Successive regioselective metalations of fused heterocycles: Synthesis of polyfunctionalized furo[3,2- b ]pyridines

Article abstract of DOI:10.1021/jo400748n

The furopyridine framework was chosen as a target for a lithiation study, in order to define the most effective conditions leading to the total functionalization of the heterocycle. Consequently, a detailed procedure for successive regioselective lithiations/electrophilic trapping of furo[3,2-b]pyridines is described and afforded several polyfunctionalized derivatives in good overall yields. A Pd-catalyzed cross-coupling reaction is also described and easily yielded the 7,7′-bifuro[3,2-b]pyridine.

Full text of DOI:10.1021/jo400748n

Article
pubs.acs.org/joc
Successive Regioselective Metalations of Fused Heterocycles:
Synthesis of Polyfunctionalized Furo[3,2‑b]pyridines
Adeline Jasselin-Hinschberger, Corinne Comoy,* Anthony Chartoire, and Yves Fort*
Groupe Het
des Aiguillettes, F-54506 Vandoeuvre-les
́
er
́
ocycles: Rea
́
ctivite
́
et Interaction (HECRIN), SRSMC UMR CNRS 7565, Universite
-Nancy, France
́
de Lorraine, B.P. 239, Boulevard
̀
S
* Supporting Information
ABSTRACT: The furopyridine framework was chosen as a target for a lithiation study, in order
to define the most effective conditions leading to the total functionalization of the heterocycle.
Consequently, a detailed procedure for successive regioselective lithiations/electrophilic
trapping of furo[3,2-b]pyridines is described and afforded several polyfunctionalized derivatives
in good overall yields. A Pd-catalyzed cross-coupling reaction is also described and easily yielded
the 7,7′-bifuro[3,2-b]pyridine.
reactions of aromatic or heteroaromatic substrates. From our
perspective, the challenge today is to successfully introduce a
different group on each position of selected substrates.
Among the five hydrogen atoms present on the furo[3,2-
b]pyridine, H2, H3, H5 and H7 appear to be prime candidates
for lithiation reactions. Indeed, due to their proximity to the
heteroatoms (O or N), directed metalations such as α-
lithiation, β- or α-pyridinodirected metalation (β- or α-PDM)
or directed ortho-metalation (DoM) may respectively be
envisioned as competitive (Figure 1). This diversity involves
INTRODUCTION
■
In our ongoing research in heterocyclic chemistry, we are
interested in the development of new strategies for the
polyfunctionalization of aromatic heterocycles, especially
fused heterocycles such as furopyridines.1−5 The functionalities
of such heterocycles are most frequently introduced before or
during the construction of one of the aromatic rings, which has
the effect of limiting potential subsequent functionalization as
well as increasing the number of steps. Indeed, in the literature,
the most reported processes for the preparation of substituted
furopyridines usually involve a Pd-catalyzed furan ring
formation starting from alkynyl-substituted pyridine deriva-
tives.6−15 In contrast, only few papers discuss the preparation of
substituted furopyridines by direct functionalization of the bare
heterocycles. Whereas this has been reported on the furan unit
(C-2 or C-3 positions of furopyridines) using hydrogen lithium
(H−Li) exchange reactions with these substrates,2,16 regiose-
lective lithiations of the pyridinic ring proved to be much more
challenging. However, Shiotani17−21 and more recently Baran22
achieved the targeted functionalization using activated pyridinic
rings (e.g., N-oxide derivative). Carrer and co-workers23 also
̈
Figure 1. Potential directed lithiations of the furo[3,2-b]pyridine
scaffold.
proposed an alternative sequence involving a palladium-
catalyzed C−H activation leading to the introduction of aryl
groups at the C-3 and C-7 positions. We have also recently
reported new detailed procedures to achieve successive
lithiation/functionalization of the furo[2,3-c]pyridine isomer,
displaying control of the regioselectivity.5 In a polar organo-
metallic chemistry context, furopyridines, and especially
furo[3,2-b]pyridines, appear of interest because of their
characteristic reactivity resulting from the annulation. Indeed,
the presence of two “nonconnected” heteroatoms is an
additional interesting parameter to understand the complex-
ation phenomena observed with the lithiated species. With the
aim of controlling regioselectivities during metalation processes,
the direct functionalization of such substrates always remains an
interesting challenge.
a judicious choice first of the lithiated basic system used for the
metalation and second, of the considered sequence (because of
the problem of functional tolerance between the introduced
features and lithium reagents).24 For example, while iodine (I2)
is useful as an electrophile to trap lithiated species during
metalation studies, it proves to be an unsuitable electrophile for
polyfunctionalizations because of side reactions (e.g., I−Li
exchange, “halogen dance” rearrangement,25 reduction, ...).
We report here the development of efficient successive
functionalizations of the furo[3,2-b]pyridine scaffold combining
several lithiation/electrophilic trapping steps. The major
In recent decades, significant researches have been reported
Received: April 9, 2013
concerning the development of regioselective lithiation
© XXXX American Chemical Society
A
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concern of this study was to carry out the various stages of
functionalization with high chemioselectivity. Our aim was to
propose a methodology that allows the introduction of
functional groups in the presence of sensitive moieties without
risking side-reactions. We have focused our attention on the
reactivity of three classical basic systems: n-butyllithium (n-
BuLi), lithium 2,2,6,6-tetramethylpiperidide (LiTMP) and
Fort’s superbase [n-BuLi/LiDMAE].
Table 1. Lithiation of 2-Chlorofuro[3,2-b]pyridine 1a
metalation
trapping step
a
conversion
bc
a
bc
,
,
conditions
conditions
(%)
yields (%)
n equiv/T (°C)
T (°C)
2a/3a
RESULTS AND DISCUSSION
■
1
2
3
4
5
6
7
8
2.0 equiv/−80
2.0 equiv/−60
2.0 equiv/−45
1.5 equiv/−45
1.2 equiv/−60
1.2 equiv/−45
1.2 equiv/−20
−80 to 25
−60 to 25
−45 to 25
−45 to 25
−60 to 25
−45 to 25
−20 to 25
0 to 25
80
75/trace
80/10
In a preliminary study,2 we reported that whatever basic
conditions were used (n-BuLi, LiTMP or [n-BuLi/LiDMAE]),
the lithiation of the furo[3,2-b]pyridine was occurring
exclusively at the C-2 position of this fused heterocycle. No
trace of deprotonation of the C-7 position invoking an ortho-
metalation process, or deprotonation of the C-3 or C-5
positions potentially obtained through a pyridinodirected
metalation (α- or β-PDM)26−28 was observed. This regiose-
lective α-lithiation reaction,29 which proceeds with greater
facility than the other lithiation processes, highlights the
competition between coordination and “acid-base” mechanisms
in favor of the acidic character of hydrogen H2. Starting from
this point, we next envisioned to prepare 2,3-disubstituted
furo[3,2-b]pyridines 2. It appeared that the functionalization of
the C-2 position of the furo[3,2-b]pyridine ring was easily and
selectively produced by the action of n-BuLi.2,30 However, to
reach complete conversion, the use of 2 equivalents of n-BuLi is
required. Under these conditions, the 2,3-dichlorofuro[3,2-
b]pyridine 2e was also obtained as a byproduct in 12% yield.30
As expected, the acidity of H3 is greatly increased by the
immediate vicinity of the chlorine atom at the C-2 position.
