Toolbox for regioselective lithiations of furo[2,3-c]pyridine

Article abstract of DOI:10.1021/jo902666w

Chemical Reaction Reprentation A detailed procedure for successive regioselective lithiations of furo[2,3-c]pyridine is described by using n-BuLi and the [n-BuLi/LiDMAE] Superbase. Several polysubstituted furo[2,3-c]pyridines have been efficiently synthesized and some of them were engaged in Pd- or Ni-catalyzed coupling reactions leading to 2,2'- or 7,7'-bifuro[2,3-c]pyridine ligands.

Full text of DOI:10.1021/jo902666w

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Toolbox for Regioselective Lithiations of Furo[2,3-c]pyridine
Anthony Chartoire, Corinne Comoy, and Yves Fort*
ꢀ
ꢁ
ꢁ
ꢁ
ꢁ
Groupe Synthese Organometallique et Reactivite, SRSMC, Nancy-Universite, CNRS, B.P. 239,
ꢀ
Boulevard des Aiguillettes, F-54506 Vandoeuvre-les-Nancy, France
yves.fort@srsmc.uhp-nancy.fr
Received December 16, 2009
A detailed procedure for successive regioselective lithiations of furo[2,3-c]pyridine is described by
using n-BuLi and the [n-BuLi/LiDMAE] superbase. Several polysubstituted furo[2,3-c]pyridines
have been efficiently synthesized and some of them were engaged in Pd- or Ni-catalyzed coupling
reactions leading to 2,20- or 7,70-bifuro[2,3-c]pyridine ligands.
Introduction
quinolines, etc.).8-15 Since these organometallic methods
are becoming more efficient, elaborate heterocycles can be
studied. Due to their potential biological applications, fused
heterocycles containing several complexing heteroatoms
appear to be the next interesting targets.
Over the past few decades, many efforts have been made to
develop metalation reactions for the functionalization of
heterocycles.1-7 Such reactions are proving to be powerful
tools because of the large range of functionalities that can be
introduced. In recent years, new reagents have been deve-
loped and toolboxes have been designed to modify regio-
selectivities and/or to tolerate sensitive functional groups during
lithiation of substituted azaheterocycles (e.g., pyridines,
In our ongoing research in heterocyclic chemistry,16-19
furopyridines have attracted our attention because of their
isosterism with (aza)indole, chromane, or dioxinopyridine
derivatives which are important moieties largely represented
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4489–4505.
*To whom correspondence should be addressed. Phone: þ33 (0)3 83 68 47
81. Fax: þ33 (0)3 83 68 47 85.
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DOI: 10.1021/jo902666w
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Published on Web 03/01/2010
J. Org. Chem. 2010, 75, 2227–2235 2227
2010 American Chemical Society

Chartoire et al.
JOCArticle
FIGURE 1. PNU-142721: an efficient HIV-1 non-nucleoside reverse
transcriptase inhibitor.
FIGURE 2. Successive regioselective metalation procedure.
SCHEME 1. Selective Functionalization of Furo[3,2-b]pyridine
SCHEME 2. Preparation of 2-Substituted Furo[2,3-c]pyridines
2a-ha,b
in many bioactive molecules.20-28 An outstanding exam-
ple is the furo[2,3-c]pyridine contained in PNU-142721,
a derivative reported by Morris and co-workers as an effi-
cient HIV-1 non-nucleoside reverse transcriptase inhibitor
(Figure 1).29,30
In the literature, substituted furopyridines are usually
synthesized by furan ring formation involving Pd-catalyzed
reactions.31-36 Functionalities are then inserted during the
cyclization process that limits the nature of introduced
groups. Despite the fact that metalation of furopyridines
presents great potential because of its 5 possible reactive
sites, only few papers report hydrogen-metal exchange
reactions with these substrates. The presence of two hetero-
atoms is an additional interesting parameter for the com-
plexation of lithiated species and thus for the regioselectivity
of the metalation process. To our knowledge, only Shiotani
and co-workers have studied the effect of several alkyl-
aReagents and conditions: (i) n-BuLi (1.5 equiv), -78 °C, 1 h, THF.
(ii) Eþ = Me3SiCl, DCl/D2O, C2Cl6, PhCHO, Me2S2, CBr4 or Bu3SnCl
(2 equiv), -95 or -78 °C, 15 min or 1 h, THF then H2O. (iii) 2f (1 equiv),
2g (1.1 equiv), PdCl2(PPh3)2 (5 mol %), DMF, 110 °C, 5 h. bIsolated
yields after centrifugal thin-layer chromatography purification. cDCl/
D2O (DCl 35 wt % in D2O, 20 equiv) was used as electrophile, 2b was
95% deuterated. dTrapping step was performed at -95 °C. eTrapping
step was performed for 15 min at -95 °C.
lithiums on furopyridines.37-40 Even if most of them were
substituted derivatives, the formation of the simple 2-lithio-
furopyridine intermediate was described, followed by elec-
trophile quenching with dimethylformamide (DMF) and
diphenyl disulfide (Ph2S2). We recently improved and exten-
ded this lithiation sequence for the synthesis of various
2-substituted furo[3,2-b]pyridines (Scheme 1).17
Among the six isomeric series of the furopyridine frame-
work ([b]-, [c]-, or [f]-fused heterocycles) we will presently
turn our attention to furo[2,3-c]pyridine 1, with the aim to
regioselectively functionalize several positions of this scaf-
fold, specifically via selective metalation on the R-position
of heteroatoms by using n-butyllithium (n-BuLi) or the
[n-BuLi/LiDMAE] superbase (Figure 2).
(24) Popowycz, F.; Merour, J.-Y.; Joseph, B. Tetrahedron 2007, 63, 8689–
8707.
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2006, 63, 1031–1064.
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Carreno, C.; Ferrer-Montiel, A.; Albericio, F. J. Med. Chem. 2007, 50, 6133–
6143.
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J.-P.; Den Hartog, A. P.; Stork, B.; Plekkenpol, R. H.; Niemann, L. C.;
Stroomer, C. N. J.; Tulp, M. T. M.; Van Stuivenberg, H. H.; McCreary,
A. C.; Hesselink, M. B.; Herremans, A. H. J.; Kruse, C. G. J. Med. Chem.
2005, 48, 6855–6869.
(29) Wishka, D. G.; Graber, D. R.; Kopta, L. A.; Olmsted, R. A.; Friis,
J. M.; Hosley, J. D.; Adams, W. J.; Seest, E. P.; Castle, T. M.; Dolak, L. A.;
Keiser, B. J.; Yagi, Y.; Jeganathan, A.; Schlachter, S. T.; Murphy, M. J.;
Cleek, G. J.; Nugent, R. A.; Poppe, S. M.; Swaney, S. M.; Han, F.; Watt, W.;
White, W. L.; Poel, T.-J.; Thomas, R. C.; Voorman, R. L.; Stefanski, K. J.;
Stehle, R. G.; Tarpley, W. G.; Morris, J. J. Med. Chem. 1998, 41, 1357–1360.
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Watt, W.; Morris, J. J. Org. Chem. 1998, 63, 7851–7859.
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Org. Lett. 2002, 4, 2409–2412.
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2008, 3647–3655.
