One-pot double functionalisation of π-deficient heterocyclic lithium reagents

Article abstract of DOI:10.1039/c0ob00734j

Herein, we report an efficient method for the double functionalisation of lithiated halogenopyridines, -pyrazines or -furopyridines through a convenient one-pot electrophilic trapping/nucleophilic substitution sequence.

Full text of DOI:10.1039/c0ob00734j

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PAPER
One-pot double functionalisation of p-deficient heterocyclic lithium reagents†
Anthony Chartoire, Corinne Comoy and Yves Fort*
Received 17th September 2010, Accepted 9th December 2010
DOI: 10.1039/c0ob00734j
Herein, we report an efficient method for the double functionalisation of lithiated halogenopyridines,
-pyrazines or -furopyridines through a convenient one-pot electrophilic trapping/nucleophilic
substitution sequence.
Introduction
Results and discussion
Over the past few decades, many efforts have been made to develop
metalation reactions for the functionalisation of heterocycles.1
Such reactions are proving to be powerful tools because of the
large range of functionalities that can be introduced. Functional-
isation by metallation generally proceeds in two main steps : 1)
Formation of a carbon-metal bond; 2) Subsequent electrophilic
trapping. During the trapping step, some released species can
exhibit nucleophilic properties, depending of the nature of the
electrophile, and might lead to nucleophilic substitution. To
our knowledge, this reactivity is surprisingly considered as a
side reaction.2 In our continuing efforts aimed at developing
simple and efficient synthesis of substituted heterocycles,3–6 we
describe here an easy procedure leading to bifunctionalised aza-
heterocycles. Indeed, by using disulfide and amide derivatives as
E-Nu trapping reagents (good electrophiles releasing nucleophilic
species during the trapping step), the one-pot process combining
electrophilic trapping and nucleophilic substitution might be
useful to allow the direct preparation of new bifunctional scaffolds
(Scheme 1).
We first studied the action of the most common disulfide :
Me2S2. Under usual conditions, we succeeded in generating lithi-
ated heterocycles by using LTMP,7 LDA8 or [n-BuLi/LiDMAE]
superbase,9 leading to halogeno-methylthio-derivatives 4a–7a in
excellent yields (Table 1, way A, 82–92%). At low temperature
(-78 ◦C), no nucleophilic substitution of in situ formed MeSLi
was detected.
With the intention to enhance the nucleophilic potential of
MeSLi released during the trapping process, we devoted the most
efforts to explore the optimal required conditions to succeed in
such a cascade procedure (Table 1, way B). Because pyrazine
derivatives are well known to be good electrophiles, we began our
study with 2-chloropyrazine 1. After lithiation of 1 with LTMP,
2 eq of Me2S2 were added at -78 ◦C for 30 min in THF to
10
quench the lithio-intermediate. After that, we envisionned to warm
up the reaction medium in order to reveal the nucleophilicity of
MeSLi. Then, the temperature was allowed◦to warm to 20 ◦C
over a period of 1 h11 and maintained at 20 C for 3 h (reaction
monitored by GC). The hydrolysis was performed at 20 ◦C, and the
2,3-bis(methylthio)pyrazine 4b was consequently obtained in an
excellent isolated yield (entry 1, 91%). The proposed mechanism
for this double functionalisation process is depicted in Scheme 2. 2-
Chloro-3-lithiopyrazine is quenched with Me2S2 to form 2-chloro-
3-methylthiopyrazine 4a and MeSLi is released. The nucleophilic
attack of MeSLi on the C-2 position leads to a stabilised lithio
intermediate and 2,3-bis(methylthio)pyrazine 4b is obtained after
elimination of LiCl.
To extend the scope of this new strategy, we next turned our
attention on other substrates. Thus, 2-fluoropyridine 2 appeared
as a judicious substrate, because pyridines are known to be less
electrophilic than pyrazines. On the other hand, fluorine atom is
well known to be a better leaving group in nucleophilic aromatic
substitution than the chlorine one. Therefore, 2-fluoropyridine 2
was lithiated with LDA, Me2S2 was added according to the way
B conditions, and the temperature was maintained at 20 ◦C for
17 h. 2,3-Bis(methylthio)pyridine 5b was then obtained with a
good isolated yield (entry 2, 69%) in presence of 5a (13%). It is
Scheme
azaheterocycles.
