One-pot multiple lithiation processes of fused heterocycles

Article abstract of DOI:10.1002/ejoc.201402967

An efficient one-pot process that involves two or three successive regioselective lithiation/electrophilic trapping stages has been developed that affords several polysubstituted derivatives in good overall yields by starting from 2-chlorofuro[3,2-b]pyrid

Full text of DOI:10.1002/ejoc.201402967

FULL PAPER
DOI: 10.1002/ejoc.201402967
One-Pot Multiple Lithiation Processes of Fused Heterocycles
Adeline Jasselin-Hinschberger,[a] Corinne Comoy,*[a] and Yves Fort*[a]
Keywords: Nitrogen heterocycles / Lithiation / Regioselectivity / Synthetic methods
An efficient one-pot process that involves two or three suc-
cessive regioselective lithiation/electrophilic trapping stages
has been developed that affords several polysubstituted de-
rivatives in good overall yields by starting from 2-chloro-
furo[3,2-b]pyridine.
Introduction
Presently, lithium reagents are essential for modern or-
ganic synthesis, as organoalkali reactions are, for the most
part, clean and high yielding.[1,2] The reactivity of such rea-
gents can be easily modulated by changing the reaction me-
dia,[3] the experimental protocol,[4] or the employed base.[5]
For some years, our team has investigated the functionaliza-
tion of heterocycles by using lithiated bases.[6] Recently, we
reported a sequential procedure for the functionalization of
furo[3,2-b]pyridine by using organolithium reagents.[7] As
outlined in Scheme 1, the procedure allows for the sequen-
tial introduction of different functional groups at the C-3,
C-7, and C-6 positions of furo[3,2-b]pyridine ring 1 in good
to excellent yields.
Because a step-by-step process requires treatment of the
reaction mixture and purification of the product at the end
of each step and we were concerned about the economics
of atom, time, labor, and waste, we planned to synthesize
these polysubstituted heterocycles by using a one-pot pro-
cedure. Few examples of multiple lithiations through a one-
pot procedure have been reported.[8] Most of them are
based on the strategy described by Snieckus and co-workers
in 1980, in which lithiated derivatives are used as key inter-
mediates for the formation of polycyclic scaffolds. These
one-pot processes generally consist of two lithiation reac-
tions: (i) the first is a standard lithiation reaction, for exam-
ple, the lithiated intermediate is trapped by an external elec-
trophile; and (ii) in the second, an organolithium reagent is
then added to obtain a new lithiated derivative, which al-
lows for the cyclization of the product by an intramolecular
nucleophilic attack. However, one-pot multiple lithiation
processes that allow the introduction of different functional
Scheme 1. How to replace a stepwise procedure with a one-pot
multiple stage lithiation process. [a] Isolated yield after centrifugal
thin-layer chromatography (THF = tetrahydrofuran, TMSCl = tri-
methylsilyl chloride, LiTMP = lithium 2,2,6,6-tetramethylpiperid-
ide, E = electrophile).
groups on different positions of a (hetero)aromatic scaffold
are more rare,[8e] and, therefore, it is a true challenge to
develop such a process.
Regarding the three-step sequences of our previous re-
search, we should note that all of the reactions occurred in
THF as the solvent and involved organolithium reagents as
the base [i.e., nBuLi (commercially available) or LiTMP
(easily prepared by action of nBuLi with 2,2,6,6-tetrameth-
ylpiperidine). Considering our observations, we decided
that a one-pot process was conceivable for the preparation
of the derivatives 3a–3g or 4a–4e by starting from 1 without
the isolation of any intermediates. To succeed we needed to
consider various parameters: (i) the conversion rate and the
yield at each stage should be high, and only one main prod-
uct should be obtained (thus, only the right amount of base
should be introduced, as an excess amount of lithiated base
could undergo a reaction with other derivatives to yield side
[a] Groupe Hétérocycles: Réactivité et Interaction (HécRIn)
SRSMC UMR CNRS 7565, Université de Lorraine,
B.P. 239, Boulevard des Aiguillettes, 54506 Vandoeuvre-lès-
Nancy, France
E-mail: corinne.comoy@univ-lorraine.fr;
yves.fort@univ-lorraine.fr
http://www.srsmc.univ-lorraine.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402967.
