Deprotonative metalation of aromatic compounds using mixed lithium-iron combinations

Article abstract of DOI:10.1016/j.tet.2012.02.019

The deprotonation of 2-methoxypyridine was attempted using putative (TMP)₃FeLi prepared from different iron sources. Using iodine to intercept the metalated 2-methoxypyridine, the best result was obtained from FeBr₂ (1 equiv) using THF at room temperature; nevertheless, in addition to the expected iodide, the corresponding 2,2′-dimer was obtained (86% total yield). The origin of the competitive formation of the 2,2′-dimer was not identified but mechanisms were suggested to explain its formation. It was observed that the nature of the electrophile employed to trap the 3-metalated 2-methoxypyridine has a strong impact on this dimer formation, the latter being favored using iodine (35% yield), but also benzophenone (28%), benzoyl chloride (22%), methyl iodide (27%), allyl bromide (15%), benzyl bromide (41%), and tetramethylthiuram disulphide (36%); for this reason, the yields of the expected derivatives were only 51, 15, 62, 0, <5, 18, and 0%, respectively. In contrast, using aldehydes readily led to the expected pyridine alcohols without dimerization (59% yield using 3,4,5-trimethoxybenzaldehyde and 66% yield using pivalaldehyde). 2,6-Dimethoxypyridine (in 68% yield), anisole (47%), 2,4-dimethoxypyrimidine (50% at C5 and 3% at C6), 2-fluoropyridine (64%), and thiophene (49%) were similarly converted into the corresponding alcohols after subsequent trapping with pivalaldehyde. Using iodine to trap the 2-metalated anisole did not lead to dimer formation, and 2-iodoanisole was isolated in 71% yield.

Full text of DOI:10.1016/j.tet.2012.02.019

Tetrahedron 68 (2012) 3063e3073
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Deprotonative metalation of aromatic compounds using mixed lithiumeiron
combinations
*
*
Elisabeth Nagaradja, Floris Chevallier, Thierry Roisnel, Viatcheslav Jouikov , Florence Mongin
ˇ
ꢀ
Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS, Universite de Rennes 1, Batiment 10A, Case 1003, Campus Scientifique de Beaulieu, 35042 Rennes, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 January 2012
Received in revised form 3 February 2012
Accepted 7 February 2012
Available online 20 February 2012
The deprotonation of 2-methoxypyridine was attempted using putative (TMP)3FeLi prepared from
different iron sources. Using iodine to intercept the metalated 2-methoxypyridine, the best result was
obtained from FeBr2 (1 equiv) using THF at room temperature; nevertheless, in addition to the
expected iodide, the corresponding 2,20-dimer was obtained (86% total yield). The origin of the
competitive formation of the 2,20-dimer was not identified but mechanisms were suggested to explain
its formation. It was observed that the nature of the electrophile employed to trap the 3-metalated
2-methoxypyridine has a strong impact on this dimer formation, the latter being favored using io-
dine (35% yield), but also benzophenone (28%), benzoyl chloride (22%), methyl iodide (27%), allyl
bromide (15%), benzyl bromide (41%), and tetramethylthiuram disulphide (36%); for this reason,
the yields of the expected derivatives were only 51, 15, 62, 0, <5, 18, and 0%, respectively. In contrast,
using aldehydes readily led to the expected pyridine alcohols without dimerization (59% yield using
3,4,5-trimethoxybenzaldehyde and 66% yield using pivalaldehyde). 2,6-Dimethoxypyridine (in 68%
yield), anisole (47%), 2,4-dimethoxypyrimidine (50% at C5 and 3% at C6), 2-fluoropyridine (64%), and
thiophene (49%) were similarly converted into the corresponding alcohols after subsequent trapping
with pivalaldehyde. Using iodine to trap the 2-metalated anisole did not lead to dimer formation, and
2-iodoanisole was isolated in 71% yield.
Keywords:
Bimetallic bases
Deprotonative metalation
Aromatic compounds
Lithium
Iron
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
The same year, Knochel and co-workers showed that ferration
(FeeH exchange) can be achieved using salt-solubilized
The deprotonative metalation using lithium bases has been
widely used as a powerful method for the regioselective function-
alization of aromatic compounds.1e5 The use of bimetal combina-
tions in order to get more efficient and/or more chemoselective
bases is a fascinating field. Pioneer studies carried out in the groups
(TMP)2Fe$2MgCl2$4LiCl (TMP¼2,2,6,6-tetramethylpiperidino).16,17
We recently accomplished the room temperature deproto-
metalation of a large range of substrates including sensitive het-
erocycles and functionalized benzenes using newly developed lith-
iumezinc,18e23 lithiumecadmium,22,24e31 lithiumecopper(I),32e34
and lithiumecobalt35 combinations, in situ prepared from
MCl2$TMEDA (M¼Zn, Cd or Cu, TMEDA¼N,N,N0,N0-tetramethyle-
thylenediamine), CuCl, or CoBr2 on the one hand, and lithium re-
agents (alkyllithiums or lithium amides) on the other hand. The
studies performed using lithiumezinc and lithiumecadmium
combinations have notably shown that the more efficient bases were
obtained by mixing the metal salt with 3 equiv of LiTMP.21,30 A main
drawback of the methods developed being the lack of reactivity of
such generated arylmetals in direct electrophilic trapping, we turned
to other bimetallic combinations in order to identify candidates able
to perform efficient deprotonations, but also to allow direct (and if
possible new) functionalizations. We recently documented the use
of lithiumecobalt combinations for this purpose,35 and here de-
scribe our efforts to deproto-metalate aromatic compounds using
similar lithiumeiron combinations.
of Schlosser6 and Lochmann7 with LIC-KOR (1:1 BuLi/tBuOK), and
8,9
ꢁ
by Caubere, Gros, and Fort in the pyridine series with BuLi/LiD-
MAE (DMAE¼2-dimethylaminoethoxide) and Me3SiCH2Li/LiDMAE
merged alkyllithiums and alkali-metal alkoxides. More recently,
0
0
other (R)n(R )n MLi-type bases, with M being softer than an alkali-
metal (M¼Mg, Al, Cr, Mn, Cu, Zn, Cd.), have been described by
different groups for their ability to deprotonate aromatic com-
pounds.10e14 From 2009, Klett, Mulvey and co-workers have
showed that it is possible to design sodiumeiron(II) bases, and
extended the ability to deprotonate to group 8 ate compounds.15
* Corresponding authors. Fax: þ33 2 2323 6955; e-mail addresses: viatcheslav.
jouikov@univ-rennes1.fr (V. Jouikov), florence.mongin@univ-rennes1.fr (F. Mongin).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.02.019

3064
E. Nagaradja et al. / Tetrahedron 68 (2012) 3063e3073
2. Results and discussion
between the 2a:3 ratio and the iron source, and it was moreover
observed for a given iron source that this ratio can be modified
(ꢀ10e20%) by varying the iodine addition time.
The synthesis of organoiron(II) ate compounds is well-
documented in the literature. They can be obtained from
FeCl2,36e40 but alternative ways employ iron(III) halides in the
presence of an excess of an organolithium.36,37 The access to mixed
lithiumeiron(II) amides is far less documented, but seems possible
similarly.41,42 The in situ generation of putative43,44 (TMP)3FeLi in
tetrahydrofuran (THF) was considered using different iron halides
(Scheme 1). Iron(III) halides were successively treated with BuLi
(1 equiv), in order to achieve their reduction and LiTMP (3 equiv)
whereas iron(II) halides were only combined with 3 equiv of LiTMP.
