TMSCH2Li and TMSCH2Li-LiDMAE: Efficient reagents for noncryogenic halogen-lithium exchange in bromopyridines

Article abstract of DOI:10.1021/jo070620j

(Chemical Equation Presented) TMSCH₂Li and TMSCH ₂Li-LiDMAE have been used efficiently for bromine-lithium exchange in 2-bromo-, 3-bromo-, and 2,5-dibromopyridines under noncryogenic conditions, while low temperatures (-78 to -100°C) are always needed with n-BuLi. The aminoalkoxide LiDMAE induced a remarkable C-2 selectivity with 2,5-dibromopyridines in toluene at 0°C, which was unprecedented at such a temperature. The lithiopyridines were successfully reacted witb electrophiles also under noncryogenic conditions giving the expected adducts in good yields.

Full text of DOI:10.1021/jo070620j

SCHEME 1. Metal-Halogen Exchanges Reported in the
Literature
TMSCH2Li and TMSCH2Li-LiDMAE: Efficient
Reagents for Noncryogenic Halogen-Lithium
Exchange in Bromopyridines
Abdelatif Doudouh,† Christopher Woltermann,‡ and
Philippe C. Gros*,†
Synthe`se Organome´tallique et Re´actiVite´, UMR CNRS 7565,
Nancy UniVersite´, UniVersite´ Henri Poincare´, BouleVard des
Aiguillettes, 54506 VandoeuVre-le`s-Nancy, France, and FMC
Corporation, Lithium DiVision, Highway 161, Box 795,
Bessemer City, North Carolina 28016
philippe.gros@sor.uhp-nancy.fr
ReceiVed March 26, 2007
SCHEME 2. Metalation of Electrophilic Halogenopyridines
with TMSCH2Li-LiDMAE
or -78 °C), solvent (toluene), as well as dilution was needed
to avoid C-2 to C-5 isomerization and degradation (Scheme 1,
eq 2).
An alternative to this sensitive lithiation process has been
reported recently by Song,6 who realized the magnesium halogen
exchange at C-2 under noncryogenic conditions (0 °C) using
i-PrMgCl in THF. The reaction proceeded smoothly allowing
the preparation of a range of C-2-substituted derivatives.
However, since the magnesation of 2,5-dibromopyridine was
known to occur mainly at C-5,7 the authors had to exchange
bromine at C-2 for iodine to direct the reaction toward the
desired position, thus implying an additional step and added
expense to the transformation (Scheme 1, eq 3).
TMSCH2Li and TMSCH2Li-LiDMAE have been used
efficiently for bromine-lithium exchange in 2-bromo-,
3-bromo-, and 2,5-dibromopyridines under noncryogenic
conditions, while low temperatures (-78 to -100 °C) are
always needed with n-BuLi. The aminoalkoxide LiDMAE
induced a remarkable C-2 selectivity with 2,5-dibromopyr-
idines in toluene at 0 °C, which was unprecedented at such
a temperature. The lithiopyridines were successfully reacted
with electrophiles also under noncryogenic conditions giving
the expected adducts in good yields.
Thus, the search for new reagents able to promote the clean
bromine-lithium exchange in pyridines under easily applicable
conditions remains challenging.
Recently, we have reported a new lithiating agent TMSCH2-
Li-LiDMAE (with LiDMAE ) Me2N(CH2)2OLi)8-10 which
promoted the clean C-6 deprotonation of chloropyridines and
even of the highly sensitive fluoropyridines at 0 °C when used
in hexane (Scheme 2).8 This unprecedented reactivity contrasted
with those of our previous reagent BuLi-LiDMAE for which
low temperatures (-78 to -100 °C) were needed to prevent
concomitant nucleophilic addition.11
This high level of functional tolerance at 0 °C led us to
consider TMSCH2Li for the selective bromine-lithium ex-
change in 2,5-dibromopyridine under noncryogenic condi-
tions.
Metal-halogen exchange in 2,5-dibromopyridine 3 has been
the subject of much attention motivated by the usefulness of
this doubly reactive intermediate for the synthesis of ligands1,2
and biologically active compounds.3 First studies by Parham4
and further developments by other groups1,2 clearly established
that the C-5 position could be lithiated selectively with n-BuLi
in THF at -78 or -100 °C (Scheme 1, eq 1).
In contrast, Wang5 reported the control of the C-2 lithiation
to be more problematic. Due to the instability of 2-lithio-5-
bromopyridine, careful attention to reaction temperature (-50
† Universite´ Henri Poincare´.
(6) Song, J. J.; Yee, N. K.; Tan, Z.; Xu, J.; Kapadia, S. R.; Senanayake,
C. H. Org. Lett. 2004, 6, 4905.
(7) Trecourt, F.; Breton, G.; Bonnet, V.; Mongin, F.; Marsais, F.;
Queguiner, G. Tetrahedron Lett. 1999, 40, 4339.
(8) Doudouh, A.; Gros, P. C.; Fort, Y.; Woltermann, C. Tetrahedron
2006, 62, 6166.
‡ FMC Corporation.
(1) Bolm, C.; Ewald, M.; Felder, M.; Schlingloff, G. Chem. Ber. 1992,
125, 1169.
(2) Romero-Salguero, F. J.; Lehn, J.-M. Tetrahedron Lett. 1999, 40, 859.
(3) Nicolaou, K. C.; Sasmal, P. K.; Rassias, G.; Reddy, M. V.; Altmann,
K.-H.; Wartmann, M.; O’Brate, A.; Giannakakou, P. Angew. Chem., Int.
Ed. 2003, 42, 3515.
(9) Gros, P. C.; Doudouh, A.; Woltermann, C. Chem. Commun. 2006,
2673.
(4) Parham, W. E.; Piccirilli, R. M. J. Org. Chem. 1977, 42, 257.
(5) Wang, X.; Rabbat, P.; O’Shea, P.; Tillyer, R.; Grabowski, E. J. J.;
Reider, P. J. Tetrahedron Lett. 2000, 41, 4335.
(10) Gros, P. C.; Doudouh, A.; Woltermann, C. Org. Biomol. Chem.
2006, 4, 4331.
(11) Choppin, S.; Gros, P. C.; Fort, Y. Org. Lett. 2000, 2, 803.
10.1021/jo070620j CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/25/2007
4978
J. Org. Chem. 2007, 72, 4978-4980