1
One-pot double functionalisation of p-deficient
Groupe Synthe`se Organome´tallique et Re´activite´, SRSMC, Nancy-
Universite´, CNRS, B.P.239, Boulevard des Aiguillettes, F-54506,
Vandoeuvre-Les-Nancy, France. E-mail: Yves.Fort@srsmc.uhp-nancy.fr;
Fax: +33 (0)3 83 68 47 85; Tel: +33 (0)3 83 68 47 81
† Electronic supplementary information (ESI) available: Copy of GC and
NMR spectra of all new compounds. See DOI: 10.1039/c0ob00734j
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Table 1 One-pot double functionalisation of p-deficient azaheterocycles
Product
Substrate
Product
Trapping step way Aa
Metalation step RLi (n eq),
T◦C, time, solvent
Trapping step way Bb
i) ii) then T◦C, time
Entry
1
4a–7a, Yields%c
Me2S2 (n eq), T◦C
4b–7b, Yields%c
3 eq, -78 ◦
C
20 ◦C, 3 h
2
3 eq, -70 ◦
C
20 ◦C, 17 h
3
4
—
—
2, LDA (1.5 eq), -70 ◦C, 4 h,
THF
20 ◦C, 17 h
reflux, 20 h
3 eq, -78 ◦
C
5
6
7
—
—
3, LTMP (1.5 eq), -78 ◦C, 1 h
reflux, 20 h
reflux, 20 h
30, THF
4 eq, -78 ◦
C
3, [n-BuLi/LiDMAE] (3eq),
-78 ◦C, 1 h, Hexane
—
—
3, [n-BuLi/LiDMAE] (3eq),
-78 ◦C, 1 h, Hexane
solvent exchangeg
reflux, 20 h
a Trapping step conditions (way A) : Me2S2 (n eq), T◦C, 1 h, THF. b Trapping step conditions (way B) : i) Me2S2 (2 eq), -78 ◦C, 30 min, THF ii) -78 to
20 ◦C, 1 h,11 then T◦C, time (h). c Isolated yields after centrifugal thin layer chromatography. d 13% of 5a was formed. e 18% of 6a was formed. f 75% of
7a was formed.12 g Evaporation of solvents then THF was added. h 36% of 7a was formed.12
to be noted that an extended reaction time (17 h) was necessary
to obtain this result (reaction monitored by GC), because of the
less electrophilic character of 2 in comparison with 1. To complete
the nucleophilic substitution of the fluorine, a slight excess of
LDA (1.5 eq) was used to afford 5b with an excellent isolated
yield (entry 3, 90%). Similar strategy was carried out with 2-
chloropyridine 3. The lithiation on the C-3 position was here
conducted with LTMP as precedently presented. After addition
of Me2S2 as trapping agent according to the way B conditions,
the mixture was refluxed during 20 h in THF and 5b was isolated
in a good yield (entry 4, 71%) in presence of 6a (18%). With 1.5
eq of LTMP, 5b was obtained with an increased yield (entry 5,
77%). The sequence was finally applied to the synthesis of 2,6-
bis(methylthio)pyridine 7b. The lithiation of 3 on the C-6 position
was accomplished with the [n-BuLi/LiDMAE] superbase, Me2S2
was then added according to the way B conditions and the mixture
was refluxed for 20 h. Only 15% of the desired 7b was isolated (entry
6), in presence of 75% of 2-chloro-6-methylthiopyridine 7a.12 It is
well known that the polarity of the solvent plays an important
role in the nucleophilic substitution. Actually, metalation with
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Table 2 Double functionalisation of furo[3,2-b]pyridine with various
disulfides
Products
9a–11a/9b–11b
Entry
1
R2S2
Yields%c
Me2S2
2
Ph2S2
Ph2S2
3d
4
10a, traces
10b, 85%
Scheme 2 Proposed mechanism for the double functionalisation process.
[n-BuLi/LiDMAE] superbase occurred in hexane instead of THF
in the case of LDA or LTMP. Consequently, we exchanged solvent
before to reflux the mixture. Solvents were evaporated and THF
was added. After 20 h refluxing in THF, formation of 7b was
observed with an interesting increased result (entry 7, 53%) in
presence of 7a (36%).12 This lower reactivity of 7a in relation to
nucleophilic addition can be explained by a less stabilised lithio
intermediate in comparison with 6a (Scheme 3).
5e
11a, -%
11b, 46%
a n-BuLi (1.2 eq),◦-20 ◦C, 1 h, THF. b R2S2 (2 eq), THF, -20 ◦C to 20 ◦
C
(20 min), then 20 C (40 min), then H2O. c Isolated yields after centrifugal
thin layer chromatography. d Trapping step conditions : Ph2S2 (2 eq), THF,
-20 ◦C to 20 ◦C (20 min), then 50 ◦C (40 min), then H2O. e Trapping step
conditions : Py2S2 (2 eq), THF, -20 ◦C to 20 ◦C (20 min), then 60 ◦C (5 h
40), then H2O.
10b was isolated, and only traces of 2-chloro-3-phenylthiofuro[3,2-
b]pyridine 10a were detected as a side product (entry 3). In the
case of Py2S2, the previously reported trapping conditions (Py2S2
(2 eq), THF, -20 ◦C to 20 ◦C over a period of 20 min, then
Scheme 3 Stabilisation forms of lithiated intermediates.
◦
20 C during 40 min) failed to yield efficiently the expected 2,3-
Recently, our group has demonstrated a great interest in the
functionalisation of furopyridine derivatives by using lithiated
bases and metal-catalysed coupling reactions.5,6 As an extension
of this work and of the methodology described in this paper,
we focused our attention on 2-chlorofuro[3,2-b]pyridine 8. The
lithiation of 8 was carried out with 1.2 eq of n-BuLi at -20 ◦C for 1 h
in THF, followed by electrophilic trapping with 2 eq of Me2S2 from
-20 to 20 ◦C (20 min) and the temperature was maintained at 20 ◦C
during 40 min. The strategy once more appeared very efficient
and 80% of 2,3-bis(methylthio)furo[3,2-b]pyridine 9b was isolated
(Table 2, entry 1). The reaction occured very easily and we decided
to extend the sequence by using other disulfide E-Nu reagents. We
chose diphenyldisulfide and bis(pyridin-2-yl)disulfide (Py2S2) to
examine the versatility of the methodology with less nucleophilic
lithium thiolates than MeSLi. In fact, when Ph2S2 was used, the
nucleophilic substitution step appeared more difficult because the
released PhSLi is less nucleophilic than MeSLi. Nevertheless, if
the temperature of the trapping step is warmed to 50 ◦C for
40 min, 85% of the desired 2,3-bis(phenylthio)furo[3,2-b]pyridine
bis(pyridin-2-ylthio)furo[3,2-b]pyridine 11b (entry 4, 11%) and the
2-chloro-3-(pyridin-2-ylthio)furo[3,2-b]pyridine 11a was obtained
as the main product (entry 4, 65%). Nucleophilicity of PySLi was
then enhanced by warming the reaction at 60 ◦C for 5 h 40. In
these conditions, partial degradation of products was observed,
nevertheless, 11b was isolated in a respectable 46% yield (entry 5).