In order to identify how the dimer 3 is formed, different ex-
periments were carried out. First, using water instead of iodine to
trap the metalated 2-methoxypyridine (iron source: FeCl3) resulted
in a very low 4% yield of 3, showing that the electrophile employed
has an impact on the dimer 3 formation. Iodine could competitively
behave as an oxidative agent in the reaction (Scheme 2); indeed,
when nitrobenzene and chloranil were tested instead of iodine
(iron source: FeBr2), the dimer 3 was isolated in 14 and 17% yield,
respectively.
BuLi
3 LiTMP
FeX3
FeX2
+
LiX
(TMP)3FeLi
+ 2 LiX
+ 3 LiX
-1/2 Bu-Bu
3 LiTMP
FeX2
(TMP)3FeLi
Scheme 1. Generation of putative (TMP)3FeLi using different iron halides.
We chose 2-methoxypyridine (1) as substrate and iodine as elec-
trophile to evaluate the ability to deprotonate of putative (TMP)3FeLi,
prepared using the different iron sources (Table 1). This substrate had
previously been metalated either at its 3-position using t-BuLi,45e47
PhLi in the presence of a catalytic amount of diisopropylamine,45e47
N
MeO
N
MeO
1/2 I2
TMP FeII
LiI
Li
TMP FeI
+
+
LiDA (DA¼diisopropylamino),45e47 LiTMP,45e47
a
mixed lith-
N
OMe
MeO
N
iumealuminum base,13 and a mixed lithiumecobalt base,35 or at its 6-
position using BuLi/LiDMAE.8 When 2-methoxypyridine (1) was
treated by the lithiumeiron base (prepared by using the methods
above) for 2 h at room temperature and the reaction mixtures then
quenched by iodine, mixtures of 3-iodo-2-methoxypyridine (2a) and
2,20-dimethoxy-3,30-bipyridine (3) were obtained in all cases but in
different yields. Except when FeF2 was employed as iron source to
prepare the base (entry 6), the conversions observed were good, even
when 1 equiv of base was used; these results show that changing the
lithium salt formed at the same time as the base (LiCl, LiBr, or even LiI)
has a low effect on the deprotonation efficiency. The use of 0.5 and
2 equiv of base led to lower conversion and some degradation, re-
spectively, and the yields were found lower. There is no direct link
3
Scheme 2. I2-mediated pathway to explain the formation of 3.
3-Iodo-2-methoxypyridine (2a), which is formed in the course
of iodine addition, can also have an impact on the dimer 3 forma-
tion. Indeed, when used instead of iodine (iron source: FeBr2), a 72%
yield was obtained for the dimer 3. To rationalize this result, dif-
ferent mechanisms can be advanced, notably one48 based on
a Fe(II)/Fe(IV) couple with two-electron transfer from iron followed
by reductive elimination (Scheme 3). Nevertheless, for steric rea-
sons, the mechanisms48 depicted in Scheme 4 involving a Fe(II)/
Fe(III) couple with one-electron transfer from iron, followed by
dimerization from the Fe(III) species, appears as a more likely al-
ternative to explain the formation of 3.
Table 1
Finally, an alternative explanation could be the presence of
a metal impurity in the iron source for which the corresponding
diaryl metal ate compounds is prone to dimerization.
Metalation of 2-methoxypyridine using putative (TMP)3FeLi
MeO
N
N
1) Putative
(TMP)3FeLi (1 equiv)
THF, rt, 2 h
I
In order to check if the reduction of FeCl3 to FeCl2 is quantitative
using 1 equiv of an organolithium (BuLi or MeLi), the reaction was
monitored using electron paramagnetic resonance (EPR). To this
purpose, the EPR spectra of THF solutions prepared from FeCl3 and
MeLi or BuLi were collected, and were compared with spectra
recorded from THF solutions of FeCl2 and FeCl3. The spectrum of
FeCl2 treated by LiTMP (3 equiv) was also recorded, and only showed
the signal characteristic of 2,2,6,6-tetramethylpiperidinooxy
(TEMPO) already observed in the course of the preparation of
LiTMP32 (Fig. 1).
The standard redox potential of methyl radicals, determined
electrochemically in DMF and converted to the aqueous scale, is
Eo(Meꢁ/Meꢂ)¼ꢂ1.19 V vs saturated calomel electrode (SCE). Those
for parent n-Prꢁ and s-Buꢁ radicals are ꢂ1.63 and ꢂ1.72 V vs SCE,
respectively.49 Values for t-Buꢁ (ꢂ1.48), s-Buꢁ (ꢂ1.38), and n-Buꢁ
(ꢃꢂ1.30 versus SCE) have also been estimated.50 For the oxidant,
+
2) I2 (3 equiv)
OMe
OMe
N
1
N
2a
OMe
3
Entry
Iron halide
FeCl3
FeBr3
FeCl2
FeBr2
FeI2
Yield of 2aa (%)
35 (53)c
28
Yield of 3a (%)
42 (32)c
58
Total yieldb (%)
77 (85)c
86
1
2
3
4
5
6
28
52
80
51 (51)d
21
35 (40)d
41
86 (91)d
62
FeF2
12
15
27e
a
After purification by column chromatography.
The rest is either degradation or starting material.
Using 2 equiv of base.
By performing the reaction in the presence of TMEDA (4 equiv).
Degradation was observed.
b
c
d
e

E. Nagaradja et al. / Tetrahedron 68 (2012) 3063e3073
3065
I
N
N
MeO
N
MeO
TMP
MeO
N
OMe
FeII
OMe
N
FeIV
TMP
TMP FeII
Li
+
N
OMe
N
OMe
LiI
N
MeO
N
OMe
3
Scheme 3. 2a-Mediated pathway based on a Fe(II)/Fe(IV) couple to explain the formation of 3.
I
N
N
MeO
N
N
MeO
MeO
N
OMe
I
TMP FeII
TMP FeIII
TMPFeI
Li
+
-
OMe
MeO
N
MeO
N
Li+
3
MeO
N
N
N
OMe
N
MeO
+
LiI +
TMP FeII
OMe
N
OMe
3
Scheme 4. 2a-Mediated pathway based on a Fe(II)/Fe(III) couple to explain the formation of 3.
however they can be considered as a fair first approach. The fact
that the EPR signal of Fe3þ species does not disappear after mixing
FeCl3 with MeLi or BuLi (Fig. 1) suggests that Eo(Fe3þ/Fe2þ) in THF is
still not positive enough to allow efficient reduction of Fe3þ by
these bases. Meꢂ is a weaker reducing agent than Buꢂ for the virtue
of its less negative standard potential. In fact, the intensity of the
EPR signal of Fe3þ after reacting FeCl3 with BuLi is about 1/10th
weaker than after the reaction with MeLi; this is seemingly in line
with the above, though this difference is comparable with the ex-
perimental error and is too small to draw further conclusions. Even
though thermodynamic conditions for the reaction of Fe3þ with
BuLi seem favorable, this reaction must be subject to kinetic limi-
tations making it inefficient compared to the direct use of FeCl2 salt
(Scheme 1).