This was confirmed by DFT calculations of Mulliken charges
(see Supporting Information for more details about DFT
calculations). As an extension of this result, we then examined
the lithiation of the C-3 position starting from 2-chlorofuro-
[3,2-b]pyridine 1 as substrate. The directed ortho-lithiation of
heterocycle 1 by n-BuLi as lithiated agent was studied, and
trimethysilyl chloride (Me3SiCl) was chosen as representative
electrophile to circumvent the potential lack of stability of
polyhalogenated derivatives. The more significant results of this
study are reported in Table 1. All reactions were monitored by
GC using an internal standard. Lithiation of 1 was then carried
out using n-BuLi (2 equiv) at −80 °C for 1 h in tetrahydrofuran
(THF) as solvent, followed by treatment of the lithiated
intermediate with Me3SiCl (2.0 equiv) for 1 h at −80 °C to
room temperature (25 °C). These conditions did not lead to
complete conversion of the substrate (only 80%), but the
expected 2-chloro-3-trimethylsilylfuro[3,2-b]pyridine 2a was
nevertheless obtained in 75% yield (GC), in the presence of
a trace of 2-chloro-3,7-bis(trimethylsilyl)furo[3,2-b]pyridine 3a
(entry 1). The temperature of lithiation was then set at −60 °C
or −45 °C (entries 2 and 3), leading to an increase of
conversion (92 and 100%, respectively). However, the presence
of compound 3a was also detected (10 and 24% respectively)
as a result of the double lithiation of 1 by the excess of n-BuLi
present in the reaction medium. Consequently, the amount of
n-BuLi was reduced (1.5 or 1.2 equiv versus 2 equiv, entries 4−
8) and various metalation temperatures were probed.
92
100
97
75/24
86/11
82
79/trace
85/trace
91
d
91
87(85) /trace
e
1.2 equiv/0
92
57/trace
a
Reagents and conditions: (i) n-BuLi (n equiv), THF, T °C, 1 h. (ii)
Me3SiCl (2.0 equiv), THF, T °C to 25 °C, 1 h then H2O. Reaction
performed on 0.8 mmol of 1. GC yields determined by internal
standard method. Isolated yield after centrifugal thin-layer
chromatography purification. Metalation was performed for 15 min.
b
c
d
e
performed at −60, −45 or −20 °C for 1 h in THF (entries
5−7). After electrophilic trapping, the 2-chloro-3-
trimethylsilylfuro[3,2-b]pyridine 2a was obtained in 79−87%
yields (GC) and only traces of 3a (<2%) were detected (GC).
To lead to total consumption of substrate 1, we envisioned to
achieve the lithiation at 0 °C for 15 min (entry 8). Under these
conditions, the conversion rate was not improved, the
degradation of the lithiated intermediate was observed, and
2a was detected in a moderate yield (57%). For a synthetic
purpose, the scope of the reaction was investigated using the
optimized lithiation conditions (entry 7) and various
representative electrophiles as trapping agents. Furopyridine
derivatives 2a−e were then easily obtained in very good yields
(58−85%, Scheme 1).
Scheme 1. Preparation of 2,3-Disubstituted Furo[3,2-
a b
,
b]pyridines 2a−e
a
Reagents and conditions: (i) n-BuLi (1.2 equiv), THF, −20 °C, 1 h.
(ii) E+ = Me3SiCl, CBr4, Bu3SnCl, PhCHO, C2Cl6 (2.0 equiv), THF,
b
−20 to 25 °C, 1 h then H2O. Isolated yields after centrifugal thin-
layer chromatography purification.
We next envisioned to achieve a third functionalization of the
furo[3,2-b]pyridine moiety using a step by step procedure. As
trimethylsilyl substitution at the C-3 position can act as a
protective group, 2-chloro-3-trimethylsilylfuro[3,2-b]pyridine
2a was chosen as substrate. Both C-5 and C-7 positions of
the fused ring have attracted our attention for this study
because of potential competing lithiations. Since the work by
Gilman31 and Wittig,32 directed ortho-metalation (DoM)
proved to be a powerful tool for the functionalization of
When 1.5 equivalents of n-BuLi were used at −45 °C for 1 h
followed by trapping with Me3SiCl (2.0 equiv) at −45 °C to
room temperature, byproduct 3a was always detected in the
reaction medium (11%, entry 4). The amount of n-BuLi was
consequently adjusted to 1.2 equiv and metalation was
B
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aromatic or heteroaromatic scaffolds. Heteroatoms contained in
the structures of directing metalation groups (DMGs) facilitate
ortho-lithiations and provide predictable regioselectivities.
Then, considering the structure of 2a, the oxygen atom can
allow a regioselective DoM29,33 using classical n-BuLi or
LiTMP34 bases. DFT calculations of Mulliken charges (see
Supporting Information) confirmed that the hydrogen atom at
the C-7 position can be considered as the most acidic. In
contrast, the use of the [n-BuLi/LiDMAE] superbase in aprotic
solvents is known to favor the formation of aggregates near the
nitrogen atom.26−28 Indeed, in such conditions, and despite the
fact that H5 is less acidic than H7, the lithiation may take place
at the C-5 position as a competitive α-pyridinodirected
metalation (α-PDM) (Figure 2).
Indeed, LiTMP (2.0 equiv) in THF as solvent, at −20 °C for 1
h, afforded efficient lithiation at the C-7 position. This was
evidenced by trapping the lithiated intermediate with various
electrophiles, producing the highly functionalized 2,3,7-
trisubstituted derivatives 3a−g in very good yields (78−92%,
Table 2).
The synthetic potential of the trisubstituted scaffolds was
further exemplified by involving the 7-bromo derivative 3b and
the 7-stannyl compound 3c into a Pd-catalyzed cross-coupling
reaction. Interestingly, under usual Stille conditions, the 7,7′-
bifuropyridine 3h was efficiently prepared in good yield (65%,
Scheme 2).
Scheme 2. Preparation of 7,7′-Bifuro[3,2-b]pyridine
a b
,
Derivative 3h
Figure 2. Potential directed lithiations of derivative 2a.
We first decided to examine the action of n-BuLi as base
toward derivative 2a. After several attempts, best results were
obtained when using n-BuLi (1.2 equiv) in THF for 1 h at −20
°C, followed by electrophilic trapping (2.0 equiv) (Table 2,
a
Reagents and conditions: (i) 3b (1.0 equiv), 3c (1.1 equiv),
b
PdCl2(PPh3)2 (5 mol %), DMF, 110 °C, 24 h. Reaction performed
on 0.53 mmol of 3b. Isolated yields after centrifugal thin-layer
chromatography purification.
Table 2. Preparation of 7-Substituted-2-chloro-3-
trimethylsilylfuro[3,2-b]pyridines 3a−g
We next turned our attention to the direct functionalization
at the C-5 position, involving the deprotonation of the less
acidic hydrogen atom H5 (Scheme 3). Such a metalation may
be considered by using the monometallic non-nucleophilic
superbase [n-BuLi/LiDMAE] which generally exhibits specific
aggregation35 on the pyridinic nitrogen atom. We then carried
out deprotonation of furopyridine derivative 2a using the [n-
BuLi/LiDMAE] superbase (3.0 equiv) in hexanes as solvent
followed by electrophilic trapping using Me3SiCl or hexachloro-
ethane (C2Cl6) (3.0 equiv). When the metalation step was
carried out at −78 °C for 1, 2 or 4 h, starting material 2a was
recovered unchanged. In contrast, H−Li exchange partially
occurred at −45 °C (less than 30%) to become complete at
−20 °C. Unfortunately, deprotonation of the C-7 position was
revealed since only 7-trimethylsilyl or 7-chloro isomers 3a and
3e were isolated in excellent yields (75 and 85%, respectively)
without any trace of 5-substituted furo[3,2-b]pyridine 6a or 6e.