We also demonstrated that the procedure was not exclusively
specific of the disulfides as the E-Nu reagents. In fact we treated 2-
chloro-3-lithiofuro[3,2-b]pyridine with various amides. 2-Amino-
3-formylfuro[3,2-b]pyridines 12b–14b were consequently obtained
in good to excellent isolated yields by quenching the lithio interme-
diate respectively with dimethylformamide, N-formylpiperidine
and N-formylmorpholine (Table 3, entries 1–3, 60–84%). The
procedure allowed as well the formation of the 2-(dimethylamino)-
3-acetylfuro[3,2-b]pyridine 15b in a very good 77% yield (entry
4) by treating the lithio intermediate with dimethylacetamide. In
that specific case, the temperature of the trapping step had to be
◦
maintained at -20 C for only 30 min to avoid deacetylation of
15b by Me2NLi in a 1,2-addition process.
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Table 3 Double functionalisation of furo[3,2-b]pyridine with various
amides
Diisopropylamine was distilled on sodium before use. Hexane and
THF were distilled and stored on sodium wire before use. Cen-
trifugal thin-layer chromatography purifications were performed
on silica gel (Merck silica gel 60 PF254 containing gypsum).
Procedure for the preparation of LTMP. To a solution of
2,2,6,6-tetramethylpiperidine (542 mg, 3.84 mmol, 1.0 eq) in THF
(10 mL◦) was added dropwise n-BuLi (2.4 mL, 3.84 mmol, 1.0 eq)
at -20 C, under argon atmosphere. After stirring for 30 min at
0 ◦C, LTMP is ready to be used.
Entry
1
Amide
Product 12b–15b Yields%c
Procedure for the preparation of LDA. To a solution of
diisopropylamine (388 mg, 3.84 mmol, 1.0 eq) in THF (10 mL)
was added dropwise n-BuLi (2.4 mL, 3.84 mmol, 1.0 eq) at -20 ◦C,
under argon atmosphere. After stirring for 30 min at 0 ◦C, LDA is
ready to be used.
2
Procedure for the preparation of [n-BuLi/LiDMAE] superbase.
To a solution of DMAE (712 mg, 8.0 mmol, 1.0 eq) in anhydrous
hexane (5 mL) at -20 ◦C was added dropwise n-BuLi (10 mL,
1.6 M in hexanes, 16.0 mmol, 2.0 eq) under argon atmosphere.
After 15 min at 0 ◦C, [n-BuLi/LiDMAE] superbase is ready to be
used.
3
4d
Lithiation sequences using the “way A” trapping conditions :
preparation of derivatives 4a–7a
2-Chloro-3-methylthiopyrazine (4a). To a solution of LTMP
(3.84 mmol, 1.2 eq) prepared as previously described in THF
(10 mL) was added dropwise 2-chloropyrazine 1 (366 mg,
3.20 mmol, 1.0 eq) at -78 ◦C in THF (5 mL), under argon
atmosphere. After 30 min of stirring at -78 ◦C, dimethyldisulfide
(903 mg, 9.60 mmol, 3.0 eq) was added in THF (5 mL) at
-78 ◦C. After the mixture was stirred for 1 h at -78 ◦C, the
hydrolysis was performed with H2O (10 mL) at -78 ◦C. The
aqueous layer was then extracted twice with AcOEt (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 9/1 as eluent and led to the
expected derivative 4a (462 mg, 90%) as a white powder; mp 44–
46 ◦C; 1H NMR dH 2.54 (s, 3H), 7.99 (d, J = 2.6 Hz, 1H), 8.30 (d,
J = 2.6 Hz, 1H); 13C NMR dC 13.6, 137.6, 141.8, 146.5, 157.3; MS
(EI) m/z 162 (37), 160 ([M]+, 100), 127 (41), 125 (59), 79 (34); ESI-
HRMS calcd for C5H6ClN2S (M+H)+ : 160.9935, found: 160.9933.
a n-BuLi (1.2 eq), ◦-20 ◦C, 1 h, THF. b Amide (2 eq), THF, -20 ◦C to 20 ◦C
(20 min), then 20 C (40 min), then H2O. c Isolated yields after centrifugal
thin layer chromatography. d Trapping step conditions : DMA (2 eq), THF,
-20 ◦C (30 min), then H2O.
Conclusions
In summary, we have developed a new efficient double function-
alisation of various p-deficient heterocycles via a one-pot cascade
process combining electrophilic trapping of lithio intermediate
and subsequent nucleophilic substitution. The sequence is not
dependent of the lithiated agent (n-BuLi, LDA, LTMP, or
[n-BuLi/LiDMAE] were used) and is applicable with several
E-Nu reagents. By this way, bifunctionalised pyrazine, pyridines
or furo[3,2-b]pyridines have been efficiently and directly obtained
in only one pot procedure (46–91%).