Thus, if the synthesis of organoiron(II) ate compounds using
MeLi in excess is documented in the literature,36,37 it failed in
working quantitatively using 1 equiv of MeLi or BuLi in our case,
compromising this approach. This result contrasts with the pre-
viously reported in situ access to (TMP)2CuLi from CuCl2$TMEDA by
BuLi-promoted reduction followed by addition of LiTMP
(2 equiv).32 With Eo(Cu2þ/Cuþ)¼0.094 V vs SCE, the driving force of
the reduction of Cu2þ by BuLi is about 1 eV (23 kcal/mol) greater
that in the case of FeCl3, explaining the difference observed.
The study was pursued using an iron(II) salt, more soluble and
less hygroscopic FeBr2, to generate the lithiumeiron base. Since
iodine did not proved to be a good choice, giving a mixture of the
iodide 2a and the dimer 3, we turned to the use of other electro-
philes to intercept the metalated 2-methoxypyridine (Table 2).
3,4,5-Trimethoxybenzaldehyde and pivalaldehyde led to the
corresponding alcohols 2b,c in 59e66% yield (entries 2 and 3). If the
deproto-metalation step probably proceeds through amino-ligand
transfer from the ferrate base without iron oxidation/reduction,
Fig. 1. EPR spectra of THF solutions (all at 10ꢂ4 M): (a) FeCl2, (b) FeCl3, (c) FeCl3þMeLi
(1 equiv), (d) FeCl3þBuLi (1 equiv), (e) signal of TEMPO radical resulting from the re-
action of FeCl2 with LiTMP (3 equiv): g¼2.0067, aN¼15.55 G. The signal in (a) is due to
the partial oxidation of Fe2þ to Fe3þ by residual oxygen.
Eo(Fe3þ/Fe2þ)¼ꢂ0.771 V vs NHE51 (ꢂ1.018 V versus SCE). In THF,
these values should be corrected for the corresponding solvent
transfer energies (with the loss in
being supposedly the largest among the concerned species),
D
Gsolv for triply-charged Fe3þ

3066
E. Nagaradja et al. / Tetrahedron 68 (2012) 3063e3073
Table 2
Electrophilic trapping of metalated 2-methoxypyridine
1) Putative
(TMP)3FeLi (1 equiv)
THF, rt, 2 h
E
3
+
2) Electrophile
(3 equiv)
3) Hydrolysis
OMe
OMe
N
1
N
2
Entry
1a
Electrophile
I2
Yield of 2 (%)
Yield of 3 (%)
I
2a, 51
35
N
OMe
OMe
OMe
OMe
MeO
OMe
MeO
2a
<5 (<5)b
b
2b, 59
(57)b
OH
CHO
N
OMe
3a
tBuCHO
0
OH
2c, 66
2d, 15
N
OMe
Ph Ph
4a
Ph2C(O)
OH
28
22
N
OMe
Ph
5a
PhC(O)Cl
O
2e, 62
2f, 0
N
OMe
6a
ICH3
27
N
OMe
OMe
7a
8a
BrCH2CH]CH2
15
41
2g, <5
2h, 18
N
N
Ph
BrCH2Ph
OMe
S
NMe2
9a
[Me2NC(S)S]2
36
S
2i, 0
N
OMe
CO2Me
c
10a
MeC^CCO2Me
2j, <5
N
OMe
2k, 15d
HO
d
11a
PhCH(CH2O)
0
N
N
OMe
Ph
Ph
Ph
Ph
c
12a
O
O
2l, 60
OMe
a
Iron source: FeBr2.
In the presence of TMEDA (4 equiv).
Dimer present in the crude but quantity not determined.
The acetate was isolated.
b
c
d

E. Nagaradja et al. / Tetrahedron 68 (2012) 3063e3073
3067
mechanistic possibilities are less obvious concerning the trapping
of the metalated 2-methoxypyridine using aldehydes. Indeed, it is
not clear whether carbonyl compounds react with iron ate com-
pounds by the addition mechanism normally found for carbanions
because of possible alternative pathways48 (Schemes 5 and 6). To
explain the high equatorial selectivity of the methylation of 4-tert-
butylcyclohexanone by Me3FeLi,52 an oxidative addition in which
the Me3Fe residue is forced to attack from the equatorial side was
proposed.48 In addition, one-electron transfers were suspected in
the 1970s to explain peculiar results observed in the course of re-
actions of Grignard reagents with ketones performed in the pres-
ence of FeCl3.53,54 In our case, it is difficult to come to a decision, in
particular since a dihydrodimer48,55 corresponding to an aldehyde
employed was not detected. Nevertheless, the dimer 3 being only
observed as traces using aldehydes, and also for steric reasons, the
mechanism depicted in Scheme 6 seems more likely.
It is known that ketones are less reactive than aldehydes toward
iron ate compounds. This was, for example, shown by Kauffmann
and co-workers who performed competitive reactions where the
reactivities of benzaldehyde and 4-methyl-2-pentanone toward
Me3FeLi and Me4FeLi2 were compared.56 In our case, the alcohol 2d
was produced in a low 15% yield upon interception with benzo-
phenone, and the dimer 3 was isolated in 28% yield (entry 4). The
low reactivity of the iron ate compounds toward ketones in general
allows their selective addition to aroyl chlorides.36,48,57 In accor-
dance, we could synthesize the corresponding ketone using ben-
zoyl chloride in 62% yield (entry 5). Both Fe(II)/Fe(IV) and Fe(II)/
Fe(III) mechanisms can be proposed (Schemes 7 and 8).
O
R1
R2
N
N
R2
R1
LiO
TMP
R1
R2
R
LiO
TMP FeII
R
OMe
FeIV OMe
R
Li
+
TMP FeII
MeO
N
R = TMP or 2-
methoxy-3-pyridyl
R = 2-methoxy-
3-pyridyl
MeO
N
N
OMe
3
Scheme 5. Alternative Fe(II)/Fe(IV) mechanism for the trapping step using aldehydes/ketones.
MeO
N
R
R = 2-methoxy-
3-pyridyl
TMP FeIII
TMPFeI
+
R
TMP FeII
R
MeO
N
Li
N
OMe
3
R2
R1
OLi
O
OLi
R2
MeO
R1
R2
R1
R
R
N
TMP FeIII
TMP FeII
R
R = TMP or 2-
methoxy-3-pyridyl
LiO
R1
R2
OLi
R1
R2
Scheme 6. Alternative Fe(II)/Fe(III) mechanism for the trapping step using aldehydes/ketones.
R'
O
Cl
N
N
Cl
R'
LiO
TMP
LiO
R
R'
Cl
TMP FeII
R
OMe
FeIV OMe
R
Li
+
TMP FeII
MeO
N
R = 2-methoxy-
3-pyridyl
R = TMP or 2-
methoxy-3-pyridyl
- LiCl
- LiCl
MeO
N
R'
N
R'
O
R
O
TMP
TMP FeII
FeIV OMe
R
+
MeO
N
OMe
N
3
Scheme 7. Fe(II)/Fe(IV) mechanism for the trapping step using aroyl chlorides.

3068
E. Nagaradja et al. / Tetrahedron 68 (2012) 3063e3073
MeO
N
N
R
R = 2-methoxy-
3-pyridyl
TMP FeIII
TMPFeI
+
R
TMP FeII
R
MeO
N
Li
OMe
3
OLi
Cl
R'
O
OLi
Cl
R'
Cl
R'
R
N
N
MeO
R
TMP FeIII
TMP FeII
-LiCl
R
O
R'
R = TMP or 2-
methoxy-3-pyridyl
MeO
Scheme 8. Fe(II)/Fe(III) mechanism for the trapping step using aroyl chlorides.