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One-Pot Multiple Lithiation Processes of Fused Heterocycles
products); (ii) as many derivatives and reagents coexist in trapping stage; (ii) the residual excess amount of TMSCl
the medium, the temperature is crucial, and a change to it may be trapped prior to the functionalization at the C-7
could alter the stability or reactivity of the components or position; and (iii) the residual excess amount of TMSCl
result in their degradation; and (iii) finally, the amount of could be removed from the reaction medium before the sec-
electrophile also serves a key role, as an excess amount ond stage. Initially, we examined the possibility of decreas-
could hinder the following functionalization.
ing the amount of TMSCl that was used as a trapping
agent. We noted that a decrease of the amount of TMSCl
resulted in a decrease in the conversion rate (see Table 2).
As a consequence, this strategy could not be successfully
applied to the one-pot process.
Results and Discussion
First, the conditions in Scheme 1 that used derivative 1
as the substrate were applied to the one-pot procedure. The
lithiation at C-3 of furopyridine 1 was achieved by using
1.2 equiv. of nBuLi as the base in THF at –20 °C for 1 h.
The obtained lithiated intermediate was trapped by using
trimethylsilylchloride (2.0 equiv.) as the electrophile at
–20 °C, and the temperature of the reaction mixture was
then warmed to 20 °C for 1 h. Upon total conversion of 1
into 2 (confirmed by TLC and GC–MS analysis), the reac-
tion medium was cooled to –20 °C, and then LiTMP
(2.0 equiv.) was added for the second lithiation stage. The
LiTMP solution was previously prepared and cooled to
–30 °C to control the temperature of the reaction mixture
during its addition. After stirring at –20 °C for 1 h, tetra-
bromomethane (CBr4; 2.0, 4.0, or 10.0 equiv.) was added,
Table 2. Screening of reaction conditions.
Entry
TMSCl [equiv.]
Conversion [%]
Yield [%][a]
1
2
3
1.2
1.5
2.0
40
55
100
38
52
85
[a] Isolated yield after centrifugal thin-layer chromatography.
To circumvent this problem, we decided to trap the resid-
and the temperature of the reaction mixture was warmed ual electrophile prior to the addition of LiTMP for the sec-
to 20 °C. The results of these first attempts are reported in ond stage. We proposed that a nucleophile could be added
Table 1. Regardless of the conditions, the expected 7- to the mixture to undergo a reaction with the residual ex-
bromo-2-chloro-3-(trimethylsilyl)furo[3,2-b]pyridine
(3b) cess amount of TMSCl. We focused our attention on
was never isolated. Upon the addition of 2.0, 4.0, or nBuLi, which has nucleophilic properties in the presence of
10.0 equiv. of CBr4, derivative 2 was recovered unchanged THF. In a previous study, we highlighted the propensity of
(in 73, 63, and 64% yield, respectively). Furthermore, 2 was nBuLi to react with a trimethysilyl group that was con-
always produced as a mixture with bis(trimethylsilyl) deriv- tained within a furopyridine framework to lead to the cor-
ative 3a (in 20, 34, and 35% yield, respectively), which re- responding desilylated compound.[6] In addition, the reac-
sulted from the trapping of 2-chloro-7-lithio-3-(trimethyl- tion between nBuLi and TMSCl has already been reported,
silyl)furo[3,2-b]pyridine in the presence of the residual ex- but it requires 17 h at room temperature, and the yield is
cess amount of TMSCl. This highlights that the TMSCl too low (47%) to be used in our one-pot process.[9] There-
that is added in the first stage is more reactive than CBr4, fore, we examined the possibility of decreasing the reaction
even in the presence of a greater excess amount of the latter time. In this context, nBuLi was added to a solution of
(up to 10.0 equiv.).
TMSCl in THF or hexanes at 20 °C for 1, 2, and 3 h. Un-
To improve the one-pot process, we tried to avoid the fortunately, no trace of the expected n-butyltrimethylsilane
formation of 3a. Three strategies were proposed: (i) a stoi- was detected. Considering this lack of reactivity, our goal
chiometric amount of TMSCl may be used during the first was thus to determine if we could improve the conditions
Table 1. One-pot procedure – first attempts.
