Deprotonation of furans using lithium magnesates

Article abstract of DOI:10.1016/j.tetlet.2005.09.066

Furan was deprotonated on treatment with 1/3 equiv of Bu₃MgLi in THF at rt. The lithium arylmagnesate formed was either trapped with electrophiles or involved in a palladium-catalyzed cross-coupling reaction with 2-bromopyridine. The highly coordinated magnesate Bu₄MgLi₂ (1/3 equiv) proved to be a better deprotonating agent than Bu₃MgLi; the monitoring of the reaction using NMR spectroscopy showed that the deprotonation of furan at rt required 2 h whereas the subsequent electrophilic trapping was instantaneous. The method was extended to benzofuran, allowing its functionalization at C2 in high yields. The deprotonation of 2-methylfuran and lithium furfurylalkoxide at C5 turned out to be difficult, requiring either long reaction times or higher temperatures.

Full text of DOI:10.1016/j.tetlet.2005.09.066

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7989–7992
Deprotonation of furans using lithium magnesates
a
a
b
Florence Mongin,a, Aurelien Bucher, Jean Pierre Bazureau, Omar Bayh,
*
´
b
b
´
Hac¸an Awad and Franc¸ois Trecourt
a
` ` ˆ
´
Synthese & ElectroSynthese Organiques, UMR CNRS 6510, Batiment 10A, Universite de Rennes 1, Campus de Beaulieu,
Avenue du Ge´ne´ral Leclerc, 35042 Rennes Cedex, France
bLaboratoire de Chimie Organique Fine et He´te´rocyclique, UMR CNRS 6014, IRCOF, Universite´ et INSA de Rouen,
Place E. Blondel, BP 08, 76131 Mont-Saint-Aignan Cedex, France
Received 18 August 2005; revised 11 September 2005; accepted 13 September 2005
Available online 26 September 2005
Abstract—Furan was deprotonated on treatment with 1/3 equiv of Bu3MgLi in THF at rt. The lithium arylmagnesate formed was
either trapped with electrophiles or involved in a palladium-catalyzed cross-coupling reaction with 2-bromopyridine. The highly
coordinated magnesate Bu4MgLi2 (1/3 equiv) proved to be a better deprotonating agent than Bu3MgLi; the monitoring of the reac-
tion using NMR spectroscopy showed that the deprotonation of furan at rt required 2 h whereas the subsequent electrophilic trap-
ping was instantaneous. The method was extended to benzofuran, allowing its functionalization at C2 in high yields. The
deprotonation of 2-methylfuran and lithium furfurylalkoxide at C5 turned out to be difficult, requiring either long reaction times
or higher temperatures.
Ó 2005 Elsevier Ltd. All rights reserved.
We describe the first magnesates in the furan series.
magnesium halides and dialkylmagnesiums rarely
deprotonate such substrates because of easier 1,4-addi-
tion reactions.7 More recently, Kondo and Sakamoto
described the regioselective magnesiation of N-substi-
tuted indoles,8 thiophenes,9 and thiazole9 using DA2Mg,
DAMgBr, and DAMgCl. Nevertheless, because of the
limited reactivity of these bases, an excess has in general
to be used to ensure good yields. Pyrrole rings of numer-
ous 1-phenyldipyrromethanes did not require protection
step to be deprotonated at the position adjacent to the
nitrogen atom using EtMgBr.10
The preparation of heteroaromatic structures is an
important synthetic goal because of the multiple applica-
tions of these molecules.1 Deprotonation reaction using
lithiated bases has been developed as one of the major
tools to functionalize heterocycles.2 Nevertheless, this
methodology often requires low temperatures, which
can be difficult to realize on an industrial scale. In addi-
tion, unlike organoboron, organotin, organozinc, and
organomagnesium compounds, organolithiums can
hardly be directly involved in cross-coupling reactions.3
In 1999, Kondo achieved the deprotonation of pyridine
and its bromo derivatives, quinoline, isoquinoline, and
ethyl thiophenecarboxylates through the formation of
an arylzincate using lithium di-tert-butyl(2,2,6,6-tetra-
methylpiperidino)zincate as a base.11
Deprotonation reactions of heterocycles using magnesi-
ated bases4 have been less extensively explored. The pio-
neering work of Marxer and Siegrist in 1974 showed
that EtMgBr was capable of deprotonating 1-phenyl-
pyrazole at the ortho position of the phenyl ring.5
Schlecker reported in 1995 the regioselective magnesia-
tion of pyridine carboxamides and carbamates with
Hauser bases (DAMgBr, DA = diisopropylamino, or
TMPMgBr, TMP = 2,2,6,6-tetramethylpiperidino) or
magnesium diamides (DA2Mg or TMP2Mg);6 alkyl-
Due to a more covalent carbon–metal bond, organozinc
derivatives are less reactive than organomagnesium
compounds.12 Since zincates ꢀsoftlyꢁ react with electro-
philes,13 we have therefore been interested in the synthe-
sis of ꢀharderꢁ arylmagnesates14 using deprotonation
reactions. Since 1999, Mulvey has documented the
preparation of mixed-metal sodium–magnesium or
potassium–magnesium amides for the site selective
deprotonation of benzene,15 toluene,16 ferrocene,17
Keywords: Deprotonation; Ate complexes; Magnesium; Furan.
*
Corresponding author. Tel.: +33 (0) 2 23 23 69 31; fax: +33 (0) 2 23
23 63 74; e-mail: florence.mongin@univ-rennes1.fr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.066