A mechanism where a reduced iron catalyst enters a one-
electron redox pathway, and an alkyl radical is formed from the
alkyl halide, is topical to rationalize iron-catalyzed couplings of
aryl Grignard reagents with alkyl halides.58e60 When the meta-
lated 2-methoxypyridine was reacted with methyl iodide, allyl
bromide, and benzyl bromide, the main product was the dimer 3,
isolated in 27, 15 and 41% yield, respectively. The cross-
functionalization was only observed significantly using benzyl
bromide, which can generate a stabilized radical, affording 2h in
18% yield (entries 6e8); it could proceed according to the pathway
depicted in Scheme 9.
The attempts to use phenyl disulfide and tetramethylthiuram
disulfide failed in giving the expected sulfur derivatives: only
starting material was recovered with the former and the dimer 3
(36% yield) with the latter (entry 9). Ethyl phenylpropiolate and
methyl methylpropiolate were tested, but similarly failed in giving
the expected conjugated alkenes: only starting material was re-
covered with the former and also the dimer 3 with the latter (entry
10). The behavior toward chlorodiphenylphosphine proved similar,
showing that the iron ate compound formed by deprotonative
metalation is a bad reagent toward such soft electrophiles. Using 2-
phenyloxirane led to the regioselective formation of the alcohol 2k,
albeit in a low 16% yield (entry 11); a higher yield but of the ketone
corresponding to the expected product (Fig. 2) was obtained with
trans-stilbene oxide (entry 12).
The method was then extended to other aromatic substrates
(Table 3). Starting from 2,6-dimethoxypyridine (4) and using
pivalaldehyde as electrophile, the expected alcohol 5c was isolated
in 68% yield (entry 3), a yield similar to that obtained from
2-methoxypyridine (1) (entry 2). In contrast, trapping with N-
fluoro-2,4,6-trimethylpyridinium tetrafluoroborate did not afford
Fig. 2. ORTEP diagram (30% probability) of compound 2l.
the expected fluoro derivative,61 but instead the dimer 6 (33%
yield) as well as the compound 7 (10% yield), which could result
from the coupling of 3-deprotonated 2,6-dimethoxypyridine with
lateral-deprotonated N-fluoro-2,4,6-trimethylpyridinium tetra-
fluoroborate (entry 4).
Compared with 2-methoxypyridine (1) (entries 1 and 2), anisole
(8) also afforded the corresponding iodide 9a and alcohol 9c, but
the yield of 9a was found higher due to the absence of the
R
R
Br
Ph
MeO
N
R = 2-methoxy-
3-pyridyl
TMP FeII
TMP FeIII
TMPFeI
+
Li
MeO
N
MeO
N
-
Li+
Br
LiBr +
Ph
N
R
OMe
3
R = TMP or 2-
methoxy-3-pyridyl
Ph
Ph
MeO
N
2h
TMP FeII
+
Scheme 9. Proposed pathway for the formation of 2h and 3.

E. Nagaradja et al. / Tetrahedron 68 (2012) 3063e3073
3069
Table 3
Extension to other aromatic substrates
1) Putative (TMP)3FeLi (1 equiv)
THF, rt, 2 h
Ar
H
Ar
E
Ar Ar
+
2) Electrophile (3 equiv)
3) Hydrolysis
Entry
1a
AreH
1:
Electrophile
AreE (E), yield (%)
AreAr, yield (%)
3, 35
Other products, yield (%)
I2
2a (I), 51
H
N
OMe
2a
3a
tBuCHO
tBuCHO
2c (CH(OH)tBu), 66
5c (CH(OH)tBu), 68
3, 0
6, 0
H
4:
MeO
N
OMe
N
7, 10
MeO
N
OMe
BF4
4a
5k (F), 0
6, 33
N
F
5a
6a
I2
9a (I), 71
10, 0
10, 0
H
8:
OMe
tBuCHO
9c (CH(OH)tBu), 47
OMe
N
OMe
12c (5-CH(OH)tBu), 50
12c0 (6-CH(OH)tBu), 3
13 (5,50), 1
N
OMe
N
H5
H6
7a
11:
N
tBuCHO
14, 7
130 (6,60), 13
MeO
N
OMe
N
OMe
OMe
H
8a
9a
15:
18:
tBuCHO
tBuCHO
16 (CH(OH)tBu), <5
19 (CH(OH)tBu), 64
17, 0
20, 0
N
H
N
F
22 (2-CH(OH)tBu), 49
10a
21:
tBuCHO
17, 0
220 (2,5-CH(OH)tBu), 18
H
H
S
a
Iron source: FeBr2.
corresponding dimer 10 (entries 5 and 6). This result gives weight
to the mechanism suggested in Scheme 4, with a radical anion less
stable than in the pyridine case.
similarly. Deprotonation next to the heteroatom of aromatics is no
more a limit with thiophene. The latter was converted into a mix-
ture of the alcohol 22 and diol 220, which were isolated in 49 and
18% yield, respectively (entry 10).
Compared with 2-methoxypyridine (1), 2,4-dimethoxypyr-
imidine (11) was converted using pivalaldehyde to the corre-
sponding alcohols 12c and c0 in a slightly lower yield due to the
competitive formation of different bis(pyrimidines). The reaction
mainly took place at the 5-position of the pyrimidine ring (12c
isolated in 50% yield), explaining the formation of traces (1%
yield) of the 5,50-dimer 13. A competitive reaction at the 6-
position was nevertheless evidenced by the formation of the al-
cohol 12c0 (3% yield); the formation of the 6,60-dimer 130 in 13%
yield shows that the 6-metalated species is less stable than its 5-
counterpart. The mixed 5,60-dimer 14 also formed in 7% yield
(entry 7).