Results and Discussion
In a preliminary study, the lithiation of furo[2,3-c]pyridine
1 by n-BuLi was examined. Taking advantage of the method-
ology described for furo[3,2-b]pyridine,17 1 was prepared
starting from 3-hydroxypyridine in a 4-step procedure inclu-
ding Sonogashira cross-coupling as the key step (see the
Supporting Information). Lithiation of 1 was next carried
out by using 2 equiv of n-BuLi at -78 °C for 1 h in
(37) Morita, H.; Shiotani, S. J. Heterocycl. Chem. 1987, 24, 373–376.
(38) Shiotani, S. J. Heterocycl. Chem. 1993, 30, 1025–1033.
(39) Shiotani, S. Heterocycles 1997, 45, 975–1011.
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10296.
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SCHEME 3. Specific Aggregation of the [n-BuLi/LiDMAE] Superbase on Pyridine Nitrogen
SCHEME 4. Competitive Lithiation on the C-2 and C-7 Positions with the [n-BuLi/LiDMAE] Superbasea,b
aReagents and conditions: (i) [n-BuLi/LiDMAE] (3 equiv), -78 °C, 1 h, toluene. (ii) Eþ = C2Cl6 or Me3SiCl (3 equiv), -78 °C, 1 h, THF then
c
H2O. bIsolated yields after centrifugal thin-layer chromatography purification. 10% of 1 was recovered. d4a and 5a are unstable and lead to
degradation compounds.
tetrahydrofurane (THF) allowing deprotonation on the C-2
position. Upon treatment with chlorotrimethylsilane
(Me3SiCl) as electrophile, compound 2a was obtained in a
good yield (70%). Under these conditions, nucleophilic
addition of n-BuLi on the C-7 position was also detected
and 7-butyl-2-trimethylsilylfuro[2,3-c]pyridine 3 was iso-
lated as a byproduct (12%). To limit this side reaction, we
decided to reduce the amount of base to 1.5 equiv of n-BuLi.
Despite a small decrease of conversion rate (90% instead of
>95%), 2a was obtained in a better yield (77%) without
nucleophilic addition of n-BuLi. For synthesis purposes this
sequence was extended by using various representative elec-
trophiles allowing subsequent functionalization (Scheme 2).
Derivatives 2a-g were formed in 71-81% yields. It is to be
noted that derivatives 2c, 2f, and 2g were more efficiently
obtained when the trapping step was performed at -95 °C,
while 2a, 2b, 2d, and 2e were prepared at -78 °C. The
potential usefulness of synthesized compounds was exempli-
fied by the efficient preparation of 2h from 2g and 2f in a 79%
yield under usual Stille conditions.
even if an ortho-directing group (Cl, SMe, OMe, etc.)18,19,42
is present (Scheme 3).
We then carried out deprotonation of furo[2,3-c]pyridine 1
using [n-BuLi/LiDMAE] superbase at -78 °C for 1 h in tolu-
ene and after chlorination with hexachloroethane (C2Cl6) as
the electrophile, a mixture of three products was detected.
Deprotonation on the C-2 position was favored since 2-chlo-
rofuro[2,3-c]pyridine 2c was isolated as the major product
with 52% yield. Nevertheless, deprotonation on the C-7
position was also observed and derivatives 4c and 5c were
obtained with low yields (4% each) underlining a lithium
chelating competition between the oxygen and the nitrogen
atoms to the advantage of the oxygen atom (Scheme 4).
Such an effect was previously observed by our group during
the metalation of azaphtalan derivatives with the [n-BuLi/
LiDMAE] superbase.43 We noticed that 2c was quite unstable
and partially led to degradation compounds at -78 °C. How-
ever, if trapping temperature was decreased to -95 °C as des-
cribed in Scheme 2, 2c was more efficiently obtained, and only
traces of 4c and 5c were detected.
To create a toolbox for the functionalization of furo[2,3-
c]pyridine 1, we next turned our attention to other possible
sites of lithiation, and especially to the C-5 and C-7 positions
(R to the pyridine nitrogen atom). For several years, our group
has had a great interest in the development of the [n-BuLi/
LiDMAE] superbase.8-11,18,19 Combining n-BuLi and lithium
dimethylaminoethoxide (LiDMAE), this monometallic non-
nucleophile superbase exhibits specific aggregation on the
pyridine nitrogen atom41 to reach regioselective and unpre-
cedented lithiation on the R-position of pyridine nitrogen,
DFT calculation of Mulliken charges was performed to
estimate relative acidities of the various hydrogen atoms of
furo[2,3-c]pyridine 1 and then to understand regioselectivity
of the deprotonation. The result showed that the hydrogen
atom in the C-2 position is actually more acidic than the
hydrogen atom in the C-7 position (see the Supporting Infor-
mation for more details about DFT calculation).
On the basis of our experience of [n-BuLi/LiDMAE] induced
metalation on the R-position of pyridine nitrogen, we then
decided to conduct complementary experiments on two deu-
terated furo[2,3-c]pyridines 2b and 4b to study the isotopic
effect (see Scheme 6 for the preparation of 4b). Metalation
(41) Khartabil, H. K.; Gros, P. C.; Fort, Y.; Ruiz-Lopez, M. F. J. Am.
Chem. Soc. 2010, 132, 2410–2416.
(42) Gros, P.; Choppin, S.; Mathieu, J.; Fort, Y. J. Org. Chem. 2002, 67,
234–237.
(43) Fort, Y.; Gros, P.; Rodriguez, A. L. Tetrahedron Lett. 2002, 43,
4045–4048.
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SCHEME 5. Study of Chelating Competition between Oxygen and Nitrogen Atomsa,b
aReagents and conditions: (i) [n-BuLi/LiDMAE] (3 equiv), -78 °C, 1 h, toluene. (ii) C2Cl6 (3 equiv), -78 °C, 1 h, THF then H2O. bIsolated yield after
centrifugal thin-layer chromatography purification. 5b and 5d were 98% deuterated.
c
SCHEME 6. Preparation of 2,7-Disubstituted and 7-Substituted
Furo[2,3-c]pyridines 5e-i and 4b-ca,b
was carried out with [n-BuLi/LiDMAE] under the same
conditions as precedently described for lithiation of furo-
[2,3-c]pyridine 1. When 2b reacted, metalation was slowed
down in the C-2 position because of the isotopic effect,
and then 7-chloro-2-deuteriofuro[2,3-c]pyridine 5b resulting
from lithiation on the C-7 position was isolated in a 16%
yield. However, 2c was again obtained as the major product
in a 52% yield evidencing that aggregation is still preferred
on the oxygen atom nearest the most acidic hydrogen atom
despite the isotopic effect on the C-2 position, which is
unusual for the [n-BuLi/LiDMAE] superbase. On the other
hand, metalation of 4b furnished exclusive lithiation on the
C-2 position, because of the isotopic effect on the C-7 posi-
tion, and then 98% deuterated 5d was obtained while 4c or 5c
was not detected. This showed that C-7Li/C-2Li exchange
was mostly improbable; otherwise formation of 2c, 4c, or 5c
would have been observed (Scheme 5).