Despite the fact that the [n-BuLi/LiDMAE] superbase usually
promotes deprotonation of the α-position of the pyridinic
nitrogen even in the presence of DMGs (Cl, SMe, OMe,
etc.),3,4,36 we note that in the case of furopyridines, the
deprotonation always occurs at the C-7 position. This is
probably due to the fact that the complexation of the superbase,
preferred on the oxygen atom at the expense of the nitrogen
one, enhances the H7 acidity versus H5 acidity,5,37 then only
the deprotonation at the C-7 position can be observed.
a c
−
a c
−
yields
(%)
yields
(%)
E
route B (route A)
E
route B
3a
3b
3c
3d
SiMe3
78 (40)
88 (38)
87 (55)
90 (46)
3e
3f
Cl
92
67
85
Br
SMe
SnBu3
3g
CHO
CH(OH)Ph
a
Reagents and conditions: (i) route A = n-BuLi (1.2 equiv), THF, −20
°C, 1 h/route B = LiTMP (2.0 equiv), THF, −20 °C, 1 h. (ii) E+ =
Me3SiCl, CBr4, Bu3SnCl, PhCHO, C2Cl6, Me2S2 or DMF (2.0 equiv),
b
THF, −20 to 25 °C, 1 h then H2O. Reaction performed on 0.53
mmol of 2a. Isolated yields after centrifugal thin-layer chromatog-
c
raphy purification.
route A). As expected, under these conditions, functionalization
of 2a was only observed at the C-7 position. Despite total
conversion, the expected derivatives 3a−d were obtained only
in moderate yields (38−55%), in the presence of byproducts
resulting from desilylation5 and reaction medium degradation.
To avoid side reactions due to the nucleophilic character of n-
BuLi, we next decided to carry out the lithiation using LiTMP,
because of its non-nucleophilic behavior (Table 2, route B).
As stated earlier, our aim was to achieve the functionalization
of each position of the heterocycle. At this stage of our study,
the functionalization of the C-6 position became possible
thanks to the activation generated by the group introduced at
C
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ab
,
Scheme 3. Competitive Lithiation of the C-5 and C-7 Positions with the [n-BuLi/LiDMAE] Superbase
a
Reagents and conditions: (i) [n-BuLi/LiDMAE] (3.0 equiv), hexanes, −20 °C, 1 h. (ii) Me3SiCl or C2Cl6 (3.0 equiv), THF, −20 to 25 °C, 1 h then
b
c
H2O. Isolated yields after centrifugal thin-layer chromatography purification. ND: not detected.
Table 3. Preparation of 6,7-Disubstituted-2-chloro-3-trimethylsilylfuro[3,2-b]pyridines 4a−g
a
Reagents and conditions: (i) LiTMP (3.0 equiv), THF, −20 °C, 1 h. (ii) E+= Me3SiCl, CBr4, CD3OD or C2Cl6 (3.0 equiv), THF, −20 to 25 °C, 1 h
b
c
d
then H2O. Isolated yields after centrifugal thin-layer chromatography purification. ND: not detected. 4b−c are unstable and lead to degradation
compounds. 4.0 equiv of LiTMP then 4.0 equiv of Me3SiCl were used.
e
the C-7 position. Lithiations of trisubstituted derivatives 3a,b or
3e were then performed using LiTMP (3.0 equiv) as base (to
avoid nucleophilic attack on the silyl group), at −20 °C for 1 h
and in THF as solvent. The lithiated species were next trapped
with Me3SiCl, CBr4, C2Cl6 or CD3OD as electrophiles (3.0
equiv). Main results are reported in Table 3. As expected and
according to the DFT calculation of Mulliken charges (see
Supporting Information for more details about DFT calcu-
lations), H6−Li exchange takes place only if a halogen atom is
present at the C-7 position (Br or Cl, 3b or 3e respectively).
This ortho-metalation could be attributed to a complex induced
proximity effect (CIPE). The complexation between LiTMP
and the halogen leads at first to a close relationship between the
lithiated base and H6. Then, because the electrons of the
heteroatom are shared with the metal, the inductive effect of
the halogen is increased. This has the effect of accentuating the
acidity of H6 and thus facilitates the deprotonation.38 In the
above-described conditions, no reaction was observed starting
from silyl derivative 3a while halogenated isomers 3b,e gave the
desired tetrasubstituted heterocycles 4b,c,e−g in very good
yields (41−90%, Table 3). On the other hand, we studied the
metalation of 3d. The hydroxymethyl group at the C-7 position
does not increase the acidity of the H6 hydrogen atom,
however the oxyanion unit which is generated in basic medium
can be considered as a potential directing group and may
facilitate the expected selective reaction. Unfortunately, no trace
of furopyridine 4d was detected, 3d being converted into silyl
ether 3i in quantitative yield.
The results described above from 2a, 3a and 3d suggest that
the lithiation of furopyridines can be achieved only if an “acid-
base” mechanism is possible. To check this hypothesis, we next
planned to carry out lithiations using the superbase [n-BuLi/
LiDMAE] starting from 7-silyl or 7-chloro isomers 3a and 3e.
Without activating substituent (3a), H−Li exchange could be
envisioned only at the C-5 position according to an α-PDM
involving an initial coordination step. On the other hand, in the
case of 3e and using the superbase [n-BuLi/LiDMAE] as
lithiated base, two reaction pathways can be proposed: (a) a
D
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a
Scheme 4. Lithiation of the C-5 or C-6 Positions of 3a or 3e with the [n-BuLi/LiDMAE] Superbase
a
Reagents and conditions: (i) [n-BuLi/LiDMAE] (3.0 to 12.0 equiv), hexanes, −45 or −20 °C, 1 h to 4h. (ii) E+= Me3SiCl or C2Cl6 (3.0 or 4.0
b
equiv) or CD3OD (40.0 equiv), THF, −45 or −20 to 25 °C, 1 h then H2O. ND: Not detected.
a b
,
Scheme 5. Lithiation of 6,7-Disubstituted-2-chloro-3-trimethylsilylfuro[3,2-b]pyridines 4e−f
a
Reagents and conditions: (i) route A = LiTMP (3.0 equiv), THF, −20 °C, 1 h or route B= [n-BuLi/LiDMAE] (3.0−6.0 equiv), hexanes, −20 °C,
b
1−4 h. (ii) E+= CD3OD (40.0 equiv), C2Cl6 or Me3SiCl (3.0 to 6.0 equiv), THF, −20 to 25 °C, 1 h then H2O. Isolated yields after centrifugal thin-
layer chromatography purification. ND: expected derivatives were not detected. 5b is not stable at room temperature and leads to degradation
c
d
compounds.