Entry
CBr4 [equiv.]
% Yield 2[a]
% Yield 3a[a]
% Yield 3b[a]
[b]
1
2
3
2.0
4.0
10.0
73
63
64
20
34
35
–
–
–
[b]
[b]
[a] Isolated yield after centrifugal thin-layer chromatography. [b] No trace of 3b was detected.
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A. Jasselin-Hinschberger, C. Comoy, Y. Fort
FULL PAPER
by the addition of an additive to the reaction medium, probably resulted from the modification of the reactivity of
which would enhance the nucleophilicity of nBuLi. In this the basic reagents during the evaporation procedure. Evap-
context, 1,4-diazabicyclo[2.2.2]octane (DABCO) and orating to dryness led to lithiated solid species, and, conse-
N,N,NЈ,NЈ-tetramethylethylenediamine (TMEDA) ap- quently, their degree of aggregation was modified, and thus
peared to be prime candidates, as they may enhance the their reactivity. The drawback of such a procedure is that
polarization of the C–Li bond and, consequently, increase the reaction conditions after the evaporation could be dif-
the reactivity of nBuLi towards TMSCl.[10] Several attempts ferent than the initial ones. If dry THF is added to solubi-
were performed to evaluate this hypothesis. The lithiated lize the solid species, their degree of aggregation may have
base was added to a mixture TMSCl/DABCO (1:1) or changed. As a consequence, evaporation to dryness could
TMSCl/TMEDA (1:1) in hexanes or THF as the solvent at not be applied to the one-pot procedure.
various temperatures (–78, –50, –20, 0, and 20 °C). After
We then focused our attention on the second protocol,
the mixture was stirred for 1 h, the hydrolysis was per- that is, an exchange of the solvent. With a boiling point of
formed, and the crude product was analyzed by GC–MS. 110–111 °C under atmospheric pressure, toluene seemed a
Regardless of the conditions, it was surprising that no trace good candidate. As previously mentioned, the reactivity of
of the expected n-butyltrimethylsilane was detected. organolithium reagents depends on their degree of aggrega-
Furthermore, when THF was used as the solvent, side tion and, consequently, on the solvent. THF and toluene
products that resulted from the degradation of the THF by have different polarities, which could disturb the remainder
the lithiated base were detected, which means that this of the one-pot process. To evaluate the relevance of this, we
strategy could not be applied to the one-pot procedure. first determined whether toluene was a good solvent for use
Hitherto, we did not find a good candidate to react with in the second stage, that is, following the metalation with
the residual TMSCl and avoid the formation of 3a.
LiTMP. In this context, we tried to metalate 2-chloro-3-
To resolve this problem, we decided to remove the resid- (trimethylsilyl)furo[3,2-b]pyridine (2) in a sequential man-
ual electrophile from the reaction medium. TMSCl has a ner by using LiTMP (2.0 equiv.) as the base in toluene at
low boiling point (57 °C under atmospheric pressure) and –20 °C. After the mixture stirred for 1 h, CBr4 (2.0 equiv.)
could easily be evaporated under reduced pressure without was added in toluene at –20 °C, and the reaction tempera-
heat. The evaporation would be performed with a vacuum ture was then warmed to 20 °C. After treatment and purifi-
line. No intermediate would be isolated, and no treatment cation, substrate 2 was recovered unchanged, which reveals
would be performed. Consequently, this procedure would that the metalation cannot occur in toluene and, inevitably,
be consistent with the definition of a one-pot process. Three invalidates our second proposed procedure.
protocols were envisioned: (i) at the end of the first stage
Finally we studied an alternative method to remove
(i.e., conversion of 1 into 2), the solvent and residual TMSCl from the reaction medium. After the first stage,
TMSCl would be evaporated under vacuum, and dry THF three partial successive distillations (1:2 in volume) were
(10 mL) would then be added for the one-pot process to be performed, and a sample of the reaction mixture was ana-
continued; (ii) another solvent with a higher boiling point lyzed by GC–MS (see Exp. Section). This showed that the
than THF would be added at the end of the first stage, and partial evaporation step did not cause a degradation (or
the choice of this solvent was crucial, since this solvent, modification in the reactivity) of derivative 2. This method
which could not be evaporated under vacuum without heat was, thus, chosen and applied to the one-pot process to
(only THF and the residual TMSCl would be removed), avoid the formation of 3a.
