Unusual t-BuLi induced ortholithiation versus halogen-lithium exchange in bromopyridines: Two alternative strategies for functionalization

Article abstract of DOI:10.1055/s-2004-831337

The reaction of lithiating agents with various 3-bromopyridines has been investigated. An unprecedented selectivity was observed with t-BuLi, which effected a clean lithiation at C-4. With 3-bromo and 2-chloro-3-bromo pyridines, the ortholithiation-exchange ratio was strongly electrophile and addition order dependent while 2-chloro-5-bromopyridine always gave exclusive C-4 substitution.

Full text of DOI:10.1055/s-2004-831337

LETTER
2319
Unusual t-BuLi Induced Ortholithiation versus Halogen–Lithium Exchange in
Bromopyridines: Two Alternative Strategies for Functionalization
t
-
BuL
i
Induced
h
Ortholithia
t
i
ion ver
l
sus
H
a
i
logen–L
p
ithium
E
xch
p
a
nge e Pierrat, Philippe Gros,* Yves Fort*
Synthèse Organométallique et Réactivité, UMR CNRS-UHP 7565, Faculté des Sciences, Université Henri Poincaré,
54506 Vandoeuvre-lès-Nancy, France
Fax +33(3)83844785; E-mail: Yves.Fort@sor.uhp-nancy.fr; E-mail: Philippe.Gros@sor.uhp-nancy.fr
Received 13 May 2004
even obtained as single product using two equivalents of
Abstract: The reaction of lithiating agents with various 3-bro-
mopyridines has been investigated. An unprecedented selectivity
was observed with t-BuLi, which effected a clean lithiation at C-4.
With 3-bromo and 2-chloro-3-bromo pyridines, the ortholithiation–
base (entries 7 and 10). The C-4 substituted derivative
could be obtained exclusively in the presence of TMSCl
(entry 1). In addition, we found that prolonged metallation
exchange ratio was strongly electrophile and addition order depen- time had no effect on the 2a:3a ratio when TMSCl was
dent while 2-chloro-5-bromopyridine always gave exclusive C-4
used (entries 1–3) while an increase of temperature
favored the formation of 3a (entry 5).5 On the other hand,
substitution.
Key words: bromine–lithium exchange, ortholithiation, bromopy-
ridines, regioselectivity
when the medium was quenched with DMDS after 30 or
60 minutes of metallation, the amount of ortholithiation
product 2c was identical to those obtained after five
minutes. Starting 1 was then recovered in 80% and no
Bromopyridines are versatile compounds since they can exchange product 3c was detected (entries 8, 9).
be selectively substituted at various positions using select-
ed lithiating agents. The well-known bromine–lithium ex-
change is generally achieved with n-BuLi1 or more rarely
with t-BuLi2 while ortholithiation is realized with lithium
dialkylamides. In most cases, the latter reaction leads to
subsequent halogen scrambling or pyridyne formation.3
Judicious combination of these reactions on dibromopy-
ridines provided efficient routes to new polyfunctional de-
rivatives.4 During a research program, we have been
drawn to investigate regiochemistry in the reaction of
various 3-bromopyridines with lithiating agents. Here we
report that t-BuLi induced an unprecedented ortholithia-
tion instead of the expected bromine–lithium exchange.
Scheme 1 Effect of order of introduction of t-BuLi
Preliminary experiments performed on 3-bromo-pyridine
(1) gave surprising results. While compounds 2a and 3a
were expectedly obtained after reaction with LTMP and
n-BuLi, respectively, t-BuLi induced a clean lithiation at
These observations suggested the formation of a reactive
intermediate evolving towards the C-4 substituted product
only when quenched in situ by TMSCl known as a base-
compatible electrophile.6,7 This was supported by the deu-
C-4 in 70% yield instead of the classical bromine–lithium
teration experiment (entry 6) which indicated the forma-
exchange (Scheme 1), the remaining part was only unre-
tion of the 4-lithio species only in 21% yield in the
acted 1. Moreover, the order of reagent introduction had a
medium at the end of metallation time.
spectacular effect. Indeed, 2a was obtained exclusively
when t-BuLi was added to a THF solution of 1 (1) while
the reverse addition led to 3a (2). This unprecedented bro-
mine tolerant lithiation was very intriguing and we decid-
ed to investigate it in more detail under various reaction
conditions (Table 1).
We next investigated further the role of the H-4 proton in
the mechanistic pathway. Thus, the 4-position was
deuterated8 and subjected to reaction with t-BuLi
(Scheme 2). As expected, different selectivities were ob-
tained with TMSCl and DMDS. With TMSCl, product 2a,
resulting from deuterium abstraction, was mainly ob-
As shown, the nature of the electrophile had a dramatic
tained. Interestingly, it was accompanied by a C-2 silylat-
effect. When the medium was quenched with D2O or di-
ed product probably due to a deuterium induced partial
methyldisulfide (DMDS) bromine–lithium exchange was
inhibition of deprotonation at C-4. In contrast, deuterium
was abstracted only in trace amounts in the presence of
the main product (entries 6–10). Compounds 3b–c were
DMDS and the reaction led mainly to bromine–lithium
exchange product 3c-d4.
SYNLETT 2004, No. 13, pp 2319–2322
0
3
.1
1
.2
0
0
4
Advanced online publication: 08.09.2004
DOI: 10.1055/s-2004-831337; Art ID: D12004ST
© Georg Thieme Verlag Stuttgart · New York