H−Li exchange at the C-6 position would highlight an “acid-
base” mechanism, due to the inductive effect generated by the
chlorine atom at the C-7 position which increases the acidity of
H6; (b) a H−Li exchange at the C-5 position would evidence a
“coordination” effect as main pathway. Various attempts were
then implemented as reported in Scheme 4: (i) [n-BuLi/
LiDMAE] (3.0−12.0 equiv), in hexanes, at −45 or −20 °C for
1−4 h; (ii) electrophile (3.0, 4.0, or 40.0 equiv), in THF, at
−45 or −20 to 25 °C for 1 h. As expected (taking into account
previous results), no trace of 5-substituted products 7a−d was
detected and starting materials were recovered unchanged.
However, functionalization was observed at the C-6 position
starting from 7-chloro derivative 3e according to a DoM
process. Reactions using 4.0 equiv of superbase, at −20 °C for 1
h followed by addition of C2Cl6 (4.0 equiv) or CD3OD (40.0
equiv) as electrophile, at −20 to 25 °C for 1 h produced
compounds 4f and 4g in 45 and 40% yields, respectively.
Finally, to complete our study, we focused our efforts on the
functionalization of the last available position of the
furopyridine. The 6-chloro derivative 4f was chosen as
representative substrate because of the activation resulting
from the neighboring chlorine atom. LiTMP appeared as a
good candidate to perform this last lithiation according to a
DoM process. However, even if not efficient starting from 2a or
3a,e, α-PDM conditions using the superbase [n-BuLi/
LiDMAE] could also be of interest because of the interesting
cooperative effect3 of nitrogen and chlorine atoms (see
Supporting Information for DFT calculations). As depicted in
Scheme 5, we envisioned the functionalization of chloro
derivative 4f by route A. According to our forecast, metalation
of 4f was easily obtained using LiTMP as base (3.0 equiv) in
THF as solvent, at −20 °C for 1 h, followed by addition of
C2Cl6 as electrophile, affording the expected pentasubstituted
furopyridine 5b in excellent isolated yield (89%). Compared to
the results obtained above, the activation induced by the
chlorine atom at the C-6 position was shown to be essential to
the success of this metalation reaction. Lithiation of 4f was next
carried out according to the conditions described in route B: (i)
[n-BuLi/LiDMAE] (3.0 to 6.0 equiv), in hexanes, at −20 °C for
1, 2 or 4 h; then (ii) addition of Me3SiCl or CD3OD as
electrophiles (3.0 to 6.0 or 40.0 equiv respectively), in THF, at
−20 to 25 °C for 1 h.
While total consumption of substrate 4f was observed in
both cases, no trace of desired products 5c and 5d resulting
from α-PDM was detected. Surprisingly, the unexpected 6-
trimethylsilyl and 6-deuterated derivatives 4e and 4g were
E
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isolated in excellent yields (70 and 80% respectively). These
results evidence a Cl−Li exchange at the C-6 position.
Although Cl−Li exchange is unusual with LiTMP, we have
already observed such a permutation in the case of the lithiation
Ni-catalyzed arylamination40). Works are in progress to explore
such reactions.
EXPERIMENTAL SECTION
■
of 7-chlorofuro[2,3-c]pyridine with [n-BuLi/LiDMAE].5
A
General. 1H and 13C NMR spectra were recorded at 400 or 250 or
200 and 100 or 63 or 50 MHz, respectively, with CDCl3 as solvent and
TMS as internal standard (for 1H NMR). HRMS spectra were
recorded on a microTOF-Q spectrometer. MS were recorded on a
GCMS-QP2010 spectrometer. Melting temperatures are uncorrected
and recorded with a thermostatic oil bath device.
probable pathway is the following: after formation of
[superbase/substrate] aggregates in apolar hexanes, the
addition of THF (with the electrophile) produces a local
decomplexation of the aggregates and releases n-BuLi near the
C−Cl bonds, thus inducing a regioselective Cl−Li exchange at
the C-6 position. As the mechanism of halogen/lithium
exchange reactions is still under debate, it is generally admitted
that in (hetero)aromatic series, the reaction proceeds through
an halogen “ate”-type intermediate (nucleophilic pathway).39
Thus, one hypothesis to explain such selectivity might be an
“ate” mechanism favored at the C-6 position (Scheme 6).
Reagents. All reagents were commercially available and were
purified by distillation when necessary. n-BuLi was used as a
commercial 1.6 M solution in hexanes (titrated before use). 2-
(Dimethylamino)ethanol (DMAE) was distilled and stored over
molecular sieves before use. Hexanes and THF were distilled and
stored on sodium wire before use. Centrifugal thin-layer chromatog-
raphy purifications were performed on silica gel (silica gel 60 PF254
containing gypsum).
General Procedure for the Preparation of LiTMP Base. To a
solution of 2,2,6,6-tetramethylpiperidine (TMP) (542 mg, 3.84 mmol,
1.0 equiv) in anhydrous tetrahydrofuran (THF) (10 mL) at −20 °C
was added dropwise n-BuLi (2.4 mL, 1.6 M in hexanes, 3.84 mmol, 1.0
equiv) under argon atmosphere. After 30 min at 0 °C, LiTMP base (C
= 0.31 M) is ready to be used.
Scheme 6. Postulated Mechanism for the Cl−Li Exchange at
a
the C-6 Position
General Procedure for the Preparation of the [n-BuLi/
LiDMAE] Superbase. To a solution of 2-(dimethylamino)ethanol
(DMAE) (712 mg, 8.0 mmol, 1.0 equiv) in anhydrous hexanes (14
mL) at −20 °C was added dropwise n-BuLi (10.0 mL, 1.6 M in
hexanes, 16.0 mmol, 2.0 equiv) under argon atmosphere. After 15 min
at 0 °C, the [n-BuLi/LiDMAE] superbase (C = 0.33 M) is ready to be
used.
Lithiation of the 2-Chlorofuro[3,2-b]pyridine 1 with n-BuLi.
General procedure. To a solution of 2-chlorofuro[3,2-b]pyridine 162
(123 mg, 0.80 mmol, 1.0 equiv) in THF (10 mL) was added dropwise
n-BuLi (0.6 mL, 0.96 mmol, 1.2 equiv) at −20 °C, under argon
atmosphere. After stirring for 1 h at −20 °C, the appropriate
electrophile (1.6 mmol, 2.0 equiv) was added in THF (5 mL) at −20
°C. The temperature was then allowed to warm to 20 °C over 20 min.
After stirring for 40 min at 20 °C, the hydrolysis was performed with
H2O (10 mL) at 20 °C. The aqueous layer was then extracted twice
with AcOEt (2 × 10 mL). After drying (MgSO4), filtration and solvent
evaporation, the crude product was purified by centrifugal thin-layer
chromatography.
2-Chloro-3-trimethylsilylfuro[3,2-b]pyridine 2a. The product
2a was prepared according to the general procedure described herein
with chlorotrimethylsilane (TMSCl) (174 mg, 1.6 mmol, 2.0 equiv) as
electrophile. Purification by centrifugal thin-layer chromatography was
performed with cyclohexane/AcOEt: 10/0 to 9/1 as eluent and led to
the expected compound 2a (153 mg, 85%) as a white powder: mp
37−39 °C. 1H NMR δH (ppm) 0.47 (s, 9H); 7.15 (dd, J = 8.3 Hz, J′ =
4.8 Hz, 1H); 7.64 (dd, J = 8.3 Hz, J′= 1.4 Hz, 1H); 8.50 (dd, J = 4.8
Hz, J′ = 1.4 Hz, 1H). 13C NMR δC (ppm) −0.6 (3C); 111.4; 117.0;
118.7; 145.9; 147.7; 149.7; 152.7. SM (IE): m/z 225 ([M]+, 25); 210
(100); 190 (16). ESI-HRMS calcd for C10H13ClNOSi (M + H)+:
226.0449; found: 226.0445.
a
Reagents and conditions: (i) [n-BuLi/LiDMAE] (3.0 to 6.0 equiv),
hexanes, −20 °C, 1−4 h. (ii) E+, THF, −20 to 25 °C, 1 h.