To achieve lithiation on the C-7 position, an easily remo-
vable protective group on the C-2 position was used.44
A
trimethylsilyl group is an excellent unit to perform lithiation
on the C-7 position. Classically used in Hiyama couplings,45
the trimethylsilyl moiety tolerates non-nucleophile lithiated
agents and can be removed by a fluoride treatment. In Table 1
we report the most significant results for lithiation of 2a.
When n-BuLi was used as the base followed by chlorina-
tion with C2Cl6, an intractable mixture of products was
detected. We then decided to use H2O as the electrophile to
simplify this mixture and to elucidate the reaction’s beha-
vior. As a consequence, after the metalation step and hydro-
lysis of the reaction medium, two products resulting from
n-BuLi nucleophilic addition and desilylation were detected.
Only traces of the starting material were recovered, corro-
borating that no lithiation occurred on the C-7 position
(entry 1). In contrast, the [n-BuLi/LiDMAE] superbase in
hexane allowed clean lithiation on the C-7 position, without
addition of a butyl moiety or deprotection of the trimethyl-
silyl group. This result once more confirmed the non-nucleo-
phile character of the [n-BuLi/LiDMAE] superbase. To
perform complete conversion of the substrate, a metalation
at -45 °C and 3 equiv of base were necessary (entry 4) since a
decrease in the amount of base or in metalation temperature
led to 70% conversion (entries 2 and 3). Despite the ability of
the [n-BuLi/LiDMAE] superbase to allow metalation on the
aReagents and conditions: (i) [n-BuLi/LiDMAE] (3 equiv), -45 °C, 1 h,
hexane. (ii) Eþ =Me3SiCl, C2Cl6, DCl/D2O, Me2S2, Bu3SnCl or PhCHO
(3equiv), -78 °C, 1 h, THF then H2O. (iii) TBAF (1.1 equiv), 24 h, rt, THF/
H2O (5/1). bIsolated yields after centrifugal thin-layer chromatography
c
purification. 5f was 100% deuterated. dKugelrohr distillation was used for
e
the purification. n-BuLi (1.2 equiv), -45 °C, 1 h, THF then H2O.
C-5 position, no trace of 6 was observed. This high regio-
selectivity in the C-7 position versus the C-5 position might
be explained by the activation effect and the stabilization of
lithiated species near the oxygen atom.
This sequence was extended by using various representa-
tive electrophiles, and compounds 5e-i were obtained in
good to excellent yields (60-85%, see Scheme 6). Despite all
our efforts, 5a could not be isolated because of the high
instability of this compound. It should also be noted that
bifunctional compounds 5e and 5h represent very interesting
molecules for further selective functionalization on the C-2
and C-7 positions.
Tetrabutyl ammonium fluoride (TBAF) was used to af-
ford desilylation conducted to the expected 7-substituted
furo[2,3-c]pyridines 4b-c in very good yields (85-89%, see
Scheme 6).
We subsequently confirmed that n-BuLi constitutes a
good alternative reagent to TBAF for removing the trimethyl-
silyl group when the C-7 position is substituted. Indeed, by
(44) Mills, R. J.; Snieckus, V. J. Org. Chem. 1983, 48, 1565–1568.
(45) Hiyama, T. J. Organomet. Chem. 2002, 653, 58–61.
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Chartoire et al.
JOCArticle
TABLE 1. Regioselective Lithiation of 2aa
metalation
temp T, °C
entry
base
n-BuLib
[n-BuLi/
equiv of base
solvent
1
2a
3
5e
6
1
2
1.2
3
-78
-78
THF
hexane
38
4
31
47
65
60
85
LiDMAE]c
[n-BuLi/
3
4
2
3
-45
-45
hexane
hexane
30
LiDMAE]c
[n-BuLi/
traces
LiDMAE]c
aReagents and conditions: (i) base (n equiv), T °C, 1 h, solvent. (ii) C2Cl6 (3 equiv), -78 °C, 1 h, THF then H2O. bH2O was added as the electrophile,
GC yields. cIsolated yields after centrifugal thin-layer chromatography purification.
treatment of 5e with 1.2 equiv of n-BuLi at -45 °C in THF,
4c was efficiently obtained in a good yield (72%) without
byproduct.
SCHEME 7. Preparation of 7,70-Bifuro[2,3-c]pyridines 7 and 8a,b
As an extension of this work, we tried to use the prepared
chlorinated compounds in the synthesis of bipyridinic ligands.
2,20-Bipyridines are largely represented as versatile ligands
due to their ability to form stable complexes with metal ions.46
Since they combine a π-electron-rich furan ring and a
π-electron-deficient pyridine ring, 7,70-bifuro[2,3-c]pyridines
might have interesting properties as ligands with applica-
tions in the domains of catalysis, photochemistry, or asym-
metric transformations. Under the usual Ni-induced homo-
coupling conditions,47 5e and 4c afforded compounds 7 and
8in very good yields (76% and 74%, respectively, see Scheme 7).
Furthermore, 8 was efficiently obtained by using TBAF on 7
in an excellent 90% isolated yield. 7,70-Bifuro[2,3-c]pyridine
ligands were then prepared in only three or four steps starting
from unsubstituted furo[2,3-c]pyridine 1, in 50% and 41%
overall yields, respectively.
Our initial goal was to offer a complete toolbox for the
functionalization of furopyridines. Since furo[2,3-c]pyridines
having potential biological properties29,48,49 are generally
substituted on the C-5 position, we next envisioned the fur-
ther metalation of the 5e compound. Due to its specific pro-
perties, the [n-BuLi/LiDMAE] superbase seemed to be the
most efficient reagent to afford deprotonation on this posi-
tion. The most significant results for the lithiation of 5e follo-
wed by electrophilic treatment with DCl/D2O, C2Cl6, or
MeSSMe are reported in Table 2.
aReagents and conditions: (i) NiCl2 6H2O, Zn, PPh3, DMF, 50 °C, 4 h.
3
(ii) TBAF (2.2 equiv), 24 h, rt, THF/H2O (5/1). bIsolated yields after
centrifugal thin-layer chromatography purification.
Metalation of 5e at -45 °C in hexane allowed lithiation on
the C-5 position. After deuterolysis with deuterium chloride
solution in deuterium oxide (DCl/D2O), 58% of the expected
7-chloro-5-deuterio-2-trimethylsilylfuro[2,3-c]pyridine 9b
was obtained. However, DCl/D2O trapping also revealed
an unexpected chlorine/lithium exchange and 24% of 7-
deuteriofuro[2,3-c]pyridine 5f was isolated. Cl/Li permuta-
tion is usually carried out with use of lithium powder with a
catalytic amount of 4,40-di-tert-butylbiphenyl (DTBB),50,51
and such an exchange appears unusual with organolithium
bases since chlorine is commonly used as a directing group in
metalation processes. Nevertheless, in this specific case, a
strong activation of the C-Cl bond induced by the neighbor-
ing oxygen atom might explain the successful sequence.