TABLE 1. Bromine-Lithium Exchange in 1 and 2 with
TABLE 2. Metalation of 3 with TMSCH2Li-Based Reagentsa
TMSCH2Lia
TMSCH2Li LiDMAE
time
(h)
1b
2b
S.M.b
(%)
entry
(equiv)
(equiv)
solvent
(%) (%)
1
2
3
4
5
6
7
8
9
2
2
2
2
2
2
2
2
2
toluene
toluene
hexane
hexane
toluene
toluene
toluene
THF
1
2
2
2
0.5
1
2
0.5
0.5
29
22
5
15
4
38
24
80
84
95
94
92
23
14
<1
<1
<1
<1
1
1
1
1
5
7
TMSCH2Li (equiv)
substrate
electrophile
yieldb (%)
2
1.5
1
2
2
1
1
1
2
1
2
MeSSMe
MeSSMe
MeSSMe
MeSSMe
PhCHO
1a, 94c
1a, 70d
1a, 47d
2a, 88c
1b, 86c
2b, 88c
Et2O
65
10
a Reaction performed on 1.84 mmol of 3. b GC yields. S.M.: starting
material.
2
PhCHO
a Reaction performed on 1.84 mmol of 1 or 2. b Isolated yield. c The
SCHEME 4. Proposed Intermediate for Stabilization of
5-Bromo-2-lithiopyridine
GC analysis revealed conversions >98%. d The remainder was unreacted
1.
SCHEME 3. Proposed Pathway for TMSCH2Li
Consumption
effects. The metalation mixtures were quenched with MeOH
and analyzed by GC (Table 2).
Since no data was available about the reactivity of TMSCH2-
Li in such halogen-metal exchange reaction, we first investi-
gated its behavior at 0 °C toward 2- and 3-bromopyridine in
hexane (Table 1). Bromine-lithium exchange in such substrates
was known to need very low temperature (-78 to -100 °C)
with n-BuLi in THF to avoid dimerization, side deprotonation
and subsequent aryne formation with the latter.12
As shown, in toluene, which was the best solvent reported
for selective C-2 lithiation with n-BuLi at -78 °C,5 TMSCH2-
Li led to a mixture of 1 and 2 at 0 °C. Extended reaction time
led to C-2 to C-5 isomerization and degradation of 3 (entries 1
and 2).
In contrast, in hexane, TMSCH2Li gave 80% of C-2 meta-
lation with a small amount of C-5 metalation (entry 3). The
effect of TMSCH2Li-LiDMAE on the reaction outcome was
also examined. In hexane, the aminoalkoxide induced a complete
conversion but a loss in selectivity was noted. The effect of
incorporating LiDMAE was remarkable in toluene leading to
the C-2 metalation in 95% yield with only 4% of the other
isomer after 30 min at 0 °C. Extended reaction time did not
produce notable isomerization of the lithiated species (entries
5-7).
Interestingly, TMSCH2Li accomplished the bromine-lithium
exchange at 0 °C very cleanly with the two substrates. The
exchange product was obtained exclusively in high yield. In
particular, no product resulting from side deprotonation of 2
was detected. The yields decreased proportionally to the amount
of TMSCH2Li, and 2 equiv of TMSCH2Li were necessary for
completion of the exchange. An explanation is the formation
of reactive TMSCH2Br which subsequently consumed TMSCH2-
Li along the exchange process. TMS(CH2)2TMS was found
present in NMR spectra and GC analysis of the crude mixtures
(Scheme 3).
The metalation and the electrophilic condensation step were
realized in the same solvent and at similar temperatures. Large
excesses of electrophiles were not necessary despite the use of
2 equiv of TMSCH2Li. The excess of the basic reagent was
here probably consumed by TMSCH2Br before addition of the
electrophile.
The effect of coordinating solvents was also examined (entries
8 and 9) to attempt the metalation of the C-5 position. In THF,
only degradation was observed while diethyl ether led to the
expected C-5 lithiation in 65% yield.
TMSCH2Li-LiDMAE was, to our knowledge, the first
reagent to regioselectively lithiate 2,5-dibromopyridine at 0 °C.
The selectivity could be explained by chelation of 2-lithio
intermediate by LiDMAE ensuring stabilization and preventing
the C-2 to C-5 isomerization (Scheme 4). The reason for a lower
selectivity in hexane remains unclear but could be due to a
slower formation of the 2-lithiopyridine in this less polar solvent.
The synthetic usefulness of this new lithiation process was
then finally illustrated by reaction with a set of electrophilic
reagents (Table 3). All of the electrophiles reacted efficiently
providing the expected products in good yields comparable with
TMSCH2Li was found to be practical and selective for the
bromine-lithium exchange in monobromopyridines at 0 °C.
This result was strongly encouraging for trying it in the selective
C-2 lithiation of 2,5-dibromopyridine 3. The reaction was
investigated under various conditions with focus on solvent
(12) Cai, D.; Larsen, R. D.; Reider, P. J. Tetrahedron Lett. 2002, 43,
4285.
J. Org. Chem, Vol. 72, No. 13, 2007 4979

