Selective monolithiation of 2,5-dibromopyridine with butyllithium

Article abstract of DOI:10.1016/S0040-4039(00)00664-X

Selective monolithiation of 2,5-dibromopyridine at either the 2-position or the 5-position is reported. Solvent and concentration strongly influence the selectivity. Coordinating solvents and higher concentration favor the 5- position while non-coordinati

Full text of DOI:10.1016/S0040-4039(00)00664-X

Tetrahedron Letters 41 (2000) 4335±4338
Selective monolithiation of 2,5-dibromopyridine with
butyllithium
Xin Wang,a,* Philippe Rabbat,a,y Paul O'Shea,a Richard Tillyer,b
E. J. J. Grabowskib and Paul J. Reiderb
aDepartment of Process Research, Merck Frosst Centre for Therapeutic Research, PO/CP 1005,
Pointe Claire-Dorval, Quebec, H9R 4P8, Canada
bMerck Research Laboratories, Merck & Co., PO Box. 2000, Rahway, NJ 07065, USA
Received 2 March 2000; revised 17 April 2000; accepted 18 April 2000
Abstract
Selective monolithiation of 2,5-dibromopyridine at either the 2-position or the 5-position is reported.
Solvent and concentration strongly in¯uence the selectivity. Coordinating solvents and higher concentration
favor the 5-position while non-coordinating solvents and lower concentration favor the 2-position. # 2000
Published by Elsevier Science Ltd.
Keywords: monolithiation; 5-bromo-2-lithiopyridine; 2-bromo-5-lithiopyridine..
As part of our drug development research, we required an ecient method for preparing 5-bromo-
2-lithiopyridine and 2-bromo-5-lithiopyridine. A literature search revealed several reports for
preparation of 5-bromo-2-lithiopyridine, but none for 2-lithio-5-bromopyridine. Bolm1 and others2
have reported selective monolithiation of 2,5-dibromopyridine at the 5-position. Thus, 2-bromo-
5-lithiopyridine was generated by lithiation of 2,5-dibromopyridine with BuLi in ether, which,
upon quenching with several electrophiles, provided the expected products in 61±83% yield. Bolm
also noted that the lithiation gave complex mixtures if THF was employed as solvent. The fact
that solvents can profoundly in¯uence the formation, structure and properties of organolithiums3
led us to examine other solvents for the lithiation of 2,5-dibromopyridine in order to ®nd suitable
conditions for selective monolithiation, especially at the previously inaccessible 2-position. In this
communication, we would like to report our preliminary ®ndings for the monolithiation of
2,5-dibromopyridine in a variety of solvents at di€erent temperatures and concentrations.
* Corresponding author. Tel: (514) 428-3511; fax: (514) 428-4936; e-mail: xin_wang@merck.com
y
Merck Frosst co-operative undergraduate student (University of Waterloo, January±May 1999).
0040-4039/00/$ - see front matter # 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)00664-X

4336
First we examined the use of coordinating solvents ether, MTBE, and THF following the
published procedures.1,2 Thus, BuLi (2.5 M in hexanes, 1.2 equiv.) was added to 2,5-dibromo-
pyridine (0.085 M) in the appropriate solvent at ^78ꢀC. After 40 minutes the reaction was quenched
with MeOH (10 mL) and the products quanti®ed by HPLC (Table 1, entries 1±5). In coordinating
solvents, 2-bromo-5-lithiopyridine is the dominant species. The selectivity of the reactions in ether,
MTBE and THF are 12:1, 6.3:1 and 5.8:1, respectively. These results are consistent with the pub-
lished1,2 observations. We also noticed a pronounced concentration e€ect. At lower concentration
(0.017 M, ether, ^78ꢀC) the selectivity for the 5-position decreases from 12:1 to 4:1 (Table 1, entry
3). At higher concentration (0.28 M, ether, ^78ꢀC) the quantity of 2,5-dibromopyridine is
increased (Table 1, entry 4).
Table 1
Monolithiation of 2,5-dibromopyridine using BuLi