No pyridyl alcohol was isolated when the reaction was per-
formed from 4-methoxypyridine; with 3-methoxypyridine (15),
the alcohol 16 was only isolated as traces (entry 8). Other 2-
substituted pyridines were involved in the reaction: whereas
2-fluoropyridine (18) led to the alcohol 19 in 64% yield (entry 9), 2-
chloropyridine did not afford any pyridine derivative when treated
3. Conclusion
Compared with the previously described ‘all-TMP’ lith-
iumezinc18e23 and lithiumecadmium22,24e31 combinations, the
base obtained by combining FeBr2 with 3 equiv of LiTMP is less
efficient as far as both conversion and chemoselectivity are con-
cerned. For example, starting from anisole (8), the iodide 9a was
isolated in 84% and 75% yield using 0.5 equiv of the lithiumezinc
and lithiumecadmium combinations, respectively, against 71%
under the same conditions but using 1 equiv of the lithiumeiron
combination. The efficiency of the latter more looks like those of
the reported ‘all-TMP’ Gilman-type lithiumecopper(I)32e34 and
lithiumecobalt35 combinations. The reactivity exhibited by the
generated arylmetal species is rather similar to that previously
observed using the corresponding lithiumecobalt bases.35

3070
E. Nagaradja et al. / Tetrahedron 68 (2012) 3063e3073
4. Experimental section
3442, 2943, 2837, 2250, 1591, 1463, 1410, 1326, 1233, 1125, 1005,
907, 725 cmꢂ1 1H NMR (300 MHz, CDCl3)
3.83 (s, 6H), 3.84 (s,
;
d
4.1. General procedure A (deprotonation using 1 equiv FeBr2
and 3 equiv LiTMP followed by trapping using I2)
3H), 4.00 (s, 3H), 5.93 (s, 1H), 6.62 (s, 2H), 6.89 (dd, 1H, J¼7.3 and
5.0 Hz), 7.46 (dd, 1H, J¼7.3 and 1.9 Hz), 8.10 (dd, 1H, J¼5.0 and
1.9 Hz), OH not seen; 13C NMR (75 MHz, CDCl3):
d 53.1, 55.7 (2C),
To
a
stirred
cooled
(0 ꢄC)
solution
of
2,2,6,6-
60.4, 69.9, 103.3 (2C), 116.7, 126.6, 135.3, 136.6, 138.3, 145.1, 152.7
(2C), 160.3; HRMS (ESI) calcd for C16H19NNaO5 [(MþNa)þ
]
ꢁ
tetramethylpiperidine (1.0 mL, 6.0 mmol) in THF (5 mL) were
added BuLi (1.6 M hexanes solution, 6.0 mmol) and, 5 min later,
FeBr2 (0.43 g, 2.0 mmol). The mixture was stirred for 15 min at 0 ꢄC
before introduction of the substrate (2.0 mmol). After 2 h at room
temperature, I2 (1.5 g, 6.0 mmol) was added. The mixture was
stirred for 1 h before addition of an aq saturated solution of
Na2S2O3 (10 mL) and extraction with EtOAc (3ꢅ20 mL). The com-
bined organic layers were dried over MgSO4, filtered, and concen-
trated under reduced pressure.
328.1161, found 328.1162.
4.2.2.
a-(tert-Butyl)-2-methoxy-3-pyridylmethanol (2c). Compound
2c was obtained according to the general procedure B starting from
2-methoxypyridine (0.21 mL), and using pivalaldehyde (0.70 mL),
and was isolated after purification by flash chromatography on
silica gel (eluent: heptane/AcOEt 90:10 to 70:30) as a yellow oil
(66% yield): IR (ATR)
1248, 1265, 1046, 1021, 1009, 783, 734, 704 cmꢂ1
(300 MHz, CDCl3) 0.87 (s, 9H), 3.87 (s, 3H), 4.61 (s, 1H), 6.83 (dd,
n
3404, 2956, 2909, 2873, 1587, 1463, 1412,
;
1H NMR
4.1.1. 3-Iodo-2-methoxypyridine (2a). Compound 2a was obtained
d
according to the general procedure
A
starting from 2-
1H, J¼7.3 and 5.0 Hz), 7.56 (dd, 1H, J¼7.3 and 1.9 Hz), 7.99 (dd, 1H,
methoxypyridine (0.21 mL), and was isolated after purification by
flash chromatography on silica gel (eluent: heptane/AcOEt 80:20)
as a white solid (51% yield): mp 64 ꢄC; 1H NMR (300 MHz, CDCl3)
J¼5.0 and 1.9 Hz), OH not seen; 13C NMR (75 MHz, CDCl3):
d 25.7
(3C), 36.6, 53.0, 76.0, 116.4, 124.7, 137.6, 145.1, 161.1. These data are
analogous to those previously described.62
d
3.96 (s, 3H), 6.61 (dd, 1H, J¼7.5 and 4.9 Hz), 7.98 (dd, 1H, J¼7.5 and
1.7 Hz), 8.10 (dd, 1H, J¼4.9 and 1.7 Hz); 13C NMR (75 MHz, CDCl3):
4.2.3. 2-Methoxy-a,a-diphenyl-3-pyridylmethanol (2d). Compound
d
54.6, 79.7, 118.1, 146.4, 147.9, 161.8. These data are analogous to
2d was obtained according to the general procedure B starting from
2-methoxypyridine (0.21 mL), and using benzophenone (1.1 g), and
was isolated after purification by flash chromatography on silica gel
(eluent: heptane/CH2Cl2 80:20) as a white powder (15% yield): mp
those previously described.35
4.1.2. 2,20-Dimethoxy-3,30-bipyridine (3). Compound
3 was ob-
tained according to the general procedure A starting from 2-
methoxypyridine (0.21 mL), and was isolated after purification by
flash chromatography on silica gel (eluent: heptane/AcOEt 80:20)
as a light yellow solid (35% yield): mp 104 ꢄC; 1H NMR (300 MHz,
134 ꢄC; IR (ATR)
n
3523, 3058, 3028, 2952, 1582, 1463, 1447, 1405,
1264, 1245, 1012, 755, 735, 699 cmꢂ1
;
1H NMR (300 MHz, CDCl3)
d
3.86 (s, 3H), 6.77e6.85 (m, 2H), 7.21e7.35 (m, 10H), 8.12 (dd, 1H,
J¼4.7 and 2.2 Hz), OH not seen; 13C NMR (75 MHz, CDCl3):
d 53.7,
CDCl3)
d
3.92 (s, 6H), 6.95 (dd, 2H, J¼5.0 and 7.2 Hz), 7.59 (dd, 2H,
81.0, 116.8, 127.4 (2C), 127.8 (4C), 128.0 (4C), 129.4, 138.5, 145.6 (2C),
J¼1.9 and 7.2 Hz), 8.18 (dd, 2H, J¼1.9 and 5.0 Hz); 13C NMR (75 MHz,
145.9, 161.0; HRMS (ESI) calcd for C19H17NNaO2 [(MþNa)þ
]
ꢁ
CDCl3):
d
53.5 (2C),116.4 (2C),119.8 (2C),139.5 (2C),146.2 (2C),161.1
314.1157, found 314.1155.
(2C). These data are analogous to those previously described.35
4.2.4. 3-Benzoyl-2-methoxypyridine (2e). Compound 2e was ob-
tained according to the general procedure B starting from 2-
methoxypyridine (0.21 mL), and using benzoyl chloride (0.70 mL),
and was isolated after purification by flash chromatography on
silica gel (eluent: heptane/CH2Cl2 40:60) as a yellow oil (62% yield):
4.1.3. 2-Iodoanisole (9a). Compound 9a was obtained according to
the general procedure A starting from anisole (0.26 mL), and was
isolated after purification by flash chromatography on silica gel
(eluent: heptane/AcOEt 80:20) as a yellow oil (71% yield): 1H NMR
(300 MHz, CDCl3)
d
3.88 (s, 3H), 6.72 (dd, 1H, J¼7.5 and 1.4 Hz), 6.83
1H NMR (300 MHz, CDCl3)
d
3.88 (s, 3H), 7.01 (dd, 1H, J¼7.3 and
(dd, 1H, J¼8.3 and 1.3 Hz), 7.31 (ddd, 1H, J¼8.3, 7.4 and 1.6 Hz), 7.77
5.0 Hz), 7.42e7.48 (m, 2H), 7.58 (tt, 1H, J¼7.4 and 1.3 Hz), 7.72 (dd,
1H, J¼7.3 and 2.0 Hz), 7.78e7.81 (m, 2H), 8.32 (dd, 1H, J¼5.0 and
(dd, 1H, J¼7.8 and 1.6 Hz); 13C NMR (75 MHz, CDCl3):
d 56.3, 86.0,
111.0, 122.5, 129.6, 139.5, 158.1. These data are analogous to those
1.9 Hz); 13C NMR (75 MHz, CDCl3):
d 53.8, 116.7, 122.7, 128.5 (2C),
previously described.24
129.9 (2C), 133.5, 137.2, 139.0, 149.4, 161.3, 194.9. These NMR data
are analogous to those previously described.33
4.2. General procedure B (deprotonation using 1 equiv
FeBr2 and 3 equiv LiTMP followed by trapping with an
electrophilesI2)
4.2.5. 3-Allyl-2-methoxypyridine (2g). Compound 2g was obtained
according to the general procedure
B
starting from 2-
methoxypyridine (0.21 mL), and using allyl bromide (0.52 mL),
and was isolated after purification by flash chromatography on
silica gel (eluent: heptane/AcOEt 80:20) as a yellow oil (<5% yield):
To
a
stirred
cooled
(0 ꢄC)
solution
of
2,2,6,6-
tetramethylpiperidine (1.0 mL, 6.0 mmol) in THF (5 mL) were
added BuLi (1.6 M hexanes solution, 6.0 mmol) and, 5 min later,
FeBr2 (0.43 g, 2.0 mmol). The mixture was stirred for 15 min at 0 ꢄC
before introduction of the substrate (2.0 mmol). After 2 h at room
temperature, the electrophile (6.0 mmol) was added. The mixture
was stirred for 1 h before addition of H2O (10 mL) and extraction
with EtOAc (3ꢅ20 mL). The combined organic layers were dried
over MgSO4, filtered, and concentrated under reduced pressure.