Besides, recent work conducted on azaindoles derivatives
exhibits similar reactivity by using t-BuLi.52 When C2Cl6 was
used as the electrophilic source, a mixture of the expected
dichloro compound 9a (71-80%) resulting from lithiation
on the C-5 position and 5e (14-21%) afforded by Cl/Li
exchange was isolated (entries 2-4). A better result was
obtained by using 4 equiv of base at -45 °C for 1 h in hexane
followed by addition of 4 equiv of electrophile from -78 °C
to room temperature in THF. It could be noted that an
increase in trapping temperature to 20 °C was necessary to
yield 9a more efficiently. To extend this lithiation sequence,
we next turned our attention to the reaction with other
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Thornburgh, B. A.; Tinholt, P. M.; Walters, R. R.; Olson, B. A.; Fitzgerald,
L.; Staton, B. A.; Raub, T. J.; Krause, M.; Li, K. S.; Hoffmann, W. E.; Hajos,
M.; Hurst, R. S.; Walker, D. P. Bioorg. Med. Chem. Lett. 2008, 18, 3611–
3615.
(49) Wishka, D. G.; Walker, D. P.; Yates, K. M.; Reitz, S. C.; Jia, S.;
Myers, J. K.; Olson, K. L.; Jacobsen, E. J.; Wolfe, M. L.; Groppi, V. E.;
Hanchar, A. J.; Thornburgh, B. A.; Cortes-Burgos, L. A.; Wong, E. H. F.;
Staton, B. A.; Raub, T. J.; Higdon, N. R.; Wall, T. M.; Hurst, R. S.; Walters,
R. R.; Hoffmann, W. E.; Hajos, M.; Franklin, S.; Carey, G.; Gold, L. H.;
Cook, K. K.; Sands, S. B.; Zhao, S. X.; Soglia, J. R.; Kalgutkar, A. S.;
Arneric, S. P.; Rogers, B. N. J. Med. Chem. 2006, 49, 4425–4436.
(50) Yus, M.; Ortiz, R.; Huerta, F. F. Tetrahedron 2003, 59, 8525–8542.
(51) Pastor, I. M.; Penafiel, I.; Yus, M. Tetrahedron Lett. 2008, 49, 6870–
6872.
(52) Lachance, N.; Bonhomme-Beaulieu, L.-P.; Joly, P. Synthesis 2009,
721–730.
J. Org. Chem. Vol. 75, No. 7, 2010 2231

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TABLE 2. Preparation of 5,7-Disubstituted-2-trimethylsilylfuro[2,3-c]pyridines 9a
trapping step
yields (%)b
entry
equiv of base
T, °C
equiv
E
9
5
1
2
3
4
5
3
3
4
5
3
-78 °C to rt
-78 °C to rtd
-78 °C to rtd
-78 °C to rtd
-78 °Ce
20
3
4
5
3
D
Cl
Cl
Cl
9b, 58c
9a, 72
9a, 80
9a, 71
9c, 39
5f, 24
5e, 21
5e, 14
5e, 20
5g, 10f
SMe
aReagents and conditions: (i) [n-BuLi/LiDMAE] (n equiv), -45 °C, 1 h, hexane. (ii) Eþ = DCl/D2O, C2Cl6 or Me2S2 (n equiv), T °C, 1 h, THF then
H2O. bIsolated yields after centrifugal thin-layer chromatography purification. c9b was 99% deuterated. dTrapping step for 1 h at -78 °C then 1 h from
-78 °C to room temperature. eIf temperature was allowed to warm to room temperature, a complex mixture (9c, 5g, 5e, 2a, and desilylated products) was
detected (GC/MS). f8% of 2a was recovered resulting from low reactivity of lithio intermediate at -78 °C.
and Foubelo in particular described such a permutation in
β-functionalized sulfur derivatives.53,54 In our case, the SMe
in the β-position of the oxygen atom exhibits these suitable
conditions to allow a SMe/Li exchange. Such a result once
more illustrates the highly activated character of the C-7
position neighboring the oxygen atom in furo[2,3-c]pyridine.
SCHEME 8. Preparation of 5-Chloro-7-methylthio-2-trimethyl-
silylfuro[2,3-c]pyridines 9da,b
Conclusion
In summary, we have described the efficient synthesis of
polysubstituted furo[2,3-c]pyridines via successive regio-
selective lithiation reactions, using n-BuLi or [n-BuLi/LiDMAE]
as bases. For each step, products were obtained in low to very
good yields (16-85%) and some of them were engaged in Pd-
or Ni-catalyzed homocoupling for efficient preparation of
2,20- or 7,70-bifuro[2,3-c]pyridines (63% or 41-50% overall
yields, respectively). From a fundamental point of view,
regioselectivity depending on the nature of the base was
studied, and unusual Cl/Li and SMe/Li permutations were
highlighted, proving the highly activated character on the
C-7 position of furo[2,3-c]pyridine.
aReagents and conditions: (i) [n-BuLi/LiDMAE] (3 equiv), -45 °C, 1 h,
hexane; (ii) C2Cl6 (3 equiv), -78 °C, 1 h, THF then H2O. bIsolated yields
after centrifugal thin-layer chromatography purification.
electrophiles. Then 9c was obtained with a moderate 39%
isolated yield, resulting from treatment with dimethyl disul-
fide. In this case, the trapping temperature had to be kept at
-78 °C to avoid desilylation by nucleophilic methythiolate,
and consequently, a decrease of the conversion rate was
observed (84%). It is worth mentioning that condensation
on benzaldehyde and acetaldehyde was studied too, demon-
strating the formation of a nonseparable mixture of 5- and
7-substituted alcohols and starting materials.
To continue our study of metalation on the C-5 position of
furo[2,3-c]pyridine derivatives, we finally focused our atten-
tion on 7-methylthiofuro[2,3-c]pyridine 5g. Lithiation of 5g
was carried out with 3 equiv of [n-BuLi/LiDMAE] at -45 °C
for 1 h in hexane followed by addition of C2Cl6 as the
electrophile in THF, and surprisingly, the methylthio group
was also partially replaced during the metalation process,
which led to a mixture of 5e, 9d, and starting material (60%,
16%, and 16% yields, respectively, see Scheme 8).
Experimental Section
1
General. H and 13C NMR spectra were recorded at 400 or
250 or 200 and 100 or 63 or 50 MHz respectively with CDCl3 as
1
solvent and TMS as internal standard (for H NMR). HRMS
spectra were recorded on a BRUKER micrOTOF-Q spectro-
meter. MS spectra were recorded on a SHIMADZU GCMS-
QP2010 spectrometer. Melting temperatures are uncorrected.
Centrifugal thin-layer chromatography purification was per-
formed with Chromatotron.
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. Toluene, hexane, and THF were distilled and stored
A methylthio group is sometimes employed as a directing
group during metalation processes; nevertheless, in some
specific cases, a sulfur/lithium exchange was observed. Yus
(53) Foubelo, F.; Gutierrez, A.; Yus, M. Tetrahedron Lett. 1997, 38,
4837–4840.
(54) Foubelo, F.; Yus, M. Chem. Soc. Rev. 2008, 37, 2620–2633.
2232 J. Org. Chem. Vol. 75, No. 7, 2010

Chartoire et al.