would be used for the remainder of the one-pot metalation
The second problem that was highlighted in Table 1 was
process; and (iii) in a combination of (i) and (ii), the THF the low conversion rate of the second stage. An explanation
would be employed as the only solvent for the one-pot pro- for this is that organolithium reagents are aggregated in
cess, and partial successive distillations to be performed at solution. When they undergo a reaction with substrates,
the end of the first stage would allow for the evaporation they produce new lithium species, which play a crucial role
of the residual TMSCl without evaporating the reaction in the chemistry. In this one-pot process, several lithiated
mixture to dryness (see Exp. Section). compounds coexist and, consequently, could interfere in the
To evaluate these procedures, the reaction was performed last metalation step.
in a graduated two-necked Schlenk flask that was con-
As a solution to this, the reaction was carried out with
nected to a vacuum line. The first functionalization was car- a larger excess amount of LiTMP (3.0, 4.0, or 6.0 equiv.).
ried out as previously described, that is, with nBuLi According to the results reported in Table 3, the threefold
(1.2 equiv.) in THF at –20 °C for 1 h followed by trapping partial evaporation of the residual TMSCl was successful,
with TMSCl (2.0 equiv.) as the electrophile in THF at as only trace amounts of derivative 3a were detected. With
–20 °C. The temperature of the reaction mixture was then the addition of 3.0 or 4.0 equiv. of LiTMP (see Table 3, En-
warmed to 20 °C, and analyses were performed to check for tries 1 and 2), the expected furopyridine 3b was isolated in
a good conversion of 1 into 2. The reaction system was 69 and 84% yield, respectively. Surprisingly, when 6.0 equiv.
gradually placed under vacuum to evaporate all the solvent. of LiTMP were used, 3b was not obtained the main product
Then, dry THF (10.0 mL) was added under argon, and a (see below).
sample of the mixture was analyzed by GC–MS. Unfortu-
Therefore, we decided to use the optimized conditions
nately, much product degradation was detected, which (see Table 3, Entry 2) to extend this new procedure to the
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One-Pot Multiple Lithiation Processes of Fused Heterocycles
Table 3. Optimization of the reaction conditions.
Entry
LiTMP [equiv.]
CBr4 [equiv.]
% Yield 2[a]
% Yield 3a[a]
% Yield 3b[a]
1
2
3
3.0
4.0
6.0
3.0
4.0
6.0
trace
trace
trace
trace
trace
trace
69
84
5
[a] Isolated yield after centrifugal thin-layer chromatography.
synthesis of various 2,3,7-trisubstituted furopyridines 3a– After the evaporation procedure (see Exp. Section) and the
3g. As shown in Table 4, a wide range of functional groups addition of LiTMP (6.0 equiv.) at –20 °C for 1 h, the chosen
can be introduced onto the furopyridine ring (e.g., halogens electrophile (CBr4 or C2Cl6, 6.0 equiv.) was added. The re-
and carbonyl groups as well as stannyl- and sulfur-contain- action temperature was then warmed to 20 °C. With this
ing substituents). Seven different furopyridine derivatives process, the expected trihalogenated furopyridines 4a and
were synthesized in good to excellent yields by using this 4b were easily obtained as main products of the one-pot
one-pot process (62–85%). According to these results, the process in 58 and in 71% yield, respectively. Once again,
one-pot procedure is up to 10% more efficient than the se- the one-pot process appears more efficient than the sequen-
quential one. It is more economic with regard to time and tial one (see Table 5). Studies are now in progress to evalu-
solvent, and intermediate 2 is not isolated, which is a real ate the reactivity of these polyhalogenated scaffolds in
advantage.
cross-coupling reactions with the goal to differentiate be-
tween each halogenated position.
Table 4. One-pot synthesis of derivatives 3a–3g.
Table 5. One-pot synthesis of trihalogenated derivatives 4a–4b.
E
Overall % yield[a]
One-pot
Step-by-step
3a
3b
3c
3d
3e
3f
SiMe3
Br
Cl
CH(OH)Ph
SnBu3
SMe
72
84
85
80
83
62
75
66
75
78
76
74
57
72
E
Overall % yield[a]
One-pot
Step-by-step
4a
4b
Br
Cl
58
71
31
62
[a] Isolated yield after centrifugal thin-layer chromatography.