7990
F. Mongin et al. / Tetrahedron Letters 46 (2005) 7989–7992
1) 1/3 equiv Bu3MgLi
1) 1/3 equiv Bu3MgLi
THF, rt, 2 h
N
THF, rt, 2 h
O
El
2) Electrophile, rt
3) H2O
O
O
O
2) 2-Bromopyridine
PdCl2(dppf) 1 mol.%
reflux, 18 h
1
2
1
3: 64%
2a: El = I, 75%
3) H2O
2b: El = CH(OH)-3,4,5-
trimethoxyphenyl, 71%
Scheme 1.
ruthenocene,18 osmocene,18 and bis(benzene)chro-
mium.19 Richey observed in 2004 that treating benzene
halides with magnesates partially results in benzyne
formation,20 also showing magnesates are capable of
abstracting aromatic protons. At the same time, we
studied the deprotonation of fluoro aromatics,21 chloro-
pyridines,22 thiophenes,23 and oxazoles24 using easily
available lithium magnesates, the obtained arylmagne-
sates being either trapped with electrophiles or involved
in palladium-catalyzed cross-couplings.
1) 1/3 equiv Bu4MgLi2
THF, rt, 2 h
El
2) Electrophile, rt
3) H2O
O
O
1
2
2a: El = I, 90%
2b: El = CH(OH)-3,4,5-
trimethoxyphenyl, 85%
2c: El = C(OH)Ph2, 65%
2d: El = PPh2, 77%
Scheme 2.
Herein, we describe the first deprotonation reactions of
furans using magnesates, and the reactivity of the furan
magnesates toward electrophiles or in palladium-catal-
yzed cross-coupling reactions with aryl halides.
deprotonated in 15 min using 1/3 equiv of Bu3MgLiÆ
TMEDA23 in THF at rt, reactions involving furan
were attempted using Bu3MgLiÆTMEDA or Bu4MgLi2Æ
TMEDA, but without significant improvement. The
signals associated with the magnesiated furan instantly
decreased upon addition of 3,4,5-trimethoxybenzalde-
hyde (1 equiv) to the reaction mixture. Benzophenone
and chlorodiphenylphosphine were also successfully
used as electrophiles to give alcohol 2c and phosphine
2d in good yields (Scheme 2).
Furan (1) can be readily metalated in high yields at C2
by reaction with BuLi in refluxing diethyl ether for
4 h,25 but the use of this base, without26 or with27 TME-
DA, in tetrahydrofuran (THF) at temperatures between
ꢀ75 °C26 and room temperature (rt)27 is effective too.
The deprotonation of furan (1) was attempted using 1/3
equiv of lithium tributylmagnesate14 (Bu3MgLi) in
THF at rt. Addition to the reaction mixture of iodine
or 3,4,5-trimethoxybenzaldehyde after 2 h afforded
iodide 2a and alcohol 2b, respectively, in good yields.
The intermediate magnesate of furan was next involved
in cross-coupling with 2-bromopyridine under palla-
dium catalysis using 1,10-bis(diphenylphosphino)ferro-
cene (dppf) as ligand,23,28 to give biaryl compound 3
in 64% yield (Scheme 1).
These conditions were tested to metalate less activated
furans such as 2-methylfuran (4). Lithiation of 2-alkyl-
ated furans has been reported using BuLi in THF at
temperatures between ꢀ7831 and 0 °C.32 The reaction
of 2-methylfuran (4) with Bu4MgLi2 (1/3 equiv) in
THF was monitored as before (the signals at 6.0 and
6.7 ppm were attributed to the hydrogens at the 3 and
4 positions of the 5-magnesiated 2-methylfuran). It
was observed that the reaction was very slow at rt, with
metalated and non-metalated species in ratios of 60:40,
70:30, and 75:25, after 2, 4, and 30 h, respectively. Heat-
ing the reaction mixture at reflux for 1 h resulted in a
85:15 ratio while quenching with ClPPh2 afforded phos-
phine 5 in 39% yield (Scheme 3).
Since dilithium tetramethylzincate exhibits a higher
reactivity than lithium trimethylzincate in various reac-
tions including halogen–metal exchange,13 Bu3MgLi
(1/3 equiv) and dilithium tetrabutylmagnesate (Bu4-
MgLi2, 1/3 equiv)29 were compared as deprotonating
agents. The highly coordinated lithium magnesate
proved to be the most efficient base: trapping the reac-
tion mixture by iodine or 3,4,5-trimethoxybenzaldehyde
after 2 h furnished iodide 2a and alcohol 2b in 90% and
85% yields, respectively, against 75% and 72% using
Bu3MgLi.
Ring deprotonation of furfuryl alcohol (6) was studied
next. 4-(2-Furyl)butan-1-ol being dideprotonated by
using simply 2 equiv of the chelate BuLi–TMEDA in
diethyl ether at rt for 1 h,33 the use of 1/2 equiv of
Bu4MgLi2 was first attempted, but without success.
Since lithium alkoxides hardly react with diorganomag-
The reaction using Bu4MgLi2 was monitored by record-
1
ing H NMR spectra of the reaction mixture.30 The
1) 1/3 equiv Bu4MgLi2
THF, reflux, 1 h
increasing of signals at 7.81 (d), 6.62 (d), and 6.37 (dd)
ppm attributed to the hydrogens at the 5, 3, and 4
positions of the magnesiated furan, respectively, showed
that furan was slowly deprotonated to reach a 95%
conversion after 1.5 h. Thiophene being completely
PPh2
2) ClPPh2, rt
3) H2O
O
O
4
5, 39%
Scheme 3.