JOCArticle
on sodium wire before use. Centrifugal thin-layer chromato-
graphy purifications were performed on silica gel (Merck silica
gel 60 PF254 containing gypsum).
matography was performed with hexane/AcOEt 8/2 to 6/4 as
eluent and led to the expected derivative 2e (206 mg, 78%) as an
orange solid: mp 47-50 °C; 1H NMR δH 2.60 (s, 3H), 6.55 (s,
1H), 7.38 (d, J=5.1 Hz, 1H), 8.36 (d, J=5.1 Hz, 1H), 8.75 (s,
1H); 13C NMR δC 15.8, 104.1, 114.6, 132.7, 135.4, 142.9, 153.3,
158.2 ; IR (KBr) ν 1255; MS (EI) m/z 165 ([M]þ, 100), 150 (36),
122 (22), 95 (15); ESI-HRMS calcd for C8H8NOS (M þ H)þ
166.0321, found 166.0313.
General Procedure for the Preparation of 2-Substituted Furo-
[2,3-c]pyridines (2a-g). To a solution of furo[2,3-c]pyridine 1
(190 mg, 1.6 mmol, 1.0 equiv) in THF (15 mL) was added
dropwise n-BuLi (1.5 mL, 2.4 mmol, 1.5 equiv) at -78 °C, under
argon atmosphere. After 1 h of stirring at -78 °C, the appro-
priate electrophile (3.2 mmol, 2.0 equiv) was added in THF
(5 mL) at -78 or -95 °C. After the mixture was stirred for 15 min
or 1 h, the hydrolysis was performed with H2O (10 mL) at the
desired trapping temperature. The aqueous layer was then
extracted twice with AcOEt (10 mL). The combined organic
layers were washed with an aqueous saturated NaHCO3 solu-
tion (20 mL). After drying (MgSO4), filtration, and solvent eva-
poration, the crude product was purified by centrifugal thin-
layer chromatography.
a. 2-Trimethylsilylfuro[2,3-c]pyridine (2a). The product was
prepared according to the general method described herein with
chlorotrimethylsilane (347 mg, 3.2 mmol, 2.0 equiv) as electro-
phile, for 1 h at -78 °C. Purification by centrifugal thin-layer
chromatography was performed with hexane/AcOEt 9/1 to 7/3
as eluent and led to the expected derivative 2a (235 mg, 77%) as a
yellow liquid: 1H NMR δH 0.37 (s, 9H), 6.94 (s, 1H), 7.49 (d, J=
5.1 Hz, 1H), 8.36 (d, J=5.1 Hz, 1H), 8.88 (s, 1H); 13C NMR δC
-1.9, 115.0, 115.9, 133.9, 134.5, 141.8, 155.3, 168.3; IR (NaCl)
ν 1255; MS (EI) m/z 191 ([M]þ, 54), 176 (100), 133 (21); ESI-
HRMS calcd for C10H14NOSi (M þ H)þ 192.0839, found
192.0834.
b. 2-Deuteriofuro[2,3-c]pyridine (2b). The product was pre-
pared according to the general method described herein with
deuterium chloride 35 wt % in deuterium oxide (2.64 mL, 32.0
mmol, 20.0 equiv) as electrophile, at -78 °C and then 1 h from
-78 °C to rt. Purification by centrifugal thin-layer chromato-
graphy was performed with hexane/AcOEt 7/3 to 5/5 as eluent
and led to the expected derivative 2b (146 mg, 76%) as a yellow
liquid: 1H NMR δH 6.82 (s, 1H), 7.57 (d, J=5.2 Hz, 1H), 8.44 (d,
J=5.2 Hz, 1H), 8.92 (s, 1H); 13C NMR δC 105.9, 116.2, 134.1,
142.5, 147.8, 148.1, 152.3; MS (EI) m/z 120 ([M]þ, 100), 92 (19),
65 (28).
f. 2-Bromofuro[2,3-c]pyridine (2f). The product was prepared
according to the general method described herein with carbone
tetrabromide (CBr4) (1062 mg, 3.2 mmol, 2.0 equiv) as electro-
phile, for 1 h at -95 °C. Purification by centrifugal thin-layer
chromatography was performed with hexane/AcOEt 10/0 to 7/3
as eluent and led to the expected derivative 2f (238 mg, 75%) as a
brown solid; this derivative is particularly unstable and should
be used within few minutes after purification. An analytical
sample gave the following data: 1H NMR δH 6.78 (s, 1H), 7.47
(d, J = 5.2 Hz, 1H), 8.41 (d, J = 5.2 Hz, 1H), 8.82 (s, 1H); 13
C
NMR δC 107.9, 114.9, 132.9, 133.5, 143.0; IR (KBr) ν 1253; MS
(EI) m/z 199 ([Mþ2]þ, 95), 197 ([M]þ, 100), 118 (12), 90 (78), 63
(83); ESI-HRMS calcd for C7H5BrNO (M þ H)þ 197.9549,
found 197.9556.
g. 2-Tri-n-butylstannylfuro[2,3-c]pyridine (2g). The product
was prepared according to the general method described herein
with chlorotri-n-butyltin (1042 mg, 3.2 mmol, 2.0 equiv) as
electrophile, for 15 min at -95 °C. Purification by centrifugal
thin-layer chromatography was performed with hexane/AcOEt
10/0 to 8/2 as eluent and led to the expected derivative 2g (522
mg, 80%) as a colorless liquid: 1H NMR δH 0.91 (t, J=7.3 Hz,
9H), 1.16-1.24 (m, 6H), 1.30-1.43 (m, 6H), 1.54-1.67 (m, 6H),
6.91 (s, 1H), 7.49 (d, J=5.2 Hz, 1H), 8.35 (d, J =5.2 Hz, 1H),
8.87 (s, 1H); 13C NMR δC 10.5, 13.8, 27.3, 29.0, 115.2, 117.1,
133.5, 134.6, 141.7, 171.2; IR (NaCl) ν 3000-2800, 1255; MS (EI
and CI) m/z 352 ([M - C4H9]þ, 100), 296 (54), 238 (95), 120 (39);
ESI-HRMS calcd for C19H32NOSn (M þ H)þ 410.1504, found
410.1508.
h. 2,20-Bifuro[2,3-c]pyridine (2h). To a suspension of PdCl2-
(PPh3)2 (18 mg, 0.025 mmol, 5 mol %) under argon atmosphere
in DMF (2 mL) were added the 2-tri-n-butylstannylfuro[2,3-
c]pyridine 2g (224 mg, 0.55 mmol, 1.1 equiv) and the 2-bromo-
furo[2,3-c]pyridine 2f (99 mg, 0.50 mmol, 1.0 equiv) in DMF
(1 mL). After being stirred at 110 °C for 5 h, the reaction medium
was diluted in CH2Cl2 (20 mL) and filtrated on Celite. Purifica-
tion by centrifugal thin-layer chromatography was performed
with hexane/AcOEt 7/3 to 0/10 as eluent and led to the expected
derivative 2h (93 mg, 79%) as an orange powder. Derivative 2h
presents a very low solubility in most solvents: mp >240 °C; 1H
NMR δH 7.32 (s, 1H), 7.64 (d, J=5.3 Hz, 1H), 8.51 (d, J=5.3
Hz, 1H), 8.99 (s, 1H); 13C NMR δC 104.8, 116.5, 134.5, 134.7,
143.6, 149.5, 152.6; IR (KBr) ν 1263; MS (EI) m/z 236 ([M]þ,
100), 207 (7), 179 (7), 153 (15), 118 (10), 63 (17); ESI-HRMS
calcd for C14H9N2O2 (M þH)þ 237.0659, found 237.0661.