3g
CHO
[a] Isolated yield after centrifugal thin-layer chromatography.
In addition, attempts were made to find the optimized
conditions for the last metalation step of the one-pot pro-
cess. When 6.0 equiv. of LiTMP were added (see Table 3,
Conclusions
In summary, an efficient one-pot process for multiple li-
Entry 3), derivative 3b was isolated in only 5% yield, and thiation stages is described. Up to three functionalities were
the main product was the 6,7-dibromo-2-chloro-3-(trimeth- introduced at different positions of 2-chlorofuro[3,2-b]pyr-
ylsilyl)furo[3,2-b]pyridine (4a), which was isolated in good idine (1) by using this one-pot method, which afforded the
yield (58% yield) and resulted from the metalation of furo- product with a high degree of selectivity in good to excellent
pyridine 3b at the C-6 position by the residual LiTMP. The yields. According to these results, this one-pot process is
potential of such derivatives is undeniable, as halogens play more efficient than its sequential analogue. The reaction
a key role in organic chemistry in that they can allow for yields have significantly improved (up to 27% more ef-
the introduction of various functional groups. We decided ficient), and only one purification step is required to obtain
to extend this process to synthesize other trihalogenated de- the polysubstituted furopyridines. This one-pot method is
rivatives. Substrate 1 was thus functionalized at the C-3 po- economical with regard to solvent and the generation of
sition by employing the conditions previously described. waste.
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A. Jasselin-Hinschberger, C. Comoy, Y. Fort
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7-Bromo-2-chloro-3-(trimethylsilyl)furo[3,2-b]pyridine (3b): The ge-
neral procedure was employed by using CBr4 (1.06 g, 3.2 mmol,
4.0 equiv.) as the electrophile. Purification by centrifugal thin-layer
chromatography (cyclohexane) afforded compound 3b (205 mg,
84%) as an orange solid; m.p. 42–45 °C. 1H NMR (CDCl3): δ =
0.46 (s, 9 H), 7.33 (d, J = 5.1 Hz, 1 H), 8.29 (d, J = 5.1 Hz, 1
H) ppm. 13C NMR (CDCl3): δ = –0.8 (3 C), 112.4, 122.3, 122.6,
146.3, 146.5, 150.3, 153.1 ppm. MS (EI): m/z (%) = 305 (26) [M +
2]+, 303 (19) [M]+, 290 (100), 288 (78), 268 (15). HRMS (ESI):
calcd. for C10H12BrClNOSi [M + H]+ 303.9555; found 303.9544.
Experimental Section
1
General Methods: The H and 13C NMR spectroscopic data were
recorded at 250 MHz for 1H NMR and 63 MHz for 13C NMR,
and CDCl3 was used as solvent with TMS as the internal standard
1
(for H NMR). HRMS spectra were recorded on a micrOTOF-Q
spectrometer. MS data were recorded on a GC–MS-QP2010 spec-
trometer. Melting temperatures were recorded with a thermostatic
oil bath device. All one-pot reactions were carried out in a two-
necked Schlenk flask that was connected to a vacuum line. All rea-
gents were commercially available and purified by distillation when
necessary. nBuLi was used as a commercial 1.6 m solution in hex-
anes (always titrated prior to use). Hexanes and THF were distilled
and stored over sodium wire prior to use. Purifications by centrifu-
gal thin-layer chromatography were performed on silica gel (silica
gel 60 PF254 that contained gypsum).
2,7-Dichloro-3-(trimethylsilyl)furo[3,2-b]pyridine (3c): The general
procedure was employed by using hexachloroethane (757 mg,
3.2 mmol, 4.0 equiv.) as the electrophile. Purification by centrifugal
thin-layer chromatography (cyclohexane/AcOEt, from 10:0 to 95:5)
afforded compound 3c (177 mg, 85%) as a white solid; m.p. 48–
1
50 °C. H NMR (CDCl3): δ = 0.46 (s, 9 H), 7.19 (d, J = 5.3 Hz, 1
H), 8.39 (d, J = 5.3 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = –0.8 (3
C), 112.4, 119.4, 124.8, 144.5, 146.3, 150.5, 153.7 ppm. MS (EI):
m/z (%) = 259 (25) [M]+, 244 (100), 224 (15), 73 (35). HRMS (ESI):
calcd. for C10H12Cl2NOSi [M + H]+ 260.0060; found 260.0042.
