, 55.8,
116.7, 124.8, 128.3, 129.2, 129.4, 131.6, 131.7, 133.6, 134.8, 135.1, 144.4,
163.9, 168.0 ppm; HRMS (ESI): m/z calcd for C15H11I2N3O2Na: 541.8838
[M+Na]+; found: 541.8837.
5-(2-Chlorophenyl)-4-iodo-2,6-dimethoxypyrimidine (3o): General proce-
dure E was employed by using compound 2o. Purification by flash chro-
matography on silica gel (10:90 EtOAc/n-heptane) gave compound 3o
(78% yield) as a white solid: M.p. 1528C; 1H NMR (CDCl3, 300 MHz):
d=3.89 (s, 3H), 4.04 (s, 3H), 7.18 (m, 1H), 7.37 (m, 2H), 7.48 ppm (m,
1H); 13C NMR (CDCl3, 75 MHz): d=54.9, 55.6, 120.6, 127.0, 129.7, 130.1,
132.2, 133.9, 134.6, 135.7, 163.3, 163.2 ppm; HRMS (ESI): m/z calcd for
C12H1035ClIN2O2Na: 398.9373 [M+Na]+; found: 398.9374.
5-(6-Chloro-2-methoxy-3-pyridyl)-4-iodo-2,6-dimethoxypyrimidine (3x):
General procedure E was employed by using compound 2x. Purification
by flash chromatography on silica gel (10:90 EtOAc/n-heptane) gave
compound 3x (66% yield) as a white solid: M.p. 1328C; 1H NMR
(CDCl3, 300 MHz): d=3.87 (s, 3H), 3.90 (s, 3H), 4.01 (s, 3H), 6.98 (d,
J=7.7 Hz, 1H), 7.35 ppm (d, J=7.7 Hz, 1H); 13C NMR (CDCl3,
75 MHz): d=54.5, 54.9, 55.6, 116.4, 117.0, 118.3, 134.4, 142.6, 148.8, 160.8,
163.3, 167.4 ppm; HRMS (ESI): m/z calcd for C12H1135ClIN3O3Na:
[M+Na]+ 429.9431; found: 429.9433. 5-(6-Chloro-5-iodo-2-methoxy-3-
pyridyl)-4-iodo-2,6-dimethoxypyrimidine (3x’) was also isolated (26%
5-(2,4-Dichlorophenyl)-4-iodo-2,6-dimethoxypyrimidine (3p): General
procedure E was employed by using compound 2p. Purification by flash
chromatography on silica gel (5:95 EtOAc/n-heptane) gave compound
3p (70% yield) as a white solid: M.p. 124–1268C; 1H NMR (CDCl3,
300 MHz): d=3.89 (s, 3H), 4.03 (s, 3H), 7.12 (d, J=8.2 Hz, 1H), 7.33
(dd, J=8.2, 2.1 Hz, 1H), 7.50 ppm (d, J=2.1 Hz, 1H); 13C NMR (CDCl3,
75 MHz): d=55.0, 55.6, 119.6, 127.5, 129.7, 133.0, 133.9, 134.3, 135.4,
135.5, 163.5, 167.2 ppm; HRMS (ESI): m/z calcd for C12H935Cl2IN2O2Na:
432.8983 [M+Na]+; found: 432.8983. 5-(2,4-Dichloro-3-iodophenyl)-4-
iodo-2,6-dimethoxypyrimidine (3p’) was also isolated (15% yield) as a
white solid: M.p. 179–1808C; 1H NMR (CDCl3, 300 MHz): d=3.90 (s,
3H), 4.04 (s, 3H), 7.12 (d, J=8.2 Hz, 1H), 7.45 ppm (d, J=8.2 Hz, 1H);
13C NMR (CDCl3, 75 MHz): d=55.0, 55.7, 104.9, 120.8, 127.6, 132.3,
133.6, 134.7, 141.1, 147.6, 163.5, 167.0 ppm; HRMS (ESI): m/z calcd for
C12H835Cl2I2N2O2Na: 558.7950 [M+Na]+; found: 558.7949.
1
yield) as a white solid: M.p. 176–1788C; H NMR (CDCl3, 300 MHz): d=
3.88 (s, 3H), 3.89 (s, 3H), 4.02 (s, 3H), 7.75 ppm (s, 1H); 13C NMR
(CDCl3, 75 MHz): d=54.7, 54.9, 55.6, 82.2, 115.7, 120.3, 134.3, 151.4,
151.7, 160.6, 163.4, 167.3 ppm; HRMS (ESI): m/z calcd for
C12H1035ClI2N3O3Na: 555.8398 [M+Na]+; found: 555.8405.