2320
P. Pierrat et al.
LETTER
Table 1 Variation of Conditions in Lithiation of 1 with t-BuLia
Entry
t-BuLi (equiv)
Time (min)
Temp (°C)
–78
E+
Yield of 1 (%)b Yield of 2 (%)b Yield of 3 (%)b
1
2
1
1
1
2
1
1
2
1
1
2
5
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
D2O
30
31
30
–
2a, 70
2a, 69
2a, 70
2a, 78
2a, 35
2b, 21d
–
–
30
–78
–
60
–78
–
4
5
5
–78
3a, 20
3a, 63
3b, 49d
3b, 99d
3c, 50
–
5
–50c
–78
–
6
5
28c
–
7
5
–78
D2O
8
5
–78
DMDS
DMDS
DMDS
30
80
–
2c, 20
2c, 20
–
9
30–60
5
–78
10
–78
3c, 99
a All reactions performed on 2 mmol of 1. All experiments were repeated thrice and gave similar results.
b GC yields.
c Metallation at –78 °C, 5 min then –50 °C, 5 min.
d Ratios determined by 1H NMR.
These results indicated that the H-4 proton played a cen-
tral role in the evolution of the reactive intermediate.
Thus, we examined the effect of pyridine ring substitution
especially by introduction of electron-withdrawing chlo-
rine, known to increase the acidity of pyridine protons.
The reactivity of 2-chloro-3-bromopyridine (4) and 2-
chloro-5-bromo-pyridine (7) was then investigated
(Scheme 3).
At first, very similar reactivities were found for 4 and 1.
n-BuLi led only to bromine–lithium exchange. The addi-
tion order of reagents was still a key paramater with t-Bu-
Li, which had to be added to 4 to obtain ortholithiation.
Electrophiles other than TMSCl also led to mixtures of
ortholithiation and exchange products. The acidifying ef-
fect of chlorine ortho to bromine was notable since con-
versions were generally increased compared to 1. For
example, the silyl derivative 5a was obtained in 85%
yield. The ortholithiation–exchange ratio was also in-
creased from 30:70 for 1 (see Table 1) to 40:60 for 4 when
MeSSMe and D2O were used as electrophiles. This again
underlined the role of the H-4 proton into the evolution
process of the reactive intermediate since a more acidic H-
4 led to higher amount of C-4 substitution.
Scheme 2 Role of the H-4 proton in reaction pathway
Then, we turned to lithiation of 2-chloro-5-bromo pyri-
dine (7) in order to check the effect of chlorine para to
bromine (Table 2). In this case, competitive ortholithia-
tion by the chlorine atom could be expected. So the lithi-
Scheme 3 Reaction of 4 with t-BuLi
Synlett 2004, No. 13, 2319–2322 © Thieme Stuttgart · New York