F. Mongin et al. / Tetrahedron Letters 46 (2005) 7989–7992
7991
2-
O
-
THF
Bu
Bu
LiO
Bu
Bu
O
Mg
O
+
+
+
1/2
1/2
1/2
Li
2 Li
O
Mg
O
O
O
THF
Bu
Bu
LiO
+
1/2
Mg
O
Scheme 4.
nesiums in chelating/polar solvents,34 one can imagine
that dilithium dibutyldi(furfurylalkoxo)magnesate, if
formed after the alcohol function deprotonation, rapidly
evolves toward lithium furfurylalkoxide and dibutyl-
magnesium, the latter being unable to deprotonate the
furan ring (Scheme 4).
the conditions optimized for furan, iodide 9a, alcohols
9b, and 9c, and phosphine 9d were provided in high
yields, ranging from 85% to 89%. Even if cross-cou-
plings using dilithium tetra(2-furyl)zincates have been
reported to proceed in slightly lower yields than
those using lithium tri(2-furyl)zincates,39 we attempted
reactions of the higher order benzofuran magnesate,
Bu(2-benzofuryl)3MgLi2,40 with aromatic halides under
palladium catalysis. The use of PdCl2(dppf)23,28 at
THF reflux allowed the reactions with iodobenzene
and 2-bromopyridine to produce compounds 10a and
10b in 66% and 58% yields, respectively (Scheme 6).
It was thus decided to attempt the deprotonation of the
lithium salt of 6 using 1/3 equiv of Bu4MgLi2 in THF at
rt. After 2 h, the reaction mixture was quenched with
heavy water to give the deuterated compound 7 in a
moderate yield (Scheme 5).
Since lithium magnesates did not prove to be efficient
enough for the deprotonation of 2-methylfuran and lith-
ium furfurylalkoxide, we attempted to deprotonate
more activated ethyl 2-furoate or ethyl 2-thiophenecarb-
oxylate using Bu4MgLi2 (1/3 equiv), Bu3MgLi (1/3
equiv) or else less nucleophilic DA3MgLi35 (1/3 equiv),
but without success.36 These failures could be due to
the presence of the ester function.
In conclusion, Bu4MgLi2 proved to be more efficient
than Bu3MgLi for the deprotonation of furan in THF
at rt. It was shown using NMR spectroscopy that the
deprotonation step required 2 h whereas the subsequent
trapping with electrophiles was instantaneous. The
method was very nicely transposed to benzofuran, giv-
ing 2-functionalized derivatives in high yields. Lithium
magnesates were not efficient enough for the deprotona-
tion of less activated 2-methylfuran and furfuryl alco-
hol; the long reaction times or reflux required in this
case are of limited scope.
The reaction was next extended to benzofuran (8). The
latter is usually deprotonated in THF at ꢀ78 °C using
either lithium dialkylamides37 or alkyllithiums.38 Under
Lithium magnesates are suitable for hydrogen–magne-
sium exchange reactions on furan and benzofuran
at rt, whereas the corresponding hydrogen–lithium
exchanges have sometimes to be performed at lower tem-
peratures. Unlike the corresponding lithio compounds,
the furan magnesium ate complexes here obtained are
enough stable to undergo cross-coupling reactions with-
out the need for conversion to organoboron, organotin,
or organozinc derivatives.
1) 1 equiv BuLi
HO
DO
THF, rt
D
O
O
2) 1/3 equiv
Bu4MgLi2
THF, rt, 2 h
3) D2O
6
7, 48%
Scheme 5.
9a: El = I, 85%
9b: El = CH(OH)-4-
chlorophenyl, 89%
9c: El = C(OH)Ph2, 87%
9d: El = PPh2, 85%
1) Electrophile, rt
2) H2O
El
O
O
Bu
MgLi2
1/3 equiv
Bu4MgLi2
O
9
1/3
O
THF, rt, 2 h
O
O
1) Iodobenzene or
2-Bromopyridine
8
10a (X = CH): 66%
10b (X = N): 58%
X
PdCl2(dppf)
1 mol.%
10
reflux, 18 h
2) H2O
Scheme 6.