To conclude, we have described here five successive
regioselective lithiations of the furo[3,2-b]pyridine framework.
Our study has required the development of specific metalation
conditions involving compatibility between various lithiated
reagents and different functional groups. While H2−Li or H3−
Li exchanges on the furan moiety were easily achieved in very
good yields, lithiations of the pyridinic ring have been more
difficult to implement. Nevertheless we have managed to carry
out five sequential functionalizations of the furopyridine
scaffold, by exploiting activating effects of halogen atoms
introduced at the C-7 or C-6 position. Regardless of the base
used for the lithiation reactions (LiTMP or superbase [n-BuLi/
LiDMAE]), the obtained results highlight mechanisms based
on acid−base character rather than complexation near the
pyridinic nitrogen atom. However, in particular cases, we also
showed that complexation (and/or CIPE) can constitute the
driving force of unusual Cl−Li exchange. Finally, as shown with
the preparation of 7,7′-bifuro[3,2-b]pyridine 3h, advantages of
our strategy are to allow further functionalizations which could
be envisioned using regioselective reactions on the furan moiety
or/and on the pyridine ring (e.g., Pd-catalyzed cross couplings,
3-Bromo-2-chlorofuro[3,2-b]pyridine 2b. The product 2b was
prepared according to the general procedure described herein with
CBr4 (531 mg, 1.6 mmol, 2.0 equiv) as electrophile. Purification by
centrifugal thin-layer chromatography was performed with cyclo-
hexane/AcOEt: 9/1 to 7/3 as eluent and led to the expected
compound 2b (108 mg, 58%) as a brown solid. This derivative is
1
particularly unstable to the light and at room temperature: H NMR
and mp are in conformity with literature.41 MS (EI) m/z 233 ([M +
2]+, 96); 231 ([M]+, 78); 205 (20); 126 (33); 124 (100). ESI-HRMS
calcd for C7H4BrClNO (M + H)+: 231.9159; found: 231.9156.
2-Chloro-3-tri-n-butylstannylfuro[3,2-b]pyridine 2c. The
product 2c was prepared according to the general procedure described
herein with chlorotri-n-butyltin (521 mg, 1.6 mmol, 2.0 equiv) as
electrophile. Purification by centrifugal thin-layer chromatography was
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Article
performed with cyclohexane/AcOEt: 10/0 to 95/5 as eluent and led to
the expected compound 2c (251 mg, 71%) as a colorless liquid: H
7-Bromo-2-chloro-3-trimethylsilylfuro[3,2-b]pyridine 3b.
The product 3b was prepared according to the general procedure
described herein with CBr4 (352 mg, 1.06 mmol, 2.0 equiv) as
electrophile. Purification by centrifugal thin-layer chromatography was
performed with cyclohexane/AcOEt: 10/0 as eluent and led to the
expected compound 3b (route A: 61 mg, 38%; route B: 142 mg, 88%)
1
NMR δH (ppm) 0.88 (t, J = 7.3 Hz, 9H); 1.24−1.39 (m, 12H); 1.55−
1.62 (m, 6H); 7.12 (dd, J = 8.2 Hz, J′ = 4.8 Hz, 1H); 7.62 (dd, J = 8.2
Hz, J′ = 1.4 Hz, 1H); 8.46 (dd, J = 4.8 Hz, J′ = 1.4 Hz, 1H). 13C NMR
δC (ppm) 10.2 (3C); 13.8 (3C); 27.3 (3C); 29.2 (3C); 111.9; 116.7;
118.5; 145.9; 147.9; 150.2; 154.5. MS (EI) m/z 386 ([M-57]+, 68);
328 (13); 272 (100). ESI-HRMS calcd for C19H30ClNNaOSn (M +
Na)+: 466.0927; found: 466.0917.
1-(2-Chlorofuro[3,2-b]pyridin-3-yl)-1-phenylmethanol 2d.
The product 2d was prepared according to the general procedure
described herein with benzaldehyde (170 mg, 1.6 mmol, 2.0 equiv) as
electrophile. Purification by centrifugal thin-layer chromatography was
performed with cyclohexane/AcOEt: 8/2 to 7/3 as eluent and led to
the expected compound 2d (166 mg, 80%) as beige solid: mp 80−83
°C. 1H NMR δH (ppm) 4.90 (br s, 1H); 6.06 (s, 1H); 7.18 (dd, J = 8.4
Hz, J′ = 4.9 Hz, 1H); 7.24−7.36 (m, 3H); 7.53−7.58 (m, 2H); 7.64
(dd, J = 8.4 Hz, J′ = 1.3 Hz, 1H); 8.45 (dd, J = 4.9 Hz, J′ = 1.3 Hz,
1H). 13C NMR δC (ppm) 69.5; 117.9; 118.1; 119.4; 126.3 (2C);
127.9; 128.6 (2C); 142.2; 142.4; 145.8; 146.7; 146.9. MS (EI) m/z
259 ([M]+, 50); 182 (100); 153 (23). ESI-HRMS calcd for
C14H10ClNNaO2 (M + Na)+: 282.0292; found: 282.0291.
1
as an orange solid: mp 42−45 °C. H NMR δH (ppm) 0.46 (s, 9H);
7.33 (d, J = 5.1 Hz, 1H); 8.29 (d, J = 5.1 Hz, 1H). 13C NMR δC (ppm)
−0.8 (3C); 112.4; 122.3; 122.6; 146.3; 146.5; 150.3; 153.1. MS (EI)
m/z 305 ([M + 2]+, 26); 303 ([M]+, 19); 290 (100); 288 (78); 268
(15). ESI-HRMS calcd for C10H12BrClNOSi (M + H)+: 303.9555;
found: 303.9544.
2-Chloro-7-tri-n-butylstannyl-3-trimethylsilylfuro[3,2-b]-
pyridine 3c. The product 3c was prepared according to the general
procedure described herein with chlorotri-n-butyltin (345 mg, 1.06
mmol, 2.0 equiv) as electrophile. Purification by centrifugal thin-layer
chromatography was performed with cyclohexane/AcOEt: 10/0 to 98/
2 as eluent and led to the expected compound 3c (route A: 150 mg,
55%; route B: 237 mg, 87%) as a colorless liquid: 1H NMR δH (ppm)
0.47 (s, 9H); 0.89 (t, J = 7.3 Hz, 9H); 1.18−1.23 (m, 6H); 1.29−1.39
(m, 6H); 1.53−1.61 (m, 6H); 7.19 (d, J = 4.6 Hz, 1H); 8.40 (d, J = 4.6
Hz, 1H). 13C NMR δC (ppm) −0.5 (3C); 10.2 (3C); 13.8 (3C); 27.4
(3C); 29.1 (3C); 111.3; 126.5; 131.7; 144.9; 149.2; 149.8; 154.6. MS
(EI) m/z 458 ([M-57]+, 100); 402 (81); 346 (90); 210 (41); 73 (56).