LETTER
t-BuLi Induced Ortholithiation versus Halogen–Lithium Exchange
2321
Table 2 Reaction of 7 with Various Lithiating Agentsa
Base (equiv), solvent, temperature, time
LiTMP (3.2 equiv), THF, –78 °C, 2 h
LiTMP (1 equiv), THF, –78 °C, 2 h
Yield of 8a (%)
Yield of 9a (%)
Yield of 10a (%) Yield of 11a (%)
–
–
–
–
–
–
–
–
–
–
–
–
–
–
80
7
–
–
MeLi (1.2 equiv), Et2O, –78 °C, 15 min
n-BuLi (1.2 equiv), THF, –78 °C, 30 min
t-BuLi (1 equiv), THF, –78 °C, 5 min
t-BuLi (1 equiv), THF, –78 °C, 5 min (reverse addition)
s-BuLi (1 equiv), THF, –78 °C, 30 min
–
85
90
–
–
95b
93
90
–
–
a All reactions were performed on 2 mmol of 7. All yields are GC yields.
b 92% Isolated yield.
ation was also attempted with LTMP, known to promote In summary, this study brings new data on the reactivity
ortholithiation of both 2-chloro and 3-bromopyridine.
of t-BuLi towards 3-bromopyridines. The reaction of t-
BuLi with bromopyridines 1 and 4 gave an intermediate
evolving mainly towards the ortholithiation product by in
situ trapping with the base tolerant TMSCl while incom-
patible electrophiles DMDS or D2O led mainly to 3-sub-
stituted pyridines. The reason for such an electrophile
effect remains unclear. Nevertheless, the deep green color
developed during the reaction could be attributed to a
radicaloid species.11 Alternatively, formation of an ate-
complex12 could also explain the unusual behavior com-
pared to classical lithiated intermediates. With 2-chloro-
5-bromopyridine, the selectivity was rather governed by
the acidity of the H-4 proton leading exclusively to
ortholithiation product. The absence of detection of pyri-
dine in the reaction medium ruled out an intermolecular
lithiation between 3-lithiopyridine and unreacted 1. In-
deed, pyridine is sluggishly metallated by t-BuLi13 and
should be accumulated in the medium.
As shown, LiTMP effected exclusive proton abstraction at
C-4 (ortho to bromine) in agreement with the higher acid-
ity of the H-4 proton.9 Bromine–lithium exchange was ob-
tained with MeLi and n-BuLi. On the other hand, one
equivalent of branched alkyllithiums s-BuLi and t-BuLi
led to a clean and efficient C-4 lithiation. In sharp contrast
with 1 and 4, no effect of reagent introduction order was
observed with 7 in full agreement with a direct lithiation
process. Moreover, the ortholithiation occurred without
any bromine–lithium exchange regardless of the electro-
phile (Scheme 4).10 The deuteration experiment clearly
indicated the quantitative formation of the 3-bromo-4-
lithio derivative before the quenching step. The reaction
was found of synthetic interest since various substituents
were introduced in good yield, particularly iodine and tin
moieties giving access to valuable new reactive precur-
sors.
Finally, this new reactivity of t-BuLi is of high synthetic
value since all reactions can be performed cleanly with a
stoichiometric amount of base. Large excess of lithium di-
alkylamides (3–4 equiv) are generally required for the
same efficiency generating large amounts of side products
in the reaction medium. This opens new perspectives in
heterocyclic synthesis since retention of both the C-Br and
C-Cl bonds provides useful templates for further poly-
functionalization. Work is now under progress to study in
more detail the mechanistic pathway as well as the syn-
thetic scope of this new selective lithiation.
Scheme 4 Lithiation of 7 with t-BuLi and reaction with electro-
philes
Synlett 2004, No. 13, 2319–2322 © Thieme Stuttgart · New York