4-(2-Chlorophenyl)-2,6-dimethoxy-5-(2,5-dimethoxyphenyl)pyrimidine
(4l): General procedure F was employed by using compound 3l and
2-chlorophenylboronic acid, gave compound 4l (92% yield) as a yellow
oil: 1H NMR (CDCl3, 300 MHz): d=3.57 (s, 3H), 3.64 (s, 3H), 3.98 (s,
3H), 4.04 (s, 3H), 6.63 (d, J=3.0 Hz, 1H), 6.66 (d, J=9.0 Hz, 1H), 6.72
(dd, J=9.0, 3.0 Hz, 1H), 7.04–7.17 (m, 3H), 7.29 ppm (dd, J=7.8, 0.6 Hz,
1H); 13C NMR (CDCl3, 75 MHz): d=54.5, 55.0, 55.7, 55.8, 111.6, 112.1,
114.4, 117.4, 122.8, 125.9, 129.4, 129.5, 130.4, 132.6, 137.7, 151.4, 153.0,
5-(2,4-Dichloro-3-iodophenyl)-2,6-dimethoxypyrimidine: The product
1
was identified by its NMR data: H NMR (CDCl3, 300 MHz): d=3.97 (s,
3H), 4.05 (s, 3H), 7.19 (d, J=8.2 Hz, 1H), 7.42 (d, J=8.2 Hz, 1H),
8.08 ppm (s, 1H).
7958
www.chemeurj.org
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 7944 – 7960

Computed Acidity of Biaryl Compounds and their Metalation
FULL PAPER
164.0, 165.3, 169.7 ppm; HRMS (ESI): m/z calcd for C20H1935ClN2O4Na:
409.0931 [M+Na]+; found: 409.0929; m/z calcd for C20H2035ClN2O4:
387.1112 [M+H]+; found: 387.1115.
9.0, 3.0 Hz, 1H), 7.10 (d, J=9.0 Hz, 1H), 7.34 (t, J=7.3 Hz, 1H), 7.39 (d,
J=3.0 Hz, 1H), 7.52–7.62 (m, 2H), 8.06 (d, J=5.4 Hz, 1H), 8.19 (d, J=
8.1 Hz, 1H), 8.62 ppm (d, J=5.4 Hz, 1H); 13C NMR (CD3OD, 75 MHz):
d=56.3, 56.6, 113.3, 114.2, 115.9, 117.6, 118.0, 121.6, 121.9, 123.2, 125.0,
130.9, 132.6, 134.9, 135.7, 140.3, 143.9, 152.9, 155.3 ppm; HRMS (ESI): m/
z calcd for C19H17N2O2: 305.1290 [M+H]+; found: 305.1292.
4-(2-Chlorophenyl)-2,6-dimethoxy-5-(3-methoxy-2-naphthyl)pyrimidine
(4q): General procedure F was employed by using compound 3q and
2-chlorophenylboronic acid, gave compound 4q (91% yield) as a white
powder: M.p. 2258C; 1H NMR (CDCl3, 300 MHz): d=3.75 (s, 3H), 3.97
(s, 3H), 4.08 (s, 3H), 6.96–7.14 (m, 4H), 7.22–7.30 (m, 2H), 7.38 (ddd,
J=8.4, 6.9, 1.2 Hz, 1H), 7.53 (s, 1H), 7.65 ppm (dd, J=8.1, 4.2 Hz, 2H);
13C NMR (CDCl3, 75 MHz): d=54.5, 55.1, 55.4, 105.3, 112.1, 123.7, 124.0,
126.0, 126.4, 126.5, 127.8, 128.4, 129.4, 129.6, 130.3, 131.4, 132.5, 134.4,
137.7, 155.7, 164.1, 165.4, 170.0 ppm; HRMS (ESI): m/z calcd for
C23H1935ClN2O3Na: 429.0982 [M+Na]+; found: 429.0979; m/z calcd for
C23H2035ClN2O3: 407.1162 [M+H]+; found: 407.1177.
Acknowledgements
The authors gratefully acknowledge the financial support of Rennes 1
University (fellowships to R.R.K. and D.T.) and the Institut Universitaire
de France.
4-(2-Aminophenyl)-5-(2-chlorophenyl)-2,6-dimethoxypyrimidine
(4o):
General procedure F, employed by using 3o and 2-aminophenylboronic
acid, gave compound 4o (94% yield) as a whitish powder: M.p. 908C
(deg.); 1H NMR (CDCl3, 300 MHz): d=3.99 (s, 3H), 4.06 (s, 3H), 4.26
(br s, 2H), 6.42 (td, J=7.5, 0.9 Hz, 1H), 6.70 (dd, J=8.1, 0.9 Hz, 1H),
6.71 (dd, J=7.5, 1.5 Hz, 1H), 6.97–7.03 (s, 2H), 7.10 (td, J=7.5, 1.5 Hz,
1H), 7.19 (td, J=7.7, 1.8 Hz, 1H), 7.38 ppm (dd, J=8.1, 1.2 Hz, 1H);
13C NMR (CDCl3, 75 MHz): d=54.6, 55.1, 112.9, 117.3, 118.3, 122.8,
126.7, 129.1, 129.3, 130.1, 130.7, 132.6, 133.4, 135.2, 144.3, 164.2, 165.7,
170.3 ppm; HRMS (ESI): m/z calcd for C18H1735ClN3O2: 342.1009
[M+H]+; found: 342.1008; m/z calcd for C18H1635ClN3O2Na: 364.0829
[M+Na]+; found: 364.0829.