ESI-HRMS calcd for C22H39ClNOSiSn (M + H)+: 516.1503; found:
516.1490.
1-(2-Chloro-3-trimethylsilylfuro[3,2-b]pyridin-7-yl)-1-phe-
nylmethanol 3d. The product 3d was prepared according to the
general procedure described herein with benzaldehyde (112 mg, 1.06
mmol, 2.0 equiv) as electrophile. Purification by centrifugal thin-layer
chromatography was performed with cyclohexane/AcOEt: 10/0 to 95/
5 as eluent and led to the expected compound 3d (route A: 81 mg,
46%; route B: 158 mg, 90%) as a yellow gummy: 1H NMR δH (ppm)
0.44 (s, 9H); 2.65 (br s, 1H); 6.25 (s, 1H); 7.29−7.37 (m, 3H); 7.46−
7.49 (m, 2H); 8.48 (d, J = 5.1 Hz, 1H). 13C NMR δC (ppm) −0.7
(3C); 70.6; 115.5; 126.6 (2C); 128.3; 128.8 (2C); 134.4; 141.6; 144.5;
146.3; 147.8; 149.6; 152.4. MS (EI) m/z 331 ([M]+, 53); 316 (100);
296 (58). ESI-HRMS calcd for C17H19ClNO2Si (M + H)+: 332.0868;
found: 332.0861.
2,3-Dichlorofuro[3,2-b]pyridine 2e. The product 2e was
prepared according to the general procedure described herein with
C2Cl6 (379 mg, 1.6 mmol, 2.0 equiv) as electrophile. Purification by
centrifugal thin-layer chromatography was performed with cyclo-
hexane/AcOEt: 10/0 to 95/5 as eluent and led to the expected
1
compound 2e (117 mg, 78%) as a white powder: mp 57−60 °C. H
NMR δH (ppm) 7.31 (dd, J = 8.4 Hz, J′ = 4.8 Hz, 1H); 7.73 (dd, J =
8.4 Hz, J′ = 1.2 Hz, 1H); 8.60 (dd, J = 4.8 Hz, J′ = 1.2 Hz, 1H). 13C
NMR δC (ppm) 109.8; 118.5; 120.4; 142.6; 144.0; 146.4; 147.1. MS
(EI) m/z 189 ([M + 2]+, 60); 187 ([M]+, 94); 159 (46); 126 (33);
124 (100). ESI-HRMS calcd for C7H3Cl2NNaO (M + Na)+:
209.9484; found: 209.9484.
Lithiation of 2-Chloro-3-trimethylsilylfuro[3,2-b]pyridine 2a
with n-BuLi or LiTMP: Preparation of Compounds 3a−g.
General Procedure with n-BuLi, Route A. To a solution of 2-chloro-3-
trimethylsilylfuro[3,2-b]pyridine 2a (120 mg, 0.53 mmol, 1.0 equiv) in
THF (10 mL) was added dropwise n-BuLi (0.4 mL, 0.64 mmol, 1.2
equiv) at −20 °C, under argon atmosphere. After stirring for 1 h at
−20 °C, the appropriate electrophile (1.06 mmol, 2.0 equiv) was
added in THF (5 mL) at −20 °C. The temperature was then allowed
to warm to 20 °C over 20 min. After stirring for 40 min at 20 °C, the
hydrolysis was performed with H2O (10 mL) at 20 °C. The aqueous
layer was then extracted twice with AcOEt (2 × 10 mL). After drying
(MgSO4), filtration and solvent evaporation, the crude product was
purified by centrifugal thin-layer chromatography.
2,7-Dichloro-3-trimethylsilylfuro[3,2-b]pyridine 3e. The
product 3e was prepared according to the general procedure described
in route B with hexachloroethane (251 mg, 1.06 mmol, 2.0 equiv) as
electrophile. Purification by centrifugal thin-layer chromatography was
performed with cyclohexane/AcOEt: 10/0 to 95/5 as eluent and led to
the expected compound 3e (127 mg, 92%) as a white solid: mp 48−50
1
°C. H NMR δH (ppm) 0.46 (s, 9H); 7.19 (d, J = 5.3 Hz, 1H); 8.39
(d, J = 5.3 Hz, 1H). 13C NMR δC (ppm) −0.8 (3C); 112.4; 119.4;
124.8; 144.5; 146.3; 150.5; 153.7. MS (EI) m/z 259 ([M]+, 25); 244
(100); 224 (15); 73 (35). ESI-HRMS calcd for C10H12Cl2NOSi (M +
H)+: 260.0060; found: 260.0042.
General Procedure with LiTMP, Route B. To a solution of LiTMP
(3.4 mL, 0.31M, 1.06 mmol, 2.0 equiv) in THF was added dropwise 2-
chloro-3-trimethylsilylfuro[3,2-b]pyridine 2a (120 mg, 0.53 mmol, 1.0
equiv) in THF (10 mL) at −20 °C, under argon atmosphere. After
stirring for 1 h at −20 °C, the appropriate electrophile (1.06 mmol, 2.0
equiv) was added in THF (5 mL) at −20 °C. The temperature was
then allowed to warm to 20 °C over 20 min. After stirring for 40 min
at 20 °C, the hydrolysis was performed with H2O (10 mL) at 20 °C.
The aqueous layer was then extracted twice with AcOEt (2 × 10 mL).
After drying (MgSO4), filtration and solvent evaporation, the crude
product was purified by centrifugal thin-layer chromatography.
2-Chloro-3,7-bis(trimethylsilyl)furo[3,2-b]pyridine 3a. The
product 3a was prepared according to the general procedure described
herein with TMSCl (115 mg, 1.06 mmol, 2.0 equiv) as electrophile.
Purification by centrifugal thin-layer chromatography was performed
with cyclohexane/AcOEt: 10/0 as eluent and led to the expected
compound 3a (route A: 63 mg, 40%; route B: 123 mg, 78%) as a white
2-Chloro-7-methylthio-3-trimethylsilylfuro[3,2-b]pyridine
3f. The product 3f was prepared according to the general procedure
described in route B with dimethyldisulfide (100 mg, 1.06 mmol, 2.0
equiv) as electrophile. Purification by centrifugal thin-layer chroma-
tography was performed with cyclohexane/AcOEt: 10/0 to 95/5 as
eluent and led to the expected compound 3f (97 mg, 67%) as a yellow
1
oil: H NMR δH (ppm) 0.45 (s, 9H); 2.61 (s, 3H); 6.95 (d, J = 5.25
Hz, 1H); 8.35 (d, J = 5.25 Hz, 1H). 13C NMR δC (ppm) −0.7 (3C);
14.1; 111.6; 114.1; 114.8; 131.3; 145.8; 149.1; 151.2. MS (EI) m/z 271
([M]+, 57); 256 (100); 236 (55); 73 (59). ESI-HRMS calcd for
C11H15ClNOSSi (M + H)+: 272.0327; found: 272.0332.
2-Chloro-7-formyl-3-trimethylsilylfuro[3,2-b]pyridine 3g.