TABLE 3. Reaction with Electrophilic Reagentsa
reasonable amounts of electrophiles (20-50% excess compared
to 3) despite the use of 2 equiv of TMSCH2Li, and the
condensation step could be realized efficiently at 0 or -20 °C
in toluene.
In summary, we have discovered a new reactivity of
TMSCH2Li and TMSCH2Li-LiDMAE reagents. These reagents
are suitable for selective bromine-lithium exchange and subse-
quent functionalization of several bromopyridines in apolar
solvents. The effect of LiDMAE on the selectivity in bromine-
lithium exchange of 2,5-dibromopyridine is remarkable. The
transformation proceeds under noncryogenic conditions con-
suming only small excesses of electrophiles opening access to
a potentially scalable process.
Experimental Section
Procedure for Bromine-Lithium Exchange in 2,5-Dibro-
mopyridine. To a solution of 2-dimethylaminoethanol (164 mg,
1.84 mmoles) in toluene (6 mL) cooled at 0 °C was added dropwise
(trimethylsilyl)methyllithium (5.52 mmol, 6 mL of a 0.92 M
solution in hexane) under a nitrogen atmosphere. After being stirred
for 30 min at the same temperature, a solution of 2,5-dibromopyr-
idine (436 mg, 1.84 mmoles) in toluene (2 mL) was added dropwise.
The obtained red solution was then stirred for 30 min at 0 °C and
treated dropwise with a solution of the appropriate electrophile (2.2
or 2.76 mmol) in toluene (2 mL) at 0 or -20 °C. After 1 h of
stirring, the mixture was hydrolyzed with water (10 mL). The
organic layer was then extracted with diethyl ether (10 mL) and
dried over MgSO4, and the solvents were evaporated. The crude
product was subjected to GC analysis and finally purified by column
chromatography using hexane-AcOEt mixtures as eluent.
Acknowledgment. We thank the FMC Corporation (Lithium
Division) for financial support.
a Reaction performed on 1.84 mmol of 3. b Isolated yield after column
chromatography. The conversions were >97% in each case.
Supporting Information Available: Experimental details and
characterization data for all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
those obtained using BuLi at low temperatures (-78 °C)5 or
by the magnesation process.6 The quenching step consumed
JO070620J
4980 J. Org. Chem., Vol. 72, No. 13, 2007