General Procedure for the Preparation of LiTMP Base: To a solu-
tion of 2,2,6,6-tetramethylpiperidine (542 mg, 3.84 mmol,
1.0 equiv.) in anhydrous tetrahydrofuran (10 mL) at –20 °C was
added dropwise nBuLi (1.6 m in hexanes, 2.4 mL, 3.84 mmol,
1.0 equiv.) under argon. After 30 min at 0 °C, the LiTMP base
(0.31 m solution) was ready to be used. The sequential functionali-
zation at the C-3, C-7, and C-6 positions of 2-chlorofuro[3,2-b]-
pyridine (1) are described in the literature.[7]
1-(2-Chloro-3-(trimethylsilyl)furo[3,2-b]pyridin-7-yl)-1-phenylmeth-
anol (3d): The general procedure was employed by using benzalde-
hyde (339 mg, 3.2 mmol, 4.0 equiv.) as the electrophile. Purification
by centrifugal thin-layer chromatography (cyclohexane/AcOEt,
from 10:0 to 95:5) afforded compound 3d (212 mg, 80%) as a yel-
General Procedure for the Evaporation Step: Dry THF (10.0 mL)
was added under argon. The reaction system was gradually put
under vacuum to evaporate approximately half of the solvent, and
the reaction mixture was then placed again under argon. This pro-
cedure (i.e., the addition of dry THF and evaporation of half of
the solvent) was repeated (2ϫ). A sample of the reaction mixture
was analyzed by GC–MS to ensure that this method did not lead
to the degradation of the products.
1
low gummy substance. H NMR (CDCl3): δ = 0.44 (s, 9 H), 2.65
(br. s, 1 H), 6.25 (s, 1 H), 7.29–7.37 (m, 4 H), 7.46–7.49 (m, 2 H),
8.48 (d, J = 5.1 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = –0.7 (3 C),
70.6, 115.5, 126.6 (2 C), 128.3, 128.8 (2 C), 134.4, 141.6, 144.5,
146.3, 148.1, 149.6, 152.4 ppm. MS (EI): m/z (%) = 331 (53) [M]+,
316 (100), 296 (58). HRMS (ESI): calcd. for C17H19ClNO2Si [M +
H]+ 332.0868; found 332.0861.
2-Chloro-7-(tri-n-butylstannyl)-3-(trimethylsilyl)furo[3,2-b]pyridine
(3e): The general procedure was employed by using Bu3SnCl
(1.04 g, 3.2 mmol, 4.0 equiv.) as the electrophile. Purification by
centrifugal thin-layer chromatography (cyclohexane/AcOEt, from
10:0 to 98:2) afforded compound 3e (342 mg, 83%) as a colorless
General Procedure for the One-pot Synthesis of Derivatives 3a–3g:
To
a
solution of 2-chlorofuro[3,2-b]pyridine (1)[6b] (123 mg,
0.80 mmol, 1.0 equiv.) in THF (10 mL) was added dropwise nBuLi
(0.6 mL, 0.96 mmol, 1.2 equiv.) at –20 °C under argon. After the
reaction mixture was stirred at –20 °C for 1 h, chlorotrimethylsilane
(174 mg, 1.6 mmol, 2.0 equiv.) was added in THF (5 mL) at –20 °C.
The temperature was then warmed to 20 °C over 20 min. The mix-
ture was stirred at 20 °C for 40 min, and then the evaporation step
was performed as described in the general procedure above. The
temperature was cooled to –20 °C, and a solution of LiTMP
(10.3 mL, 3.2 mmol, 4.0 equiv.) was quickly added under argon.
The resulting mixture was stirred at –20 °C for 1 h, and then the
appropriate electrophile (3.2 mmol, 4.0 equiv.) was added in THF
(5 mL). The temperature was then warmed to 20 °C over 20 min.