7992
F. Mongin et al. / Tetrahedron Letters 46 (2005) 7989–7992
18. Andrikopoulos, P. C.; Armstrong, D. R.; Clegg, W.;
Acknowledgments
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OꢁHara, C. T.; Parkinson, J. A.; Tooke, D. M. J. Am.
Chem. Soc. 2004, 126, 11612–11620.
We thank Sylvain Declercq for his contribution to this
study.
19. Hevia, E.; Honeyman, G. W.; Kennedy, A. R.; Mulvey, R.
E.; Sherrington, D. C. Angew. Chem., Int. Ed. 2005, 44,
68–72.
20. Farkas, J., Jr.; Stoudt, S. J.; Hanawalt, E. M.; Pajerski,
A. D.; Richey, H. G. Organometallics 2004, 23, 423–
427.
Supplementary data
Experimental procedures and analyses of compounds
are furnished. Supplementary data associated with this
article can be found, in the online version, at
doi:10.1016/j.tetlet.2005.09.066.
´
´
21. Awad, H.; Mongin, F.; Trecourt, F.; Queguiner, G.;
Marsais, F.; Blanco, F.; Abarca, B.; Ballesteros, R.
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´
´
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40. Bu(2-benzofuryl)3MgLi2 is a medium structure since
Bu4MgLi2, Bu3(2-benzofuryl)MgLi2, Bu2(2-benzofuryl)2-
MgLi2, and (2-benzofuryl)4MgLi2 can also be present.