Preparation of 7-Substituted Furo[2,3-c]pyridine (4b,c). a. 7-
Deuteriofuro[2,3-c]pyridine (4b). To a solution of 7-deuterio-
2-trimethylsilylfuro[2,3-c]pyridine 5f (181 mg, 0.94 mmol, 1.0
equiv) in a mixture of THF/H2O (5 mL/1 mL) was added
tetrabutyl ammonium fluoride (1 mL, 1 M in THF, 1.00 mmol,
1.1 equiv) at 0 °C. After 24 h of stirring at room temperature
H2O (5 mL) was added. The aqueous layer was then extracted
twice with AcOEt (5 mL). The combined organic layers were
washed with an aqueous saturated NaHCO3 solution (10 mL).
After drying (MgSO4), filtration, and solvent evaporation, the
crude product was purified by centrifugal thin-layer chroma-
tography with hexane/AcOEt 7/3 to 5/5 as eluent and led to
the expected derivative 4b (101 mg, 89%) as an orange liquid:
1H NMR δH 6.78 (d, J=0.8 Hz, 1H), 7.52 (dd, J=5.2 Hz, J0 =
1.1 Hz, 1H), 7.72 (d, J=0.8 Hz, 1H), 8.39 (dd, J=5.2 Hz, J0 =
1.1 Hz, 1H); 13C NMR δC 105.7, 115.8, 133.3, 133.6, 142.0,
c. 2-Chlorofuro[2,3-c]pyridine (2c). The product was prepared
according to the general method described herein with hexa-
chloroethane (758 mg, 3.2 mmol, 2.0 equiv) as electrophile, for
1 h at -95 °C. Purification by centrifugal thin-layer chromato-
graphy was performed with hexane/AcOEt 10/0 to 7/3 as eluent
and led to the expected derivative 2c (174 mg, 71%) as an orange
1
solid: mp, H NMR, IR, and MS are in conformity with lite-
rature;55 13C NMR δC 102.9, 115.2, 133.0, 135.0, 143.3, 146.0,
151.6.
d. Furo[2,3-c]pyridin-2-ylphenylmethanol (2d). The product
was prepared according to the general method described herein
with benzaldehyde (339 mg, 3.2 mmol, 2.0 equiv) as electrophile,
for 1 h at -78 °C. Purification by centrifugal thin-layer chro-
matography was performed with hexane/AcOEt 5/5 to 0/10 as
eluent and led to the expected derivative 2d (292 mg, 81%) as a
beige solid: mp 110-113 °C; 1H NMR δH 4.50 (br s, 1H), 5.97 (s,
1H), 6.61 (s, 1H), 7.34-7.53 (m, 6H), 8.25 (d, J = 4.8 Hz, 1H),
8.64 (s, 1H); 13C NMR δC 70.6, 102.9, 116.1, 127.0, 128.7, 128.9,
133.5, 135.0, 140.3, 142.3, 152.4, 163.3; IR (KBr) ν 3400-2900,
1258; MS (EI) m/z 225 ([M]þ, 73), 208 (68), 148 (37), 105 (100),
77 (61); ESI-HRMS calcd for C14H12NO2 (M þ H)þ 226.0863,
found 226.0868.
e. 2-Methylthiofuro[2,3-c]pyridine (2e). The product was pre-
pared according to the general method described herein with
dimethyl disulfide (301 mg, 3.2 mmol, 2.0 equiv) as electrophile,
for 1 h at -78 °C. Purification by centrifugal thin-layer chro-
(55) Shiotani, S.; Taniguchi, K. J. Heterocycl. Chem. 1997, 34, 925–929.
J. Org. Chem. Vol. 75, No. 7, 2010 2233

Chartoire et al.
JOCArticle
147.8, 151.8; IR (NaCl) ν 1269; MS (EI) m/z 120 ([M]þ, 100), 92
(19), 64 (22).
δC -1.7, 12.1, 112.2, 115.4, 132.7, 141.8, 143.4, 152.6, 167.3; IR
(NaCl) ν 1253; MS (EI) m/z 237 ([M]þ, 100), 204 (21), 192 (33),
176 (17), 103 (11), 73 (16); ESI-HRMS calcd for C11H16NOSSi
(M þ H)þ 238.0716, found 238.0710.
b. 7-Chlorofuro[2,3-c]pyridine (4c). To a solution of 7-chloro-
2-trimethylsilylfuro[2,3-c]pyridine 5e (212 mg, 0.94 mmol, 1.0
equiv) in a mixture of THF/H2O (5 mL/1 mL) was added tetra-
butyl ammonium fluoride (1 mL, 1 M in THF, 1.00 mmol, 1.1
equiv) at 0 °C. After 24 h of stirring at room temperature H2O
(5 mL) was added. The aqueous layer was then extracted twice
with AcOEt (5 mL). The combined organic layers were washed
with an aqueous saturated NaHCO3 solution (10 mL). After
drying (MgSO4), filtration, and solvent evaporation, the crude
product was purified by centrifugal thin-layer chromatography
with hexane/AcOEt 9/1 to 8/2 as eluent and led to the expected
d. 7-Tri-n-butylstannyl-2-trimethylsilylfuro[2,3-c]pyridine (5h).
The product was prepared according to the general method
described herein with chlorotri-n-butyltin (1300 mg, 4.00 mmol,
3.0 equiv) as electrophile. Purification was performed with Kugel-
rohr distillation and led to the expected derivative 5h (473 mg,
74%) as an orange liquid: 1H NMR δH 0.37 (s, 9H), 0.82-0.90 (m,
9H), 1.21-1.47 (m, 12H), 1.52-1.69 (m, 6H), 6.92 (s, 1H), 7.36 (d,
J=5.1 Hz, 1H), 8.53 (d, J=5.1 Hz, 1H); 13C NMR δC -1.9, 10.2,
13.8, 27.4, 29.2, 114.1, 115.0, 130.0, 143.5, 156.6, 162.2, 166.7; IR
(NaCl) ν3000-2800, 1253; MS (EI) m/z482([Mþ1]þ,8), 424(36),
364 (11), 310 (100), 192 (25), 73 (22); ESI-HRMS calcd for
C22H40NOSiSn (Mþ H)þ 482.1899, found 482.1887.
1
derivative 4c (123 mg, 85%) as a white powder: mp and H
NMR, are in conformity with literature;55 13C NMR δC 107.1,
115.9, 134.3, 135.8, 142.0, 147.9, 148.6; IR (KBr) ν 1285; MS (EI)
m/z 155 ([Mþ2]þ, 33), 153 ([M]þ, 100), 118 (64), 90 (19), 63 (39).
General Procedure for the Preparation of [n-BuLi/LiDMAE]
Superbase. To a solution of DMAE (712 mg, 8.0 mmol, 1.0
equiv) in anhydrous hexane or toluene (14 mL) at -5 °C was
added dropwise n-BuLi (10 mL, 1.6 M in hexanes, 16.0 mmol,
2.0 equiv) under argon atmosphere. After 15 min at 0 °C,
[n-BuLi/LiDMAE] superbase is ready to be used.
e. Phenyl(2-trimethylsilylfuro[2,3-c]pyridin-7-yl)methanol (5i).