2322
P. Pierrat et al.
LETTER
(10) General Procedure for Ortholithitaion of 4 with t-BuLi.
A solution of 2-chloro-5-bromopyridine (386 mg, 2 mmol)
in THF (6 mL) was cooled to –78 °C and t-BuLi (1.17 mL,
2 mmol) was added dropwise under nitrogen. After 5 min at
–78 °C, the brown solution was treated with a solution of the
appropriate electrophile (3 mmol) in THF (4 mL). The
reaction medium was then allowed to warm to r.t. (1 h) and
the mixture was hydrolyzed at 0 °C with H2O (10 mL). The
aqueous layer was then extracted with Et2O. The organic
layer was dried (MgSO4) and the solvent was evaporated
under reduced pressure. The crude product was purified by
column chromatography. Selected data for compound 10c
obtained as an orange oil, (358 mg, 75%), eluent: hexane–
EtOAc (90:10). 1H NMR (200 MHz, CDCl3): d = 2.5 (s, 3
H), 6.9 (s, 1 H), 8.3 (s, 1 H). 13C NMR (50 MHz, CDCl3):
d = 14.8, 117.7, 118.8, 149.8, 150.4, 154.4. MS (EI):
m/z (%) = 241 (28), 239 (100) [M+], 237 (74), 206 (18), 143
(19), 81 (16). Anal. Calcd for C6H5BrClNS (%): C, 30.21; H,
2.11; N, 5.87. Found: C, 30.33; H, 2.12; N, 5.78.
References
(1) Gilman, H.; Spatz, S. M. J. Org. Chem. 1951, 16, 1485.
(2) Woolard, F. X.; Paetsch, J.; Ellman, J. A. J. Org. Chem.
1997, 62, 6102.
(3) (a) Mallet, M.; Quéguiner, G. Tetrahedron 1982, 38, 3035.
(b) Gribble, G. W.; Saulnier, M. G. Heterocycles 1993, 35,
151. (c) Karig, G.; Spencer, J. A.; Gallagher, T. Org. Lett.
2001, 3, 835.
(4) Gu, Y. G.; Bayburth, E. K. Tetrahedron Lett. 1996, 37, 2565.
(5) Temperatures below –78 °C did not change the selectivity.
(6) This kind of reactivity has aleady been observed during our
previous works on lithiation of 2-methoxypyridine with
BuLi–Me2N(CH2)2OLi reagent. In this case the intermediate
evolved towards C-6 lithiation or nucleophilic addition
depending on the nature of the electrophile. See: Gros, P.;
Fort, Y.; Caubère, P. J. Chem. Soc., Perkin Trans. 1 1997,
20, 3071.
(7) TMSCl is known to display some compatibility towards
hindered bases. See: (a) Comins, D.; La Munyon, D.
Tetrahedron Lett. 1988, 29, 773. (b) Trécourt, F.; Mallet,
M.; Marsais, F.; Quéguiner, G. J. Org. Chem. 1988, 53,
1367.
(11) Ashby, E. C.; Pham, T. N. J. Org. Chem. 1987, 52, 1291.
(12) For evidence of formation of ate-complex in halogen-metal
exchange see: Jedlicka, B.; Crabtree, R. H. Organometallics
1997, 16, 6021.
(13) Under these reaction conditions (1 equiv, –78 °C in THF),
t-BuLi did not metallate pyridine even after 1 h, and gave
only 2-tert-butylpyridine in 10–15%.
(8) Compound 1-d4 was obtained in 70% yield (d >98%, 1H
NMR) by reaction of 1 with LDA (3 equiv) in THF at –78 °C
for 0.5 h and condensation with MeOD (5 equiv).
(9) Marsais, F.; Quéguiner, G. Tetrahedron 1983, 39, 2009.
Synlett 2004, No. 13, 2319–2322 © Thieme Stuttgart · New York