1H NMR (300 MHz, CDCl3)
d
3.33 (br d, 2H, J¼6.7 Hz), 3.95 (s, 3H),
5.05 (dq, 1H, J¼7.1 and 1.6 Hz), 5.10 (t, 1H, J¼1.4 Hz), 5.90e6.03 (m,
1H), 6.82 (dd, 1H, J¼7.2 and 5.0 Hz) 7.38 (ddt, 1H, J¼7.2, 1.9, and
0.9 Hz), 8.03 (dd, 1H, J¼5.0 and 1.9 Hz); 13C NMR (75 MHz, CDCl3):
d
33.8, 53.4, 116.3, 116.7, 122.9, 135.6, 137.7, 144.4, 161.9.
4.2.6. 3-Benzyl-2-methoxypyridine (2h). Compound 2h was ob-
tained according to the general procedure B starting from 2-
methoxypyridine (0.21 mL), and using benzyl bromide (0.71 mL),
and was isolated after purification by flash chromatography on
silica gel (eluent: heptane/AcOEt 95:5 to 70:30) as a yellow oil (18%
4.2.1.
a-(3,4,5-Trimethoxyphenyl)-2-methoxy-3-pyridylmethanol
(2b). Compound 2b was obtained according to the general pro-
cedure B starting from 2-methoxypyridine (0.21 mL), and using
3,4,5-trimethoxybenzaldehyde (0.18 g, 6.0 mmol), and was isolated
after purification by flash chromatography on silica gel (eluent:
yield): IR (ATR)
1311, 1254, 1102, 1020, 781, 731, 697 cmꢂ1
CDCl3)
3.91 (s, 2H), 3.96 (s, 3H), 6.79 (dd, 1H, J¼7.3 and 5.0 Hz),
n
3059, 3027, 2949, 2852, 1585, 1463, 1451, 1410,
;
1H NMR (300 MHz,
heptane/AcOEt 90:10 to 40:60) as a yellow oil (59% yield): IR (ATR)
n
d

E. Nagaradja et al. / Tetrahedron 68 (2012) 3063e3073
3071
7.20e7.33 (m, 6H), 8.03 (dd, 1H, J¼5.0 and 1.9 Hz); 13C NMR
from 2,6-dimethoxypyridine (0.26 mL), and using pivalaldehyde
(0.70 mL), and was isolated after purification by flash chromatog-
raphy on silica gel (eluent: heptane/AcOEt 90:10 to 80:20) as a yel-
(75 MHz, CDCl3):
d 35.7, 53.5, 116.9, 124.2, 126.3, 128.6 (2C), 129.2
(2C), 138.1, 139.8, 144.7, 162.1; HRMS (ESI) calcd for C13H13NNaO
[(MþNa)þꢁ] 222.0895, found 222.0894.
low oil (68% yield): IR (ATR)
n
3455, 2954, 1602, 1587, 1480, 1390,
0.84 (s, 9H), 2.44
1309, 1019, 735 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d
4.2.7. (E)-Methyl 3-(2-methoxy-3-pyridyl)butenoate (E-2j). Compound
E-2j was obtained according to the general procedure B starting
from 2-methoxypyridine (0.21 mL), and using methyl 2-butynoate
(0.62 mL), and was isolated after purification by flash chromatog-
raphy on silica gel (eluent: heptane/AcOEt 80:20) as a yellow oil (1%
(m, 1H), 3.84 (s, 3H), 3.85 (s, 3H), 4.52 (s, 1H), 6.23 (d, 1H, J¼8.0 Hz),
7.44 (d, 1H, J¼7.8 Hz); 13C NMR (75 MHz, CDCl3):
d 25.6 (3C), 36.6,
52.8, 53.2, 75.9, 100.2,115.2,140.4,159.3,161.6; HRMS (ESI) calcd for
C12H19NNaO3 [(MþNa)þꢁ] 248.1263, found 248.1263.
yield): 1H NMR (300 MHz, CDCl3)
d
2.48 (d, 3H, J¼1.4 Hz), 3.75 (s,
4.2.12. 2,20,6,60-Tetramethoxy-3,30-bipyridine (6). Compound
6
3H), 3.97 (s, 3H), 5.96 (q, 1H, J¼1.3 Hz), 6.89 (dd, 1H, J¼7.3 and
was obtained according to the general procedure B starting from
2,6-dimethoxypyridine (0.26 mL), and using 1-fluoro-2,4,6-
trimethylpyridinium tetrafluoroborate (0.72 g, 3 mmol in this
case), and was isolated after purification by flash chromatography
on silica gel (eluent: heptane/AcOEt 90:10) as a pale beige powder
5.0 Hz), 7.44 (dd, 1H, J¼7.3 and 1.9 Hz), 8.14 (dd, 1H, J¼5.0 and
1.9 Hz); 13C NMR (75 MHz, CDCl3):
d 19.2, 51.2, 53.6, 116.8, 119.7,
126.8, 137.1, 146.8, 154.4, 160.6, 167.0. These data are analogous to
those previously described.33
(33% yield): mp 145 ꢄC; 1H NMR (300 MHz, CDCl3)
d 3.91 (s, 6H),
4.2.8. (Z)-Methyl
3-(2-methoxy-3-pyridyl)butenoate
(Z-2j).