2-Fluoro-3-methylthiopyridine (5a). To a solution of LDA
(3.84 mmol, 1.2 eq) prepared as previously described in THF
(10 mL) was added dropwise 2-fluoropyridine 2 (310 mg,
3.20 mmol, 1.0 eq) at -70 ◦C in THF (5 mL), under argon
atmosphere. After 4 h of stirring at -70 ◦C, dimethyldisulfide
(903 mg, 9.60 mmol, 3.0 eq) was added in THF (5 mL) at
-70 ◦C. After the mixture was stirred for 1 h at -70 ◦C, the
hydrolysis was performed with H2O (10 mL) at -70 ◦C. The
aqueous layer was then extracted twice with AcOEt (10 mL). After
drying (MgSO4), filtration and solvent evaporation, the crude
product was purified by centrifugal thin-layer chromatography
with cyclohexane/AcOEt : 9/1 to 8/2 as eluent and led to the
expected derivative 5a (375 mg, 82%) as a yellow liquid; 1H NMR
dH 2.47 (s, 3H), 7.10–7.18 (m, 1H), 7.56–7.65 (m, 1H), 7.94–7.99
(m, 1H); 13C NMR dC 14.9 (d, J = 1.9 Hz), 121.9 (d, J = 4.3 Hz),
137.6 (d, J = 4.0 Hz), 143.4 (d, J = 14.0 Hz), 158.3, 162.0; MS
Experimental section
General. 1H and 13C NMR spectra were recorded at 250 and
63 MHz respectively with CDCl3 as solvent and TMS as internal
standard (for 1H NMR). HRMS spectra were recorded on a
BRUKER micrOTOF-Q spectrometer. GC-MS were recorded
on a SHIMADZU GCMS-QP2010 spectrometer. Melting tem-
peratures were measured on a Totoli apparatus and are uncor-
rected. Centrifugal thin-layer chromatography purification was
R
performed with Chromatotronꢀ.
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. 2-(Dimethylamino)ethanol
(DMAE) was distilled and stored over molecular sieves before use.
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(EI) m/z 143 ([M]+, 100), 128 (23), 101 (25); ESI-HRMS calcd for
as eluent and led to the expected derivative 5b (492 mg, 90%) as
an orange liquid; 1H NMR dH 2.46 (s, 3H), 2.58 (s, 3H), 6.96 (dd,
J = 4.8 Hz, J¢ = 7.7 Hz, 1H), 7.41 (dd, J = 1.6 Hz, J¢ = 7.7 Hz, 1H),
8.27 (dd, J = 1.6 Hz, J¢ = 4.8 Hz, 1H); 13C NMR dC 13.7, 16.1,
119.3, 132.5, 134.0, 146.0, 158.7; MS (EI) m/z 171 ([M]+, 45), 156
(100), 124 (25), 79 (34); ESI-HRMS calcd for C7H10NS2 (M+H)+ :
172.0249, found: 172.0259.
C6H7FNS (M+H)+ : 144.0278, found: 144.0262.
2-Chloro-3-methylthiopyridine (6a). To a solution of LTMP
(3.84 mmol, 1.2 eq) prepared as previously described in THF
(10 mL) was added dropwise 2-chloropyridine 3 (363 mg,
3.20 mmol, 1.0 eq) at -78 ◦C in THF (5 mL), under argon
◦
atmosphere. After 1 h 30 of stirring at -78 C, dimethyldisulfide
(903 mg, 9.60 mmol, 3.0 eq) was added in THF (5 mL) at
-78 ◦C. After the mixture was stirred for 1 h at -78 ◦C, the
hydrolysis was performed with H2O (10 mL) at -78 ◦C. The
aqueous layer was then extracted twice with AcOEt (10 mL). After
drying (MgSO4), filtration and solvent evaporation, the crude
product was purified by centrifugal thin-layer chromatography
with cyclohexane/AcOEt : 9/1 to 8/2 as eluent and led to the
expected derivative 6a (459 mg, 90%) as an orange solid; mp, 1H
NMR, 13C NMR and MS are in conformity with literature;4,13 ESI-
HRMS calcd for C6H7ClNS (M+H)+ : 159.9982, found: 159.9994.
2,3-Bis(methylthio)pyridine (5b) starting from 2-chloropyridine
(3). To a solution of LTMP (4.80 mmol, 1.5 eq) prepared as
previously described in THF (10 mL) was added dropwise 2-
◦
chloropyridine 3 (363 mg, 3.20 mmol, 1.0 eq) at -78 C in THF
(5 mL), under argon atmosphere. After 1 h 30 min of stirring at
-78 ◦C, dimethyldisulfide (602 mg, 6.40 mmol, 2.0 eq) was added
in THF (5 mL) at -78 ◦C. After the mixture was stirred for 30 min
at -78 ◦C, the temperature was allowed to warm to 20 ◦C over a
period of 1 h (for a good reproducibility, 35 min from -78 ◦C to
0 ◦C and 25 min from 0 ◦C to 20 ◦C). The temperature was then
refluxed during 20 h before that the hydrolysis was performed with
H2O (10 mL) at 20 ◦C. The aqueous layer was then extracted twice
with AcOEt (10 mL). After drying (MgSO4), filtration and solvent
evaporation, the crude product was purified by centrifugal thin-
layer chromatography with cyclohexane/AcOEt : 9/1 to 8/2 as
eluent and led to the expected derivative 5b (421 mg, 77%).
2-Chloro-6-methylthiopyridine (7a). 7a was prepared accord-
ing to the procedure described in the literature.9
Lithiation sequences using the “way B” trapping conditions :
preparation of derivatives 4b–7b
2,3-Bis(methylthio)pyrazine (4b). To a solution of LTMP
(3.84 mmol, 1.2 eq) prepared as previously described in THF
(10 mL) was added dropwise 2-chloropyrazine 1 (366 mg,
3.20 mmol, 1.0 eq) at -78 ◦C in THF (5 mL), under argon
atmosphere. After 30 min of stirring at -78 ◦C, dimethyldisulfide
(602 mg, 6.40 mmol, 2.0 eq) was added in THF (5 mL) at -78 ◦C.