After the reaction was stirred at 20 °C for 40 min, the hydrolysis
step was performed by adding H2O (10 mL) at 20 °C. The aqueous
layer was then extracted with AcOEt (2ϫ 10 mL). The combined
organic layers were dried with MgSO4 and filtered, and the solvent
was evaporated. The crude product was purified by centrifugal
thin-layer chromatography.
1
liquid. H NMR (CDCl3): δ = 0.47 (s, 9 H), 0.89 (t, J = 7.3 Hz, 9
H), 1.18–1.23 (m, 6 H), 1.29–1.39 (m, 6 H), 1.53–1.61 (m, 6 H),
7.19 (d, J = 4.6 Hz, 1 H), 8.40 (d, J = 4.6 Hz, 1 H) ppm. 13C NMR
(CDCl3): δ = –0.5 (3 C), 10.2 (3 C), 13.8 (3 C), 27.4 (3 C), 29.1 (3
C), 111.3, 126.5, 131.7, 144.9, 149.2, 149.8, 154.6 ppm. MS (EI):
m/z (%) = 458 (100) [M – 57]+, 402 (81), 346 (90), 210 (41), 73 (56).
HRMS (ESI): calcd. for C22H39ClNOSiSn [M + H]+ 516.1503;
found 516.1490.
2-Chloro-7-methylthio-3-(trimethylsilyl)furo[3,2-b]pyridine (3f): The
general procedure was employed by using Me2S2 (301 mg,
3.2 mmol, 4.0 equiv.) as the electrophile. Purification by centrifugal
thin-layer chromatography (cyclohexane/AcOEt, from 10:0 to 95:5)
afforded compound 3f (135 mg, 62%) as a yellow oil. 1H NMR
(CDCl3): δ = 0.45 (s, 9 H), 2.61 (s, 3 H), 6.95 (d, J = 5.25 Hz, 1
H), 8.35 (d, J = 5.25 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = –0.7
(3 C), 14.1, 111.6, 114.1, 114.8, 131.3, 145.8, 149.1, 151.2 ppm. MS
(EI): m/z (%) = 271 (57) [M]+, 256 (100), 236 (55), 73 (59). HRMS
(ESI): calcd. for C11H15ClNOSSi [M + H]+ 272.0327; found
272.0332.
2-Chloro-3,7-bis(trimethylsilyl)furo[3,2-b]pyridine (3a): The general
procedure was employed by using TMSCl (348 mg, 3.2 mmol,
4.0 equiv.) as the electrophile. Purification by centrifugal thin-layer
chromatography (cyclohexane) afforded compound 3a (172 mg,
1
72%) as a white solid; m.p. 42–44 °C. H NMR (CDCl3): δ = 0.41
2-Chloro-7-formyl-3-(trimethylsilyl)furo[3,2-b]pyridine (3g): The ge-
neral procedure was employed by using N,N-dimethylformamide
(s, 9 H), 0.46 (s, 9 H), 7.17 (d, J = 4.7 Hz, 1 H), 8.46 (d, J = 4.7 Hz,
1 H) ppm. 13C NMR (CDCl3): δ = –1.4 (3 C), –0.6 (3 C), 110.9, (DMF, 234 mg, 3.2 mmol, 4.0 equiv.) as the electrophile. Purifica-
123.3, 130.5, 145.0, 149.5, 150.6, 152.4 ppm. MS (EI): m/z (%) =
297 (26) [M]+, 282 (47), 262 (30), 93 (24), 73 (100). HRMS (ESI):
calcd. for C13H21ClNOSi2 [M + H]+ 298.0845; found 298.0851.
tion by centrifugal thin-layer chromatography (cyclohexane/Ac-
OEt, from 10:0 to 95:5) afforded compound 3g (152 mg, 75%) as
1
a white solid; m.p. 73–75 °C. H NMR (CDCl3): δ = 0.47 (s, 9 H),
7230
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Eur. J. Org. Chem. 2014, 7226–7231

One-Pot Multiple Lithiation Processes of Fused Heterocycles
7.53 (d, J = 5 Hz, 1 H), 8.71 (d, J = 5 Hz, 1 H), 10.51 (s, 1 H) ppm.