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4-(2-Aminophenyl)-5-(3-chloro-2-naphthyl)-2,6-dimethoxypyrimidine
(4r): General procedure F was employed by using compound 3r and
2-aminophenylboronic acid, gave compound 4r (91% yield) as a white
powder: M.p. 1808C; 1H NMR (CDCl3, 300 MHz): d=3.97 (s, 3H), 4.08
(s, 3H), 4.50 (br s, 2H), 6.31 (td, J=7.5, 0.9 Hz, 1H), 6.64 (dd, J=8.1,
0.9 Hz, 1H), 6.77 (dd, J=7.8, 1.5 Hz, 1H), 6.92 (ddd, J=7.7, 7.2, 1.5 Hz,
1H), 7.36–7.48 (m, 2H), 7.50 (s, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.73 (d, J=
8.1 Hz, 1H), 7.90 ppm (s, 1H); 13C NMR (CDCl3, 75 MHz): d=54.6, 55.0,
112.9, 117.1, 118.1, 122.5, 126.2, 126.8, 127.0, 127.4, 128.0, 130.0, 130.7,
131.4, 131.7, 131.8, 132.9, 133.4, 145.0, 164.2, 166.0, 170.7; ppm HRMS
(ESI): m/z calcd for C22H1935ClN3O2: 392.1166 [M+H]+; found: 392.1165;
m/z calcd for C22H1835ClN3O2Na: 414.0985 [M+Na]+; found: 414.0981.
2,4,5,8-Tetramethoxydibenzo
of compound 4l (0.19 g, 0.50 mmol) and Cs2CO3 (0.32 g, 1.0 mmol) in 1,4-
dioxane (5 mL) were added Pd(OAc)2 (10 mg, 50 mmol, 10 mol%) and
ACHTUNGTREN[NUNG f,h]quinazoline (5l): To a degassed solution
AHCTUNGTRENNUNG
Cy3P·BF4 (17 mg, 0.10 mmol, 20 mol%). The resulting mixture was
heated for 18 h at 1058C before cooling and diluting with Et2O (10 mL),
washing with water (10 mL), and extracting with CH2Cl2 (3ꢆ20 mL).
After drying over Na2SO4, the solvent was evaporated under reduced
pressure and cyclized compound 5l was isolated (68% yield) by purifica-
tion by flash chromatography on silica gel (10:90 EtOAc/n-heptane) as a
colorless oil. 1H NMR (CDCl3, 300 MHz): d=3.99 (s, 3H), 4.06 (s, 3H),
4.15 (s, 3H), 4.22 (s, 3H), 7.11 (d, J=9.0 Hz, 1H), 7.14 (d, J=9.0 Hz,
1H), 7.65 (ddd, J=8.1, 6.9, 1.2 Hz, 1H), 7.73 (ddd, J=8.7, 6.9, 1.8 Hz,
1H), 9.15 (dd, J=7.8, 1.5 Hz, 1H), 9.54 ppm (dd, J=8.4, 0.9 Hz, 1H);
13C NMR (CDCl3, 75 MHz): d=54.6, 55.0, 56.4, 56.7, 104.4, 110.0, 110.4,
119.0, 121.0, 125.4, 127.0, 128.3, 129.5, 130.2, 133.0, 151.0, 152.6, 154.5,
162.3, 169.2 ppm; HRMS (ESI): m/z calcd for C20H19N2O4: 351.1345
[M+H]+; found: 351.1344; m/z calcd C20H18N2O4Na: 373.1164 [M+Na]+;
found: 373.1164.
1-(2,5-Dimethoxyphenyl)-9H-pyridoACTHNUGRTNEUNG[3,4-b]indole (5h): was prepared by
following a previously reported procedure.[9i] To a degassed solution of
compound 3h (0.21 g, 0.50 mmol), 2-aminophenylboronic acid (0.27 g,
2 mmol), and CsF (0.15 g, 1.0 mmol) in 1,4-dioxane (5 mL) were added
[PdACHTUNGTRENNUNG(dba)2] (14 mg, 25 mmol, 5 mol%) and PPh3 (13 mg, 50 mmol,
10 mol%). The resulting mixture was heated for 16 h at 1058C before
cooling and diluting with Et2O (10 mL), washing with water (10 mL), and
extracting with CH2Cl2 (3ꢆ20 mL). After drying over Na2SO4, the sol-
vent was evaporated under reduced pressure and cyclized compound 5h
was isolated (70% yield) by purification by flash chromatography on
silica gel (10:90 EtOAc/n-heptane) as a beige powder: M.p. 1108C.
1H NMR (CDCl3, 300 MHz): d=3.80 (s, 3H), 3.88 (s, 3H), 7.05 (dd, J=
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Received: February 12, 2013
Published online: April 12, 2013
7960
www.chemeurj.org
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 7944 – 7960