After the mixture was stirred◦for 30 min at -78 ◦C, the temperature
was allowed to warm to 20 C over a period of 1 h (for a good
reproducibility, 35 min from -78 ◦C to 0 ◦C and 25 min from
2,6-Bis(methylthio)pyridine (7b). To
a
solution of [n-
BuLi/LiDMAE] superbase (8.00 mmol, 3.0 eq) prepared as
previously described in hexane (5 mL) was added dropwise 2-
chloropyridine 3 (303 mg, 2.67 mmol, 1.0 eq) at -78 ◦C in hexane
(5 mL), under argon atmosphere. After 1 h of stirring at -78 ◦C,
dimethyldisulfide (1004 mg, 10.68 mmol, 4.0 eq) was added in
THF (10 mL) at -78 ◦C. After the mixture was stirred for 30 min
at -78 ◦C, the temperature was allowed to warm to 20 ◦C over
◦
0
◦C to 20 ◦C). The temperature was then maintained at 20 ◦C
a period of 1 h (for a good reproducibility, 35 min from -78 C
◦
◦
◦
to 0 C and 25 min from 0 C to 20 C). The solvents are then
removed under reduced pressure (vacuum line), and THF (20 mL)
was added under argon atmosphere. The temperature was then
refluxed during 20 h before that the hydrolysis was performed
with H2O (10 mL) at 20 ◦C. The aqueous layer was then extracted
twice with AcOEt (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 9/1
as eluent and led to the expected derivative 7b in mixture with 7a
(398 mg, 53 + 36%, NMR yields) as a yellow liquid; 1H-NMR dH
during 3 h before that the hydrolysis was performed with H2O
(10 mL) at 20 ◦C. The aqueous layer was then extracted twice
with AcOEt (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 9/1 as
eluent and led to the expected derivative 4b (501 mg, 91%) as a
white powder; mp 88–90 ◦C; 1H NMR dH 2.59 (s, 6H), 8.06 (s, 2H);
13C NMR dC 13.2 (2C), 138.1 (2C), 154.7 (2C); MS (EI) m/z 172
([M]+, 80), 157 (100), 142 (25); ESI-HRMS calcd for C6H9N2S2
(M+H)+ : 173.0202, found: 173.0195.
2.58 (s, 6H), 6.86 (d, J = 7.8 Hz, 2H), 7.27 (t, J = 7.8 Hz, 1H); 13
C
2,3-Bis(methylthio)pyridine (5b) starting from 2-fluoropyridine
(2). To a solution of LDA (4.80 mmol, 1.5 eq) prepared as
previously described in THF (10 mL) was added dropwise 2-
NMR dC 12.3 (2C), 115.7 (2C), 134.7, 158.4 (2C); MS (EI) m/z
171 ([M]+, 100), 137 (63), 110 (25).
◦
fluoropyridine 2 (310 mg, 3.20 mmol, 1.0 eq) at -70 C in THF
2-Chlorofuro[3,2-b]pyridine (8). To a solution of furo[3,2-
b]pyridine5 (1.43 g, 12.0 mmol, 1.0 eq) in THF (100 mL)
was added dropwise n-BuLi (11.25 mL, 18.0 mmol, 1.5 eq) at
-78 ◦C, under argon atmosphere. After 1 h of stirring at -78 ◦C,
hexachloroethane (5.69 g, 24.0 mmol, 2.0 eq) was added in THF
(50 mL) at -95 ◦C. After the mixture was stirred for 1 h at -95 ◦C,
the hydrolysis was performed with H2O (100 mL) at -95 ◦C. The
aqueous layer was then extracted twice with AcOEt (100 mL).
After drying (MgSO4), filtration and solvent evaporation, the
crude product was purified by chromatography on silica gel with
cyclohexane/AcOEt : 10/0 to 8/2 as eluent and led to the expected
(5 mL), under argon atmosphere. After 4 h of stirring at -70 ◦C,
dimethyldisulfide (602 mg, 6.40 mmol, 2.0 eq) was added in THF
(5 mL) at -70 ◦C. After the mixture was stirred◦for 30 min at -70 ◦C,
the temperature was allowed to warm to 20 C over a pe◦riod of
◦
1 h (for a good reproducibility, 35 min from -70 C to 0 C and
25 min from 0 ◦C to 20 ◦C). The temperature was then maintained
at 20 ◦C during 17 h before that the hydrolysis was performed
with H2O (10 mL) at 20 ◦C. The aqueous layer was then extracted
twice with AcOEt (10 mL). After drying (MgSO4), filtration and
solvent evaporation, the crude product was purified by centrifugal
thin-layer chromatography with cyclohexane/AcOEt : 9/1 to 8/2
◦
derivative 8 (1.29 g, 70%) as a yellow solid; mp14 44–50 C; H
1
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NMR dH 6.83 (d, J = 0.8 Hz, 1H), 7.21 (dd, J = 4.9 Hz, J¢ =
8.4 Hz, 1H), 7.68 (ddd, J = 0.8 Hz, J¢ = 1.2 Hz, J¢¢ = 8.4 Hz, 1H),
8.51 (dd, J = 1.2 Hz, J¢ = 4.9 Hz, 1H); 13C NMR dC 105.0, 117.8,
119.2, 146.4, 146.5, 147.7, 147.9; MS (EI) m/z 155 (33), 153 ([M]+,
100), 127 (28), 125 (74), 90 (81), 63 (59); ESI-HRMS calcd for
C7H5ClNO (M+H)+ : 154.0054, found: 154.0056. It is to be noted
that 2,3-dichlorofuro[3,2-b]pyridine is formed during the reaction
but is easily removed by chromatography. 8 is quite unstable and
has to be stored carefully.