13C NMR (CDCl3): δ = –0.8 (3C), 111.6, 115.6, 123.8, 145.2, 146.7,
151.6, 155.5, 187.8 ppm. MS (EI): m/z (%) = 253 (29) [M]+, 238
(100), 218 (8), 93 (45). HRMS (ESI): calcd. for C11H13ClNO2Si [M
+ H]+ 254.0399; found 254.0390.
versité de Lorraine. Brigitte Fernette is thanked for recording the
NMR spectra.
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General Procedure for the One-Pot Synthesis of Derivatives 4a and
4b: To
a solution of 2-chlorofuro[3,2-b]pyridine (1, 123 mg,
0.80 mmol, 1.0 equiv.) in THF (10 mL) was added dropwise nBuLi
(0.6 mL, 0.96 mmol, 1.2 equiv.) at –20 °C under argon. After the
resulting mixture was stirred at –20 °C for 1 h, TMSCl (174 mg,
1.6 mmol, 2.0 equiv.) was added in THF (5 mL) at –20 °C. The
temperature was warmed to 20 °C over 20 min. The mixture was
stirred at 20 °C for 40 min, and then the evaporation step was per-
formed as described in the general procedure above. The reaction
temperature was cooled to –20 °C, and a solution of LiTMP in
THF (15.5 mL, 4.8 mmol, 6.0 equiv.) was quickly added under ar-
gon. The resulting mixture was stirred at –20 °C for 1 h, and then
the appropriate electrophile (4.8 mmol, 6.0 equiv.) was added in
THF (5 mL). The temperature was warmed to 20 °C over 20 min.
The mixture was stirred at 20 °C for 40 min, and the hydrolysis step
was performed by adding H2O (10 mL) at 20 °C. The aqueous layer
was then extracted with AcOEt (2ϫ 10 mL). The combined organic
layers were dried with MgSO4 and filtered, and the solvent was
evaporated. The crude product was purified by centrifugal thin-
layer chromatography.
6,7-Dibromo-2-chloro-3-(trimethylsilyl)furo[3,2-b]pyridine (4a): The
general procedure was employed by using CBr4 (1.59 g, 4.8 mmol,
6.0 equiv.) as the electrophile. Purification by centrifugal thin-layer
chromatography (cyclohexane) afforded compound 4a (178 mg,
1
58%) as a brown solid; m.p. 126–128 °C. H NMR (CDCl3): δ =
0.45 (s, 9 H), 8.59 (s, 1 H) ppm. 13C NMR (CDCl3): δ = –0.8 (3
C), 112.9, 115.4, 118.5, 146.8, 147.9, 150.5, 151.1 ppm. MS (EI):
m/z (%) = 383 (29) [M]+, 368 (100), 73 (55). HRMS (ESI): calcd.
for C10H11Br2ClNOSi [M + H]+ 381.8660; found 381.8668.
[7] A. Jasselin-Hinschberger, C. Comoy, A. Chartoire, Y. Fort, J.
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hedron 1991, 47, 9279–9288.
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Aragonés, T. Varea, R. Acerete, M. E. Gonzalez-Nunez, G.
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Received: July 22, 2014
2,6,7-Trichloro-3-(trimethylsilyl)furo[3,2-b]pyridine (4b): The gene-
ral procedure was employed by using C2Cl6 (1.14 g, 4.8 mmol,
6.0 equiv.) as the electrophile. Purification by centrifugal thin-layer
chromatography (cyclohexane) afforded compound 4b (167 mg,
1
71%) as a white solid; m.p. 86–88 °C. H NMR (CDCl3): δ = 0.45
(s, 9 H), 8.51 (s, 1 H) ppm. 13C NMR (CDCl3): δ = –0.8 (3 C),
112.8, 123.6, 126.2, 144.7, 145.9, 150.7, 151.6 ppm. MS (EI): m/z
(%) = 293 (30) [M]+, 278 (100), 107 (25), 93 (45). HRMS (ESI):
calcd. for C10H11Cl3NOSi [M + H]+ 293.9670; found 293.9646.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of all compounds.
Acknowledgments
The authors gratefully acknowledge financial support from the
Centre National de la Recherche Scientifique (CNRS) and the Uni-
Published Online: September 24, 2014
Eur. J. Org. Chem. 2014, 7226–7231
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7231