3.94 (s, 6H), 6.36 (d, 2H, J¼8.0 Hz), 7.52 (d, 2H, J¼8.0 Hz); 13C NMR
Compound Z-2j was obtained according to the general procedure B
starting from 2-methoxypyridine (0.21 mL), and using methyl 2-
butynoate (0.62 mL), and was isolated after purification by flash
chromatography on silica gel (eluent: heptane/AcOEt 80:20) as
(75 MHz, CDCl3): d 53.4 (2C), 53.5 (2C), 100.4 (2C), 142.5 (2C), 110.6
(2C), 159.7 (2C), 162.1 (2C). These data are analogous to those
previously described.35
a yellow oil (1% yield): 1H NMR (300 MHz, CDCl3)
d
2.15 (d, 3H,
4.2.13. 2,6-Dimethoxy-3-[(4,6-dimethyl-2-pyridyl)methyl]pyridine
(7). Compound 7 was obtained according to the general procedure
B starting from 2,6-dimethoxypyridine (0.26 mL), and using N-
fluoro-2,4,6-trimethylpyridinium tetrafluoroborate (0.72 g, 3 mmol
in this case61), and was isolated after purification by flash chro-
matography on silica gel (eluent: heptane/AcOEt 90:10) as a yellow
J¼1.5 Hz), 3.56 (s, 3H), 3.94 (s, 3H), 5.99 (q, 1H, J¼1.5 Hz), 6.90 (dd,
1H, J¼7.3 and 5.1 Hz), 7.33 (dd, 1H, J¼7.2 and 1.9 Hz), 8.13 (dd, 1H,
J¼5.0 and 1.9 Hz); 13C NMR (75 MHz, CDCl3):
d 25.6, 51.1, 53.5, 116.4,
119.2,124.1,136.6,146.1,151.7,159.7,165.8. These data are analogous
to those previously described.33
oil (10% yield): IR (ATR)
n
2951, 1718, 1607, 1588, 1479, 1388, 1319,
2.20 (s, 3H), 2.48
4.2.9. [2-(2-Methoxy-3-pyridyl)-2-phenyl]ethyl acetate (2k). Compound
2k was obtained according to the general procedure B starting
from 2-methoxypyridine (0.21 mL), and using (R)-styrene oxide
(0.70 mL), and was isolated as its acetate after purification by flash
chromatography on silica gel (eluent: heptane/CH2Cl2 80:20 to
1248, 1021, 733 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d
(s, 3H), 3.89 (s, 3H), 3.92 (s, 3H), 3.95 (s, 2H), 6.23 (d, 1H, J¼8.0 Hz),
6.64 (s, 1H), 6.78 (s, 1H), 7.31 (d, 1H, J¼8.0 Hz); 13C NMR (75 MHz,
CDCl3):
d 21.0, 24.3, 37.1, 53.4, 54.6, 100.3, 113.0, 120.7, 121.8, 141.7,
147.8, 157.5, 159.8, 160.4, 161.8; HRMS (ESI) calcd for C15H18N2NaO2
80:20) as a yellow oil (15% yield): IR (ATR)
1462, 1451, 1411, 1223, 1018, 780, 737, 699 cmꢂ1; 1H NMR (300 MHz,
CDCl3) 1.97 (s, 3H), 3.93 (s, 3H), 4.57e4.67 (m, 3H), 6.84 (dd, 1H,
n
2950, 2168, 1737, 1584,
[(MþNa)þꢁ] 281.1266, found 281.1266.
d
4.2.14. a-(tert-Butyl)-2-methoxyphenylmethanol (9c). Compound
J¼7.3 and 5.0 Hz), 7.20e7.33 (m, 5H), 7.40 (dd, 1H, J¼7.4 and 1.9 Hz),
9c was obtained according to the general procedure B starting from
anisole (0.26 mL), and using pivalaldehyde (0.70 mL), and was
isolated after purification by flash chromatography on silica gel
8.10 (dd, 1H, J¼5.0 and 1.9 Hz); 13C NMR (75 MHz, CDCl3):
d 21.1,
43.3, 54.1, 65.4,116.9,124.2,127.1,128.4 (2C),128.7 (2C),137.2,139.9,
144.7, 161.6, 171.1; HRMS (ESI) calcd for C16H17NNaO3 [(MþNa)þ
]
(eluent: heptane/AcOEt 95:5) as a yellow oil (47% yield): IR (ATR)
3478, 2956, 1701, 1601, 1490, 1464, 1238, 1043, 1005, 735 cmꢂ1; 1H
NMR (300 MHz, CDCl3)
n
ꢁ
294.1106, found 294.1105.
d
0.93 (s, 9H), 2.63 (d, 1H, J¼6.0 Hz), 3.81 (s,
4.2.10. [(2-Methoxy-3-pyridyl)(phenyl)methyl]
phenyl
ketone
3H), 4.73 (d, 1H, J¼6.0 Hz), 6.87 (dd, 1H, J¼8.3 and 0.9 Hz), 6.95 (td,
1H, J¼7.4 and 1.1 Hz), 7.23 (dd, 1H, J¼8.2 and 1.8 Hz), 7.29 (dd, 1H,
(2l). Compound 2l was obtained according to the general pro-
cedure B starting from 2-methoxypyridine (0.21 mL), and using
trans-stilbene oxide (1.2 g), and was isolated after purification by
flash chromatography on silica gel (eluent: heptane/CH2Cl2 98:2 to
J¼7.5 and 1.8 Hz); 13C NMR (75 MHz, CDCl3):
d 26.2 (3C), 36.8, 55.3,
78.1, 110.7, 120.3, 128.2, 129.5, 130.2, 157.1; HRMS (ESI) calcd for
C12H18NaO2 [(MþNa)þꢁ] 217.1204, found 217.1203.
80:20) as colorless crystals (60% yield): mp 128 ꢄC, IR (ATR)
n
3063,
2949, 2252,1687,1595,1464,1449,1407,1258,1212,1103,1021, 905,
725, 698 cmꢂ1; 1H NMR (300 MHz, CDCl3)
3.91 (s, 3H), 6.25 (s,1H),
4.2.15.
a-(tert-Butyl)-2,4-dimethoxy-5-pyrimidylmethanol
d
(12c). Compound 12c was obtained according to the general pro-
cedure B starting from 2,4-dimethoxypyrimidine (0.26 mL), and
using pivalaldehyde (0.70 mL), and was isolated after purification
by flash chromatography on silica gel (eluent: heptane/AcOEt 95:5)
6.81 (dd, 1H, J¼7.4 and 5.0 Hz), 7.18 (dd, 1H, J¼7.4 and 1.8 Hz),
7.54e7.29 (m, 8H), 8.02 (dt, 2H, J¼6.2 and 1.2 Hz), 8.07 (dd, 1H,
J¼5.0 and 1.8 Hz); 13C NMR (75 MHz, CDCl3):
d 53.0, 53.7, 116.9,
123.4, 127.6, 128.7 (2C), 128.8 (2C), 129.1 (2C), 129.6 (2C), 133.0,
136.6, 136.9, 138.3, 145.4, 161.1, 198.1; HRMS (ESI) calcd for
C20H17NNaO2 [(MþNa)þꢁ] 326.1157, found 326.1154.
as a yellow oil (50% yield): IR (ATR)
1265, 1200, 1049, 1018, 732 cmꢂ1; 1H NMR (300 MHz, CDCl3)
(s, 9H), 3.98 (s, 3H), 4.00 (s, 3H), 4.60 (s, 1H), 8.25 (s, 1H), OH not
seen; 13C NMR (75 MHz, CDCl3):
25.7 (3C), 36.8, 53.9, 54.9, 75.0,
n
2958, 1568, 1467, 1382, 1356,
d
0.92
X-ray data for compound 2l: C20H17NO2, M¼303.35, monoclinic,
d
ꢂ
P21/c, a¼8.3683(11), b¼12.6774(19), c¼14.7765(16) A,
b
¼97.105(6)ꢄ,
115.5, 157.9, 164.5, 168.6; HRMS (ESI) calcd for C11H18N2NaO3
3
V¼1555.6(4) A , Z¼4, rc¼1.295 g cmꢂ3
,
m
¼0.084 mmꢂ1
. A final
[(MþNa)þꢁ] 249.1215, found 249.1216.