herein with bis(pyridin-2-yl)disulfide (352 mg, 1.6 mmol, 2.0
eq) as the E-Nu reagent. Purification by centrifugal thin-layer
chromatography was performed with cyclohexane/AcOEt : 5/5
to 2/8 as eluent and led to the expected derivative 11a (137 mg,
65%) as a white powder; mp 121–123 ◦C; 1H NMR dH 6.96–7.10
(m, 2H), 7.30 (dd, J = 4.3 Hz, J¢ = 8.1 Hz, 1H), 7.47 (dd, J =
7.3 Hz, J¢ = 7.3 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 8.35 (d,
J = 3.8 Hz, 1H), 8.59 (d, J = 4.3 Hz, 1H); 13C NMR dC 106.6,
118.4, 120.0, 120.4, 120.8, 136.8, 147.1, 147.3, 147.5, 149.7, 151.7,
157.4; MS (EI) m/z 227 ([M-35]+, 100); ESI-HRMS calcd for
C12H8ClN2OS (M+H)+ : 263.0040, found: 263.0049.
General procedure for the double functionalisation of furo[3,2-
b]pyridine : preparation of derivatives 9b–15b and 11a. To a
solution of 2-chlorofuro[3,2-b]pyridine 8 (123 mg, 0.80 mmol,
1.0 eq) in THF (10 mL) was added dropwise n-BuLi (0.6 mL,
0.96 mmol, 1.2 eq) at -20 ◦C, under argon atmosphere. After 1
h of stirring at -20 ◦C, the appropriate E-Nu reagent (1.6 mmol,
2.0 eq) was added in THF (5 mL) at -20 ◦C. The temperature was
2,3-Bis(pyridin-2-ylthio)furo[3,2-b]pyridine (11b). To a solu-
tion of 2-chlorofuro[3,2-b]pyridine 8 (123 mg, 0.80 mmol, 1.0 eq)
in THF (10 mL) was added dropwise n-BuLi (0.6 mL, 0.96 mmol,
1.2 eq) at -20 ◦C, under argon atmosphere. After 1 h of stirring at
-20 ◦C, bis(pyridin-2-yl)disulfide (352 mg, 1.6 mmol, 2.0 eq) was
added in THF (5 mL) at -20 ◦C. The temperature was allowed to
warm to 20 ◦C over a period of 20 min and was next warm at 60 ◦C
during 5 h 40 min before that the hydrolysis was performed with
H2O (10 mL) at 20 ◦C. The aqueous layer was then extracted twice
with AcOEt (10 mL). After drying (MgSO4), filtration and solvent
evaporation, the crude product was purified by centrifugal thin-
layer chromatography with cyclohexane/AcOEt : 5/5 to 2/8 as
eluent and led to the expected derivative 11b (124 mg, 46%) as an
orange solid; mp 86–89 ◦C; 1H NMR dH 6.96 (ddd, J = 1.0 Hz, J¢ =
4.9 Hz, J¢¢ = 7.3 Hz, 1H), 7.04–7.16 (m, 2H), 7.22 (dd, J = 0.8 Hz,
J¢ = 8.0 Hz, 1H), 7.28–7.70 (m, 3H), 7.83 (dd, J = 1.2 Hz, J¢ =
8.4 Hz, 1H), 8.27–8.34 (m, 1H), 8.36–8.44 (m, 1H), 8.64 (dd, J =
1.2 Hz, J¢ = 4.7 Hz, 1H); 13C NMR dC 113.2, 117.9, 119.0, 120.3,
120.7, 121.4, 121.5, 123.1, 134.0, 136.6, 137.2, 147.2, 149.5, 150.0,
156.2, 156.4, 157.7; MS (EI) m/z 227 ([M-110]+, 100); ESI-HRMS
calcd for C17H12N3OS2 (M+H)+ : 338.0416, found: 338.0429.
◦
allowed to warm to 20 C over a period of 20 min and was next
maintained at 20 ◦C during 40 min before that the hydrolysis was
performed with H2O (10 mL) at 20 ◦C. The aqueous layer was
then extracted twice with AcOEt (10 mL). After drying (MgSO4),
filtration and solvent evaporation, the crude product was purified
by centrifugal thin-layer chromatography.
2,3-Bis(methylthio)furo[3,2-b]pyridine (9b). The product was
prepared according to the general method described herein with
dimethyldisulfide (151 mg, 1.6 mmol, 2.0 eq) as the E-Nu
reagent. Purification by centrifugal thin-layer chromatography was
performed with cyclohexane/AcOEt : 9/1 to 8/2 as eluent and
led to the expected derivative 9b (135 mg, 80%) as a yellow oil;
1H NMR dH 2.53 (s, 3H), 2.65 (s, 3H), 7.16 (dd, J = 4.8 Hz, J¢ =
8.3 Hz, 1H), 7.65 (dd, J = 1.3 Hz, J¢ = 8.3 Hz, 1H), 8.53 (dd, J =
1.3 Hz, J¢ = 4.8 Hz, 1H); 13C NMR dC 15.4, 17.5, 113.7, 117.4,
118.6, 146.1, 148.6, 148.8, 158.1; MS (EI) m/z 211 ([M]+, 100),
196 (88), 178 (81); ESI-HRMS calcd for C9H10NOS2 (M+H)+
212.0198, found: 212.0205.