The product 3g was prepared according to the general procedure
described in route B with dimethylformamide (77 mg, 1.06 mmol, 2.0
equiv) as electrophile. Purification by centrifugal thin-layer chroma-
tography was performed with cyclohexane/AcOEt 10/0 to 95/5 as
eluent and led to the expected compound 3g (114 mg, 85%) as a white
solid: mp 73−75 °C. 1H NMR δH (ppm) 0.47 (s, 9H); 7.53 (d, J = 5
Hz, 1H); 8.71 (d, J = 5 Hz, 1H); 10.51 (s, 1H). 13C NMR δC (ppm)
−0.8 (3C); 111.6; 115.6; 123.8; 145.2; 146.7; 151.6; 155.5; 187.8. MS
1
solid: mp 42−44 °C. H NMR δH (ppm) 0.41 (s, 9H); 0.46 (s, 9H);
7.17 (d, J = 4.7 Hz, 1H); 8.46 (d, J = 4.7 Hz, 1H). 13C NMR δC (ppm)
−1.4 (3C); −0.6 (3C); 110.9; 123.3; 130.5; 145.0; 149.5; 150.6; 152.4.
MS (EI) m/z 297 ([M]+, 26); 282 (47); 262 (30); 93 (24); 73 (100).
ESI-HRMS calcd for C13H21ClNOSi2 (M + H)+ 298.0845; found:
298.0851.
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(EI) m/z 253 ([M]+, 29); 238 (100); 218 (8); 93 (45). ESI-HRMS
calcd for C11H13ClNO2Si (M + H)+: 254.0399; found: 254.0390.
2,2′-Bischloro-3,3′-bistrimethylsilyl-7,7′-bifuro[3,2-b]-
pyridine 3h. Under argon atmosphere, to a solution of PdCl2(PPh3)2
(6 mg, 0.009 mmol, 5 mol %) in DMF (3 mL) was added the 7-
stannanylfuro[3,2-b]pyridine compound 3c (100 mg, 0.19 mmol, 1.1
equiv) and 7-bromofuro[3,2-b]pyridine derivative 3b (52 mg, 0.17
mmol, 1.0 equiv). After 24h at 110 °C, the reaction medium was
diluted in methylene chloride (CH2Cl2) (20 mL) and washed with an
aqueous saturated Na2SO3 solution (10 mL). After drying (MgSO4)
and solvent evaporation, the crude product was purified by centrifugal
thin layer chromatography with cyclohexane/AcOEt 10/0 as eluent
2,7-Dichloro-6-deuterio-3-trimethylsilylfuro[3,2-b]pyridine
4g. The product 4g was prepared according to the general procedure
described herein with CD3OD (765 mg, 21.2 mmol, 40.0 equiv) as
electrophile. Purification by centrifugal thin-layer chromatography was
performed with cyclohexane/AcOEt: 10/0 to 99/1 as eluent and led to
the expected compound 4g (115 mg, 82%) as a colorless doughy solid:
1H NMR δH (ppm) 0.48 (s, 9H); 8.50 (s, 1H). 13C NMR δC (ppm)
−0.8 (3C); 111.6; 117.0; 127.0; 145.1; 147.1; 150.3; 151.0. MS (CI)
m/z 262 ([M + H], 70), 245 (100), 225 (25), 73 (13). ESI-HRMS
calcd for C10H11Cl2DNOSi (M + H)+: 261.0122; found: 261.0136.
2-Chloro-7-{phenyl[(trimethylsilyl)oxy]methyl}-3-(trimethyl-
silyl)furo[3,2-b]pyridine 3i. To a solution of LiTMP (6.8 mL, 0.31
M, 2.12 mmol, 4.0 equiv) in THF was added dropwise 1-(2-chloro-3-
trimethylsilylfuro[3,2-b]pyridin-7-yl)-1-phenylmethanol 3d (176 mg,
0.53 mmol, 1.0 equiv) in THF (10 mL) at −20 °C, under argon
atmosphere. After stirring for 1 h at −20 °C, TMSCl (230 mg, 2.12
mmol, 4.0 equiv) was added in THF (5 mL) at −20 °C. The
temperature was then allowed to warm to 20 °C over 20 min. After
stirring for 40 min at 20 °C, the hydrolysis was performed with H2O
(10 mL) at 20 °C. The aqueous layer was then extracted twice with
AcOEt (2 × 10 mL). After drying (MgSO4), filtration and solvent
evaporation, the crude product was purified by centrifugal thin-layer
chromatography with cyclohexane/AcOEt 10/0 to 98/2 as eluent and
led to the expected compound 3i (210 mg, 98%) as a an orange oil: 1H
NMR δH (ppm) 0.44 (s, 18H); 1.43 (s, 18H,); 6.20 (s, 1 H); 7.24−
7.47 (m, 6H); 8.46 (d, J=5.0 Hz, 1 H). 13C NMR δC (ppm) −0.7
(3C); 27.1 (3C); 70.7; 115.8; 126.6 (2C); 127.9; 128.5 (2C); 135.5;
140.1; 142.6; 146.4; 147.8; 149.4; 152.5. MS (EI) m/z 403 ([M]+, 75);
388 (100); 368 (50); 73 (94). ESI-HRMS calcd for C20H27ClNO2Si2
(M+H)+: 404.1263; found: 404.1271.
Lithiation of 6,7-Disubstituted-2-chloro-3-trimethylsilyl-
furo[3,2-b]pyridines 4e and f. General Procedure with the
Superbase [n-BuLi/LiDMAE] Route A. To a solution of [n-BuLi/
LiDMAE] (4.8 mL, 0.33M, 1.59 mmol, 3.0 equiv) in n-hexanes was
added dropwise 6,7-disubstituted-2-chloro-3-trimethylsilylfuro[3,2-b]-
pyridine 4e or 4f (0.53 mmol, 1.0 equiv) in n-hexanes (10 mL) at −20
°C, under argon atmosphere. After stirring for 1 h at −20 °C, the
appropriate electrophile (1.59 mmol, 3.0 equiv) was added in THF (5
mL) at −20 °C. The temperature was then allowed to warm to 20 °C
over 20 min. After stirring for 40 min at 20 °C, the hydrolysis was
performed with H2O (10 mL) at 20 °C. The aqueous layer was then
extracted twice with AcOEt (2 × 10 mL). After drying (MgSO4),
filtration and solvent evaporation, the crude product was purified by
centrifugal thin-layer chromatography.
1
and led to the expected compound 3h (50 mg, 65%) as an oil: H
NMR δH (ppm) 0.50 (s, 18H); 7.78 (d, J = 5.1 Hz, 2H); 8.68 (d, J =
5.1 Hz, 2H). 13C NMR δC (ppm) −0.6 (6C); 92.4 (2C); 102.1 (2C);
111.8 (2C); 118.8 (2C); 123.7 (2C); 146.4 (2C); 153.8 (2C). MS
(EI) m/z 450 ([M]+, 28); 433 (65); 413 (30); 209 (30); 73 (100).
ESI-HRMS calcd for C20H23Cl2N2O2Si2 (M + H)+: 449.0667; found:
449.0670.