ꢂ
refinement on F2 with 3563 unique intensities and 209 parameters
converged at wR(F2)¼0.1021 (R(F)¼0.0426) for 2877 observed
4.2.16.
a-(tert-Butyl)-2,4-dimethoxy-6-pyrimidylmethanol
reflections with I>2
s(I). CCDC 862151.
(12c0). Compound 12c0 was obtained according to the general
procedure B starting from 2,4-dimethoxypyrimidine (0.26 mL), and
using pivalaldehyde (0.70 mL), and was identified after purification
by flash chromatography on silica gel (eluent: heptane/AcOEt 95:5)
4.2.11.
a-(tert-Butyl)-2,6-dimethoxy-3-pyridylmethanol (5c). Compound
5c was obtained according to the general procedure B starting

3072
E. Nagaradja et al. / Tetrahedron 68 (2012) 3063e3073
by NMR (3% yield): 1H NMR (300 MHz, CDCl3)
d
0.92 (s, 9H), 3.95 (s,
(300 MHz, CDCl3)
J¼1.1 Hz), 6.94 (m, 1H), 6.97 (m, 1H), 7.23 (dd, 1H, J¼4.9 and 1.3 Hz);
13C NMR (75 MHz, CDCl3):
25.9 (3C), 35.7, 78.9, 124.2, 125.2, 126.1,
d
0.99 (s, 9H), 2.11 (d, 1H, J¼2.1 Hz), 4.65 (d, 1H,
3H), 3.98 (s, 3H), 4.16 (s, 1H), 6.25 (s, 1H), OH not seen; 13C NMR
(75 MHz, CDCl3):
164.5, 168.6.
d
25.7 (3C), 36.8, 53.9, 54.9, 75.0, 115.5, 157.9,
d
145.9. These NMR data are in accordance with those previously
described.63
4.2.17. 2,20,4,40-Tetramethoxy-5,50-bipyrimidine (13). Compound 13
was obtained according to the general procedure B starting from
2,4-dimethoxypyrimidine (0.26 mL), and using pivalaldehyde
(0.70 mL), and was identified after purification by flash chroma-
tography on silica gel (eluent: heptane/AcOEt 95:5) by NMR (1%
4.2.23. 2,5-Thienylenebis(a
-(tert-butyl)methanol) (220). Compound
220 was obtained according to the general procedure B starting
from thiophene (0.17 mL), and using pivalaldehyde (0.70 mL), and
was isolated after purification by flash chromatography on silica gel
yield): 1H NMR (300 MHz, CDCl3)
d
4.00 (s, 6H), 4.01 (s, 6H), 8.12 (s,
54.3 (2C), 55.0 (2C), 108.3 (2C),
(eluent: heptane/AcOEt 80:20) as a yellow oil (18% yield): IR (ATR)
n
2H); 13C NMR (75 MHz, CDCl3):
d
3427, 2955, 2869, 1479, 1363, 1214, 1043, 1003, 808, 734 cmꢂ1 1H
;
158.8 (2C), 165.1 (2C), 168.7 (2C). These NMR data are analogous to
those previously described.33
NMR (300 MHz, CDCl3)
d
0.99 (s, 18H), 1.96 (d, 2H, J¼3.3 Hz), 4.59
(d, 2H, J¼3.3 Hz), 6.79 (s, 2H); 13C NMR (75 MHz, CDCl3):
d 26.0 (6C),
35.8 (2C), 79. 2 (2C), 124.5 (2C), 144.6 (2C); HRMS (ESI) calcd for
4.2.18. 2,20,4,40-Tetramethoxy-6,60-bipyrimidine
(130). Compound
C14H24NaO2S [(MþNa)þꢁ] 279.1395, found 279.1394.
130 was obtained according to the general procedure B starting from
2,4-dimethoxypyrimidine (0.26 mL), and using pivalaldehyde
(0.70 mL), and was identified after purification by flash chroma-
tography on silica gel (eluent: heptane/AcOEt 95:5) by NMR (13%
Acknowledgements
The authors gratefully acknowledge the financial support of the
Institut Universitaire de France and of Region Bretagne (fellowship
given to E.N.).
yield): 1H NMR (300 MHz, CDCl3)
2H); 13C NMR (75 MHz, CDCl3):
162.9 (2C), 165.5 (2C), 173.1 (2C).
d
4.00 (s, 6H), 4.05 (s, 6H), 7.40 (s,
54.3 (2C), 55.0 (2C), 99,5 (2C),
ꢀ
d
4.2.19. 2,20,40,6-Tetramethoxy-4,50-bipyrimidine (14). Compound 14
was obtained according to the general procedure B starting from
2,4-dimethoxypyrimidine (0.26 mL), and using pivalaldehyde
(0.70 mL), and was identified after purification by flash chroma-
tography on silica gel (eluent: heptane/AcOEt 95:5) by NMR (7%
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2012.02.019. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
yield): 1H NMR (300 MHz, CDCl3)
d
3,98 (s, 3H), 4.02 (s, 3H), 4.04 (s,
3H), 4.09 (s, 3H), 7.07 (s, 1H), 9.24 (s, 1H); 13C NMR (75 MHz, CDCl3):
54.1, 54.4, 54.8, 55.3, 100.9, 111.9, 159.5, 164.6, 164.9, 165.7, 170.6,
d
References and notes
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4. 2 . 2 0.
a- ( t e r t - B utyl) - 3 - met h o xy- 2-p y rid yl me t h a no l
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n
3476, 2963, 2873,
1732, 1588, 1576, 1461, 1434, 1278, 1223, 1051, 1017, 796, 735 cmꢂ1
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1H NMR (300 MHz, CDCl3)
d 0.92 (s, 9H), 3.83 (s, 3H), 4.80 (s, 1H),
7.19e7.21 (m, 2H), 8,19 (dd, 1H, J¼4.1 and 1.9 Hz), OH not seen; 13C
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d
26.1, 37.5, 55.5, 74.3, 118.6, 123.3, 138.6,
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a-(tert-Butyl)-2-fluoro-3-pyridylmethanol (19). Compound
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3374, 2967, 1602, 1579, 1435, 1365, 1265, 1050, 1012, 734 cmꢂ1 1H
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n
;
d
(dd,1H, J¼7.5 and 4.8 Hz), 7.92 (d,1H, J¼7.4 and 1.1 Hz), 8.11 (dd,1H,
J¼4.8 and 2.0 Hz); 13C NMR (75 MHz, CDCl3):
d 25.5 (3C, d,
ꢀ
JF¼1.1 Hz), 36.6 (s), 74,4 (d, JF¼3.3 Hz), 121.3 (d, JF¼4.2 Hz), 124.5 (d,
JF¼28 Hz), 140.2 (d, JF¼5.2 Hz), 146.4 (d, JF¼15 Hz), 160.9 (d,
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d
ꢂ69.8; HRMS (ESI) calcd
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4.2.22.
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phene (0.17 mL), and using pivalaldehyde (0.70 mL), and was iso-
lated after purification by flash chromatography on silica gel
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