:
2-(Dimethylamino)-3-formylfuro[3,2-b]pyridine
(12b). The
product was prepared according to the general method described
herein with dimethylformamide (117 mg, 1.6 mmol, 2.0 eq)
as the E-Nu reagent. Purification by centrifugal thin-layer
chromatography was performed with cyclohexane/AcOEt : 5/5
to 0/10 as eluent and led to the expected derivative 12b (128 mg,
84%) as a beige powder; mp 113–115 ◦C; 1H NMR dH 3.45 (s, 6H),
6.98 (dd, J = 5.1 Hz, J¢ = 8.1 Hz, 1H), 7.39 (dd, J = 1.3 Hz, J¢ =
8.1 Hz, 1H), 8.35 (dd, J = 1.3 Hz, J¢ = 5.1 Hz, 1H), 10.15 (s, 1H);
13C NMR dC 40.5 (2C), 95.2, 115.3, 116.5, 142.1, 145.6, 150.2,
163.4, 181.4; IR (KBr) n 1629 (br); MS (EI) m/z 190 ([M]+, 44),
162 (25), 147 (100); ESI-HRMS calcd for C10H11N2O2 (M+H)+ :
191.0815, found: 191.0822.
2,3-Bis(phenylthio)furo[3,2-b]pyridine (10b). To a solution of
2-chlorofuro[3,2-b]pyridine 8 (123 mg, 0.80 mmol, 1.0 eq) in THF
(10 mL) was added dropwise n-BuLi (0.6 mL, 0.96 mmol, 1.2
eq) at -20 ◦C, under argon atmosphere. After 1 h of stirring at
◦
-20 C, diphenyldisulfide (349 mg, 1.6 mmol, 2.0 eq) was added
in THF (5 mL) at -20 ◦C. The temperature was allowed to warm
to 20 ◦C over a period of 20 min and was next warm at 50 ◦C
during 40 min before that the hydrolysis was performed with H2O
(10 mL) at 20 ◦C. The aqueous layer was then extracted twice
with AcOEt (10 mL). After drying (MgSO4), filtration and solvent
evaporation, the crude product was purified by centrifugal thin-
layer chromatography with cyclohexane/AcOEt : 9/1 to 8/2 as
eluent and led to the expected derivative 10b (228 mg, 85%) as
1
2-(Piperidin-1-yl)-3-formylfuro[3,2-b]pyridine
(13b). The
a yellow gummy; H NMR dH 7.10–7.22 (m, 4H), 7.25–7.31 (m,
product was prepared according to the general method described
herein with N-formylpiperidine (181 mg, 1.6 mmol, 2.0 eq)
as the E-Nu reagent. Purification by centrifugal thin-layer
chromatography was performed with cyclohexane/AcOEt : 7/3
to 5/5 as eluent and led to the expected derivative 13b (132 mg,
5H), 7.40–7.45 (m, 2H), 7.64 (dd, J = 1.3 Hz, J¢ = 8.3 Hz, 1H), 8.55
(dd, J = 1.3 Hz, J¢ = 4.8 Hz, 1H); 13C NMR dC 115.4, 118.3, 119.9,
126.3, 128.3, 128.5, 129.0, 129.4, 130.8, 132.0, 135.3, 147.0, 147.6,
149.3, 158.9; MS (EI) m/z 335 ([M]+, 100), 302 (25), 226 (71),
198 (50), 154 (28); ESI-HRMS calcd for C19H14NOS2 (M+H)+ :
336.0511, found: 336.0513.
◦
1
72%) as an orange solid; mp 63–65 C; H NMR dH 1.74–1.76
(m, 6H), 3.93–3.96 (m, 4H), 6.97 (dd, J = 5.1 Hz, J¢ = 8.1 Hz,
1H), 7.37 (dd, J = 1.3 Hz, J¢ = 8.1 Hz, 1H), 8.31 (dd, J = 1.3 Hz,
J¢ = 5.1 Hz, 1H), 10.13 (s, 1H); 13C NMR dC 24.1, 26.1 (2C),
2-Chloro-3-(pyridin-2-ylthio)furo[3,2-b]pyridine
(11a). The
product was prepared according to the general method described
1844 | Org. Biomol. Chem., 2011, 9, 1839–1845
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49.4 (2C), 94.5, 115.2, 116.4, 141.8, 145.4, 150.4, 161.8, 181.2; IR
(KBr) n 1667 (br); MS (EI) m/z 230 ([M]+, 33), 202 (25), 147 (18),
134 (100); ESI-HRMS calcd for C13H15N2O2 (M+H)+ : 231.1128,
found: 231.1136.
Acknowledgements
The authors would like to thank Sandrine Adach and Brigitte
Fernette for recording mass spectra and NMR spectra.
2-(Morpholin-4-yl)-3-formylfuro[3,2-b]pyridine
(14b). The
Notes and references
product was prepared according to the general method described
herein with N-formylmorpholine (184 mg, 1.6 mmol, 2.0 eq)
as the E-Nu reagent. Purification by centrifugal thin-layer
chromatography was performed with cyclohexane/AcOEt : 5/5
to 0/10 as eluent and led to the expecte◦d derivative 14b (112 mg,
1 (a) H. W. Gschwend and H. R. Rodriguez, Org. React. (N. Y.), 1979, 26,
1–360; (b) V. Snieckus, Chem. Rev., 1990, 90, 879–933; (c) G. Queguiner,
F. Marsais, V. Snieckus and J. Epsztajn, Adv. Heterocycl. Chem., 1991,
52, 187–304; (d) P. Gros, Y. Fort, G. Queguiner and P. Caubere,
Tetrahedron Lett., 1995, 36, 4791–4794; (e) P. Gros, Y. Fort and P.