The product was prepared according to the general method
described herein with benzaldehyde (424 mg, 4.00 mmol, 3.0 equiv)
as electrophile. Purification by centrifugal thin-layer chromatogra-
phy was performed with hexane/AcOEt: 9/1 to 7/3 as eluent and led
to the expected derivative 5i (237 mg, 60%) as a white solid: mp
1
69-72 °C; H NMR δH 0.31 (s, 9H), 6.22 (s, 1H), 6.90 (s, 1H),
7.20-7.60 (m, 6H), 8.30 (d, J=5.1 Hz, 1H); 13C NMR δC -2.0,
71.3, 115.0, 115.6, 127.0, 127.6, 128.2, 135.1, 140.1, 142.7, 145.0,
151.3, 168.1; IR (KBr) ν 3412, 1253; MS (EI) m/z 297 ([M]þ, 100),
220 (100), 191 (61), 176 (18), 73 (30); ESI-HRMS calcd for
C17H20NO2Si (M þH)þ 298.1258, found 298.1247.
General Procedure for the Preparation of 2,7-Disubstituted
Furo[2,3-c]pyridines (5e-i). To a solution of [n-BuLi/LiDMAE]
(12 mL, 4.00 mmol, 3.0 equiv) prepared as described herein in
hexane was added dropwise a solution of 2-trimethylsilylfuro-
[2,3-c]pyridine 2a (254 mg, 1.33 mmol, 1.0 equiv) in anhydrous
hexane (3 mL) at -45 °C, under argon atmosphere. After the
mixture was stirred for 1 h at -45 °C, the appropriate electro-
phile (4.00 mmol, 3.0 equiv) was added in THF (5 mL) at -78 °C.
After 1 h of stirring at -78 °C, the hydrolysis was performed with
H2O (10 mL) at the desired trapping temperature. The aqueous
layer was then extracted twice with AcOEt (10 mL). The combined
organic layers were washed with an aqueous saturated NaHCO3
solution (20 mL). After drying (MgSO4), filtration, and solvent
evaporation, the crude product was purified by centrifugal thin-
layer chromatography.
a. 7-Chloro-2-trimethylsilylfuro[2,3-c]pyridine (5e). The pro-
duct was prepared according to the general method described
herein with hexachloroethane (948 mg, 4.00 mmol, 3.0 equiv) as
electrophile. Purification by centrifugal thin-layer chromato-
graphy was performed with hexane/AcOEt 10/0 to 8/2 as eluent
and led to the expected derivative 5e (255 mg, 85%) as a yellow
liquid: 1H NMR δH 0.40 (s, 9H), 7.00 (s, 1H), 7.44 (d, J=5.2 Hz,
1H), 8.14 (d, J=5.2 Hz, 1H); 13C NMR δC -1.9, 115.5, 115.8,
134.3, 136.4, 141.5, 150.9, 169.4; IR (NaCl) ν 1253; MS (EI) m/z
225 ([M]þ, 51), 210 (100), 174 (77), 93 (18), 63 (21); ESI-HRMS
calcd for C10H13ClNOSi (M þH)þ 226.0449, found 226.0453.
b. 7-Deuterio-2-trimethylsilylfuro[2,3-c]pyridine (5f). The pro-
duct was prepared according to the general method described
herein with deuterium chloride 35 wt % in deuterium oxide (2.19
mL, 26.60 mmol, 20.0 equiv) as electrophile. Purification by
centrifugal thin-layer chromatography was performed with
hexane/AcOEt 9/1 to 7/3 as eluent and led to the expected
derivative 5f (204 mg, 80%) as an orange liquid: 1H NMR
General Procedure for the Preparation of 7,70-Bifuro[2,3-c]-
pyridines (7 and 8). To a blue stirred solution of NiCl2 6H2O
3
(238 mg, 1.0 mmol, 1.0 equiv) and PPh3 (1048 mg, 4.0 mmol, 4.0
equiv) in DMF (5 mL) at 50 °C was added activated zinc powder
(65 mg, 1.0 mmol, 1.0 equiv). Then the mixture was stirred
during 1 h at 50 °C and the color changed to become red-brown
before addition of furo[2,3-c]pyridine derivatives 5e or 4c (1.0
mmol, 1.0 equiv). The mixture was then stirred for 3 h at 50 °C.
After cooling at room temperature, mixture was treated with
NH4OH 40% solution (5 mL), then the aqueous layer was then
extracted twice with AcOEt (10 mL). After drying (MgSO4),
filtration, and solvent evaporation, the crude product was
quickly filtrated on a pad of silica gel before purification by
centrifugal thin-layer chromatography.
a. 2,20-Bistrimethylsilyl-7,70-bifuro[2,3-c]pyridine (7). The
product was prepared according to the general method des-
cribed herein starting from 7-chloro-2-trimethylsilylfuro[2,3-c]-
pyridine 5e (225 mg, 1.0 mmol, 1.0 equiv). Purification by centri-
fugal thin-layer chromatography was performed with CH2Cl2/
MeOH 98/2 as eluent and led to the expected bifuro[2,3-c]pyri-
dinyl derivative 7 (144 mg, 76%) as a beige powder: mp 121-
1
123 °C; H NMR δH 0.32 (s, 18H), 7.07 (s, 2H), 7.63 (d, J =
5.2 Hz, 2H), 8.61 (d, J=5.2 Hz, 2H); 13C NMR δC -1.6, 115.3,
116.4, 136.0, 139.5, 142.1, 153.6, 168.4; IR (KBr) ν 1253; MS
(EI) m/z 380 ([M]þ, 92), 365 (100), 175 (35), 73 (39); ESI-HRMS
calcd for C20H25N2O2Si2 (M þH)þ 381.1449, found 381.1445.
b. 7,70-Bifuro[2,3-c]pyridine (8). The product was prepared
according to the general method described herein starting from
7-chlorofuro[2,3-c]pyridine 4c (154 mg, 1.0 mmol, 1.0 equiv).
Purification by centrifugal thin-layer chromatography was per-
formed with CH2Cl2/MeOH 99/1 to 98/2 as eluent and led to the
expected bifuro[2,3-c]pyridinyl derivative 8 (88 mg, 74%) as a
δ
H 0.37 (s, 9H), 6.95 (s, 1H), 7.49 (d, J=5.2 Hz, 1H), 8.36 (d, J=
5.2 Hz, 1H); 13C NMR δC -1.9, 115.0, 115.8, 133.7, 134.4, 141.9,
155.2, 168.1; IR (NaCl) ν 1253; MS (EI) m/z 192 ([M]þ, 49), 177
(100), 83 (8).
1
white powder: mp, H NMR, and IR are in conformity with
c. 7-Methylthio-2-trimethylsilylfuro[2,3-c]pyridine (5g). The
product was prepared according to the general method des-
cribed herein with dimethyl disulfide (376 mg, 4.00 mmol, 3.0
equiv) as electrophile. Purification by centrifugal thin-layer
chromatography was performed with hexane/AcOEt 10/0 to
9/1 as eluent and led to the expected derivative 5g (230 mg, 73%)
as a yellow oil: 1H NMR δH 0.38 (s, 9H), 2.72 (s, 3H), 6.93 (s,
1H), 7.23 (d, J=5.2 Hz, 1H), 8.23 (d, J=5.2 Hz, 1H); 13C NMR
literature;56 13C NMR δC 106.1, 117.0, 135.8, 139.8, 142.2,
148.7, 150.4; MS (EI) m/z 236 ([M]þ, 100), 210 (25), 63 (23).