Lithiation of 7-Substituted-2-chloro-3-trimethylsilylfuro[3,2-
b]pyridines 3a,b,d and e. To a solution of LiTMP (5.1 mL, 0.31 M,
1.59 mmol, 3.0 equiv) in THF was added dropwise 7-substituted-2-
chloro-3-trimethylsilylfuro[3,2-b]pyridines 3a,b,d or e (0.53 mmol, 1.0
equiv) in THF (10 mL) at −20 °C, under argon atmosphere. After
stirring for 1 h at −20 °C, the appropriate electrophile (1.59 mmol, 3.0
equiv) was added in THF (5 mL) at −20 °C. The temperature was
then allowed to warm to 20 °C over 20 min. After stirring for 40 min
at 20 °C, the hydrolysis was performed with H2O (10 mL) at 20 °C.
The aqueous layer was then extracted twice with AcOEt (2 × 10 mL).
After drying (MgSO4), filtration and solvent evaporation, the crude
product was purified by centrifugal thin-layer chromatography.
7-Bromo-2-chloro-3,6-bistrimethylsilylfuro[3,2-b]pyridine
4b. The product 4b was prepared according to the general procedure
described herein with TMSCl (173 mg, 1.59 mmol, 3.0 equiv) as
electrophile. Purification by centrifugal thin-layer chromatography was
performed with cyclohexane/AcOEt: 10/0 as eluent and led to the
expected compound 4b (146 mg, 73%) as an yellow doughy solid. 1H
NMR δH (ppm) 0.43 (s, 9H); 0.54 (s, 9H) 8.53 (s, 1H). The product
is not stable enough to have a 13C spectrum. ESI-HRMS calcd for
C13H20BrClNOSi2 (M + H)+: 375.9950; found: 375.9926.
6,7-Dibromo-2-chloro-3-trimethylsilylfuro[3,2-b]pyridine 4c.
The product 4c was prepared according to the general procedure
described herein with CBr4 (527 mg, 1.59 mmol, 3.0 equiv) as
electrophile. Purification by centrifugal thin-layer chromatography was
performed with cyclohexane/AcOEt: 10/0 as eluent and led to the
expected compound 4c (83 mg, 41%) as a brown solid: mp 126−128
1
°C. H NMR δH (ppm) 0.45 (s, 9H); 8.59 (s, 1H). 13C NMR δC
General Procedure with LiTMP Route B. To a solution of LiTMP
(5.1 mL, 0.31M, 1.59 mmol, 3.0 equiv) in THF was added dropwise
6,7-disubstituted-2-chloro-3-trimethylsilylfuro[3,2-b]pyridine 4e or 4f
(0.53 mmol, 1.0 equiv) in THF (10 mL) at −20 °C, under argon
atmosphere. After stirring for 1 h at −20 °C, the appropriate
electrophile (1.59 mmol, 3.0 equiv) was added in THF (5 mL) at −20
°C. The temperature was then allowed to warm to 20 °C over 20 min.
After stirring for 40 min at 20 °C, the hydrolysis was performed with
H2O (10 mL) at 20 °C. The aqueous layer was then extracted twice
with AcOEt (2 × 10 mL). After drying (MgSO4), filtration and solvent
evaporation, the crude product was purified by centrifugal thin-layer
chromatography.
2,5,6,7-Tetrachloro-3-trimethylsilylfuro[3,2-b]pyridine 5b.
The product 5b was prepared according to the general procedure
described herein (route B) with C2Cl6 (376 mg, 1.59 mmol, 3.0 equiv)
as electrophile. Purification by centrifugal thin-layer chromatography
was performed with cyclohexane/AcOEt: 10/0 as eluent and led to the
expected compound 5b (155 mg, 89%) as a white solid: mp 127−129
°C. 1H NMR δH (ppm) 0.45 (s, 9H); 13C NMR δC (ppm) −0.9 (3C);
112.6; 124.5; 125.7; 143.9; 145.7; 149.7; 151.7. MS (EI) m/z 329
([M]+, 24); 314 (100); 113 (15); 73 (38). ESI-HRMS calcd for
C10H10Cl4NOSi (M + H)+: 327.9280; found: 327.9277.
(ppm) −0.8 (3C); 112.9; 115.4; 118.5; 146.8; 147.9; 150.5; 151.1. MS
(EI) m/z 383 ([M]+, 29); 368 (100); 73 (55). ESI-HRMS calcd for
C10H11Br2ClNOSi (M + H)+: 381.8660; found: 381.8668.
2,7-Dichloro-3,6-bistrimethylsilylfuro[3,2-b]pyridine 4e. The
product 4e was prepared according to the general procedure described
herein with TMSCl (173 mg, 1.59 mmol, 3.0 equiv) as electrophile.
Purification by centrifugal thin-layer chromatography was performed
with cyclohexane/AcOEt: 10/0 as eluent and led to the expected
1
compound 4e (159 mg, 90%) as an yellow solid: mp 69−71 °C. H
NMR δH (ppm) 0.45 (s, 9H); 0.53 (s, 9H); 8.42 (s, 1H). 13C NMR δC
(ppm) −0.7 (3C); 0.2 (3C); 111.0; 117.3; 128.9; 133.1; 145.3; 149.5;
151.9. ESI-HRMS calcd for C13H20Cl2NOSi2 (M + H)+: 332.0455;
found 332.0463.
2,6,7-Trichloro-3-trimethylsilylfuro[3,2-b]pyridine 4f. The
product 4f was prepared according to the general procedure described
herein with C2Cl6 (376 mg, 1.59 mmol, 3.0 equiv) as electrophile.
Purification by centrifugal thin-layer chromatography was performed
with cyclohexane/AcOEt: 10/0 as eluent and led to the expected
compound 4f (123 mg, 79%) as a white solid: mp 86−88 °C. 1H NMR
δH (ppm) 0.45 (s, 9H); 8.51 (s, 1H). 13C NMR δC (ppm) −0.8 (3C);
112.8; 123.6; 126.2; 144.7; 145.9; 150.7; 151.6. MS (EI) m/z 293
([M]+, 30); 278 (100); 107 (25); 93 (45). ESI-HRMS calcd for
C10H11Cl3NOSi (M + H)+: 293.9670; found: 293.9646.
H
dx.doi.org/10.1021/jo400748n | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(24) See for example: (a) Schlosser, M.; Mongin, F. Chem. Soc. Rev.
2007, 36, 1161−1172. (b) Cottet, F.; Marull, M.; Lefebvre, O.;
Schlosser, M. Eur. J. Org. Chem. 2003, 1559−1568. (c) Cottet, F.;
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ASSOCIATED CONTENT
■
S
* Supporting Information
NMR spectra of all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
(25) Schnurch, M.; Spina, M.; Khan, A. F.; Mihovilovic, M. D.;
̈
Corresponding Author
*E-mail: yves.fort@univ-lorraine.fr, corinne.comoy@univ-
lorraine.fr.
Stanetty, P. Chem. Soc. Rev. 2007, 36, 1046−1057.
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̀
e, P. Tetrahedron
e, P. J. Chem.
Lett. 1995, 36, 4791−4794. (b) Gros, P.; Fort, Y.; Cauber
Soc., Perkin Trans. 1 1997, 3071−3080.
̀
Notes
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(28) Gros, P.; Fort, Y. Eur. J. Org. Chem. 2009, 4199−4209.
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The authors declare no competing financial interest.
360.
ACKNOWLEDGMENTS
■
(30) Chartoire, A.; Comoy, C.; Fort, Y. Org. Biomol. Chem. 2011, 9,
1839−1845.
We gratefully acknowledge financial support from CNRS and
Universite
́
de Lorraine. We thank Sandrine Adach, Franco
̧
is
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