Caubere, J. Chem. Soc., Perkin Trans. 1, 1997, 3071–3080; (f) J. Mortier
and M. Vaultier, C. R. Acad. Sci. Ser. IIc Chim., 1998, 1, 465–478;
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(h) A. Turck, N. Ple, F. Mongin and G. Queguiner, Tetrahedron, 2001,
57, 4489–4505; (i) P. Gros and Y. Fort, Eur. J. Org. Chem., 2002, 3375–
3383; (j) C. G. Hartung and V. Snieckus, Modern Arene Chemistry,
2002, 330–367; (k) M. C. Whisler, S. MacNeil, V. Snieckus and P. Beak,
Angew. Chem., Int. Ed., 2004, 43, 2206–2225; (l) M. Schlosser, Angew.
Chem., Int. Ed., 2005, 44, 376–393; (m) R. E. Mulvey, F. Mongin, M.
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(n) M. Schlosser and F. Mongin, Chem. Soc. Rev., 2007, 36, 1161–1172;
(o) P. C. Gros and Y. Fort, Eur. J. Org. Chem., 2009, 4199–4209.
2 (a) R. Radinov, K. Chanev and M. Khaimova, J. Org. Chem., 1991,
56, 4793–4796; (b) N. Ple, A. Turck, F. Bardin and G. Queguiner,
J. Heterocycl. Chem., 1992, 29, 467–470; (c) N. Ple, A. Turck, A.
Heynderickx and G. Queguiner, Tetrahedron, 1998, 54, 4899–4912.
3 E. Banaszak, C. Comoy and Y. Fort, Tetrahedron Lett., 2006, 47, 6235–
6238.
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7 (a) A. Turck, L. Mojovic and G. Queguiner, Synthesis, 1988, 881–884;
(b) P. Gros, S. Choppin and Y. Fort, J. Org. Chem., 2003, 68, 2243–
2247; (c) N. Hebbar, Y. Ramondenc, G. Ple, G. Dupas and N. Ple,
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8 T. Gungor, F. Marsais and G. Queguiner, J. Organomet. Chem., 1981,
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1
60%) as an orange powder; mp 94–96 C; H NMR dH 3.87 (t,
J = 5.1 Hz, 4H), 4.06 (t, J = 5.1 Hz, 4H), 7.02 (dd, J = 5.0 Hz,
J¢ = 8.1 Hz, 1H), 7.42 (dd, J = 1.3 Hz, J¢ = 8.1 Hz, 1H), 8.35
(dd, J = 1.3 Hz, J¢ = 5.0 Hz, 1H), 10.14 (s, 1H); 13C NMR dC
48.2 (2C), 66.6 (2C), 95.1, 115.6, 116.9, 141.8, 145.7, 149.9,
161.6, 181.7; IR (KBr) n 1659 (br); MS (EI) m/z 232 ([M]+,
75), 201 (58), 174 (41), 147 (100), 133 (43), 119 (33), 91 (40);
ESI-HRMS calcd for C12H13N2O3 (M+H)+ : 233.0921, found:
233.0922.
2-(Dimethylamino)-3-acetylfuro[3,2-b]pyridine (15b). To a so-
lution of 2-chlorofuro[3,2-b]pyridine 8 (123 mg, 0.80 mmol, 1.0 eq)
in THF (10 mL) was added dropwise n-BuLi (0.6 mL, 0.96 mmol,
1.2 eq) at -20 ◦C, under argon atmosphere. After 1 h of stirring at
-20 ◦C, dimethylacetamide (139 mg, 1.6 mmol, 2.0 eq) was added
in THF (5 mL) at -20 ◦C. The temperature was then maintained
at -20 ◦C during 30 min before that the hydrolysis was performed
with H2O (10 mL) at -20 ◦C. The aqueous layer was then extracted
twice with AcOEt (10 mL). After drying (MgSO4), filtration and
solvent evaporation, the crude product was purified by centrifugal
thin-layer chromatography with cyclohexane/AcOEt : 7/3 to 5/5
as eluent and led to the expected derivative 15b (126 mg, 77%) as
◦
1
a yellow powder; mp 66–68 C; H NMR dH 2.84 (s, 3H), 3.25
(s, 6H), 6.95 (dd, J = 5.0 Hz, J¢ = 8.0 Hz, 1H), 7.39 (dd, J =
1.3 Hz, J¢ = 8.0 Hz, 1H), 8.36 (dd, J = 1.3 Hz, J¢ = 5.0 Hz,
1H); 13C NMR dC 31.1, 40.8 (2C), 96.4, 115.1, 115.9, 142.2,
144.9, 149.1, 164.9, 192.3; IR (KBr) n 1648 (br); MS (EI) m/z
204 ([M]+, 85), 189 (100), 175 (20), 161 (33), 133 (40), 119 (19);
ESI-HRMS calcd for C11H13N2O2 (M+H)+ : 205.0972, found:
205.0983.
9 S. Choppin, P. Gros and Y. Fort, Org. Lett., 2000, 2, 803–805.
10 2 or 3 eq of Me2S2 gave similar results.
11 For a good reproducibility: 35 min from -78 ◦C to 0 ◦C then 25 min
from 0 ◦C to 20 ◦C.
12 NMR yields, non separable mixture.
13 G. S. Ponticello, R. D. Hartman, W. C. Lumma Jr. and J. J. Baldwin, J.
Org. Chem., 1979, 44, 3080–3082.
14 S. Shiotani and K. Taniguchi, J. Heterocycl. Chem., 1996, 33, 1051–
1056.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 1839–1845 | 1845
©