Preparation of 2,5,7-Trisubstituted Furo[2,3-c]pyridines
(9a-d). a. 5,7-Dichloro-2-trimethylsilylfuro[2,3-c]pyridine (9a).
To a solution of [n-BuLi/LiDMAE] (8 mL, 2.66 mmol, 4.0 equiv)
(56) Shiotani, S.; Taniguchi, K. J. Heterocycl. Chem. 1997, 34, 493–499.
2234 J. Org. Chem. Vol. 75, No. 7, 2010

Chartoire et al.
JOCArticle
prepared as described herein in hexane was added dropwise a
solution of 7-chloro-2-trimethylsilylfuro[2,3-c]pyridine 5e (150 mg,
0.66 mmol, 1.0 equiv) in anhydrous hexane (3 mL) at -45 °C, under
argon atmosphere. After the mixture was stirred for 1 h at -45 °C,
hexachloroethane (630 mg, 2.66 mmol, 4.0 equiv) was added as
the electrophile, in THF (3 mL) at -78 °C. After 1 h of stirring at
-78 °C the temperature was allowed to warm to room temperature
for 1 h, and the hydrolysis was performed with H2O (10 mL). 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 hexane/AcOEt 10/0 to 95/5 as eluent and led to the expected
After drying (MgSO4), filtration, and solvent evaporation, the
crude product was purified by centrifugal thin-layer chroma-
tography with cyclohexane/Et2O 10/0 to 9/1 as eluent and led to
the expected derivative 9c (70 mg, 39%) as a white powder: mp
46-49 °C; 1H NMR δH 0.38 (s, 9H), 2.59 (s, 3H), 6.86 (s, 1H),
7.27 (s, 1H); 13C NMR δC -1.9, 15.0, 112.1, 115.1, 133.0, 137.7,
149.1, 151.1, 170.3; IR (KBr) ν 1253; MS (EI) m/z 271 ([M]þ,
100), 238 (39), 225 (14), 93 (22), 73 (47); ESI-HRMS calcd for
C11H14ClNNaOSSi (M þNa)þ 294.0146, found 294.0148.
d. 5-Chloro-7-methylthio-2-trimethylsilylfuro[2,3-c]pyridine
(9d). To a solution of [n-BuLi/LiDMAE] (6 mL, 2.00 mmol,
3.0 equiv) prepared as described herein in hexane was added
dropwise a solution of 7-methylthio-2-trimethylsilylfuro[2,3-
c]pyridine 5g (158 mg, 0.66 mmol, 1.0 equiv) in anhydrous
hexane (3 mL) at -45 °C, under argon atmosphere. After 1 h
of stirring at -45 °C, hexachloroethane (474 mg, 2.00 mmol, 3.0
equiv) was added as the electrophile, in THF (3 mL) at -78 °C.
After 1 h of stirring at -78 °C the hydrolysis was performed with
H2O (10 mL). 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/Et2O 10/0 to 9/1 as
eluent and led to the expected derivative 9d (29 mg, 16%) as a
colorless oil: 1H NMR δH 0.38 (s, 9H), 2.70 (s, 3H), 6.86 (s, 1H),
7.20 (s, 1H); 13C NMR δC -1.8, 12.4, 111.2, 115.0, 135.8, 142.7,
143.3, 151.7, 169.6; IR (NaCl) ν 1253; MS (EI) m/z 271
([M]þ, 100), 256 (12), 238 (21), 226 (30), 120 (12), 73 (37); ESI-
HRMS calcd for C11H15ClNOSSi (M þ H)þ 272.0327, found
272.0334.
1
derivative 9a (138 mg, 80%) as a white solid: mp 56-58 °C; H
NMR δH 0.40 (s, 9H), 6.95 (s, 1H), 7.42 (s, 1H); 13CNMR δC -2.0,
115.0, 115.3, 132.4, 139.2, 141.5, 150.4, 172.0; IR (KBr) ν 1253; MS
(EI) m/z 259 ([M]þ, 44), 244 (100), 208 (55), 93 (19); ESI-HRMS
calcd for C10H12Cl2NOSi (Mþ H)þ 260.0060, found 260.0066.
b. 7-Chloro-5-deuterio-2-trimethylsilylfuro[2,3-c]pyridine (9b).
To a solution of [n-BuLi/LiDMAE] (6 mL, 2.00 mmol, 3.0 equiv)
prepared as described herein in hexane was added dropwise
a solution of 7-chloro-2-trimethylsilylfuro[2,3-c]pyridine 5e
(150 mg, 0.66 mmol, 1.0 equiv) in anhydrous hexane (3 mL) at
-45 °C, under argon atmosphere. After 1 h of stirring at -45 °C,
deuterium chloride 35 wt % in deuterium oxide (1.1 mL, 13.20
mmol, 20.0 equiv) was added as the electrophile, in THF (5 mL)
at -78 °C. After 1 h of stirring from -78 °C to room tempera-
ture, the hydrolysis was performed with H2O (10 mL). The
aqueous layer was then saturated with NaHCO3 and extracted
twice with AcOEt (10 mL). After drying (MgSO4), filtration,
and solvent evaporation, the crude product was purified by
centrifugal thin-layer chromatography with hexane/AcOEt 10/0
to 8/2 as eluent and led to the expected derivative 9b (87 mg,
58%) as a colorless liquid: 1H NMR δH 0.38 (s, 9H), 6.99 (s, 1H),
7.42 (s, 1H); 13C NMR δC -1.9, 115.4, 115.8, 134.2, 136.3, 141.1,
150.8, 169.3; MS (EI) m/z 226 ([M]þ, 66), 211 (100), 175 (54).
c. 7-Chloro-5-methylthio-2-trimethylsilylfuro[2,3-c]pyridine (9c).
To a solution of [n-BuLi/LiDMAE] (6 mL, 2.00 mmol, 3.0
equiv) prepared as described herein in hexane was added drop-
wise a solution of 7-chloro-2-trimethylsilylfuro[2,3-c]pyridine
5e (150 mg, 0.66 mmol, 1.0 equiv) in anhydrous hexane (3 mL) at
-45 °C, under argon atmosphere. After 1 h of stirring at -45 °C,
dimethyl disulfide (188 mg, 2.00 mmol, 3.0 equiv.) was added as
the electrophile, in THF (3 mL) at -78 °C. After 1 h of stiring at
-78 °C the hydrolysis was performed with H2O (10 mL). The
aqueous layer was then extracted twice with AcOEt (10 mL).
Acknowledgment. We gratefully acknowledge financial
ꢁ
support from CNRS and Nancy-Universite, UHP. We thank
Sandrine Adach and Brigitte Fernette for recording mass
spectra and NMR spectra and Charles Despres for English
assistance.
Note Added after ASAP Publication. Schemes 2 and 6 con-
tained errors in the version published ASAP March 1, 2010; the
correct version posted on the web March 3, 2010.
Supporting Information Available: Procedure for the synth-
esis of 1, spectroscopic data for 3, 5b, 5c, and 5d, and NMR
spectra of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 7, 2010 2235