4337
Next, we investigated the non-coordinating solvents toluene and dichloromethane and, to our
delight, the selectivity is completely reversed (Table 1, entries 6±10). After 2 hours reaction time at
^78ꢀC, the selectivity of monolithiation in CH2Cl2 (0.085 M) was 11:1 in favor of the 2-position,
while in toluene (0.085 M) it was at 20:1. The concentration also plays an important role in the
selectivity of monolithiation in toluene. The more dilute the solution the better the selectivity for
the 2-position is. For example, at a concentration of 0.017 M, the selectivity for 5-bromo-2-
lithiopyridine over 2-bromo-5-lithiopyridine reached equilibrium at 34:1 after 7 hours. Furthermore,
at this low concentration, only a small amount of 2,5-dilithiopyridine (0.61%) and 2,5-dibromo-
pyridine (2.5%) were detected (Table 1, entry 8). We also carried out the following trapping
experiment to further verify the kinetic regioselectivity in toluene. To a solution of 2,5-dibromo-
pyridine (1.0 equiv.) and TMSCl (2.0 equiv.) in toluene (0.085 M) at ^78ꢀC was added BuLi (1.2
equiv.). After the reaction mixture was warmed to room temperature and subjected to normal
workup, 2-trimethylsilyl-5-bromopyridine (49%) and 2-bromo-5-trimethylsilylpyridine (3%) were
isolated in a ratio of 16 to 1, consistent with the result in entry 7. It should also be noted that 1.2
equiv. of BuLi are necessary as the lithiation using less than 1.2 equiv. of BuLi has a substantial
amount of 2,5-dibromopyridine (>10%) remaining.
In all solvents at ^78ꢀC, as the reaction time increased the ratio of 5-bromo-2-lithiopyridine
over 2-bromo-5-lithiopyridine increased. This strongly suggests that under these reaction conditions,
5-bromo-2-lithiopyridine is thermodynamically more stable than 2-bromo-5-lithiopyridine. In
coordinating solvents, 2-bromo-5-lithiopyridine is kinetically favored. On the other hand, in non-
coordinating solvents, 5-bromo-2-lithiopyridine is both kinetically and thermodynamically
favored. All the lithiated pyridines are stable, at a concentration of 0.28 M or lower, in THF, ether
and toluene for up to 12 hours at ^78ꢀC. However, decomposition of these species was especially
noticeable in MTBE and CH2Cl2 at ^78ꢀC after 2 hours reaction time.
Table 2
Monolithiation of 2,5-dibromopyridine in toluene

4338
We also ran the experiments at ^50ꢀC and found that the temperature is not a major factor in
controlling the initial selectivity, although the equilibrium is achieved in a shorter period of time
(Table 1, entries 10 and 11). Decomposition of the lithiated pyridines began after 1 hour at ^50ꢀC
even in THF, ether and toluene.
We then brie¯y examined the scope of the reaction of 2-lithio-5-bromopyridine with several
electrophiles under our reaction conditions. The results are summarized in Table 2.4 Especially
worth noting are the reactions with enolizable ketones5 (acetophenone and acetone), which gave
the tertiary alcohols6 in very good yields (Table 2, entries 6 and 7). Also, no other regioisomers
were detected in the reaction mixtures.
From a practical point of view, we recommend that the lithiation reactions to form 2-bromo-5-
lithiopyridine and 5-bromo-2-lithiopyridine be run in ether and toluene at ^78ꢀC, respectively. In
the case of 2-bromo-5-lithiopyridine, the electrophile should be added within 40 minutes of the
addition of BuLi. However, in the case of 5-bromo-2-lithiopyridine the electrophile should be
added at least 2 hours after the addition of BuLi. We have successfully applied these reaction
conditions to the synthesis of adducts of 2-bromo-5-lithiopyridine and 5-bromo-2-lithiopyridine
in ether and toluene on 500 g scales.
In conclusion, we have discovered an ecient procedure to generate previously inaccessible 2-
lithio-5-bromopyridine (up to 34:1 selectivity ratio) via monolithiation of 2,5-dibromopyridine
using BuLi (1.2 equiv.) in toluene at ^78ꢀC. We also identi®ed two key factors that strongly
in¯uence the selectivity of this reaction: solvent and concentration.
Acknowledgements
We thank Bob Reamer for carrying out NMR studies on lithiopyridines and Chun Li for
measurements of HRMS of all products.
References
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2. Alderweireldt, F. C.; Vrijens, I.; Esmans, E. L.; Wotring, L. L.; Townsend, L. B.; Balzarini, J.; De Clercq, E.
Nucleosides Nucleotides 1989, 8, 891. Wicha, J.; Masnyl, M. Heterocycles 1981, 16, 521. Romero-Salguero, F. J.;
Lehn, J.-M. Tetrahedron Lett. 1999, 40, 859.
3. Peterson, M. A.; Mitchell, J. J. Org. Chem. 1997, 62, 8237 and references cited therein.
4. All products exhibited satisfactory physical data (1H NMR, 13C NMR and HRMS) consistent with their assigned
structures.
5. Canonne, P.; Foscolos, G. B.; Caron, H.; Lemay, G. Tetrahedron 1982, 38, 3563 and references cited therein; Cai,
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6. Representative procedure: To a solution of 2,5-dibromopyridine (1.0 g, 4.2 mmol) in toluene (50 mL) at ^78ꢀC was
slowly added BuLi (2.5 M in hexanes, 2.0 mL, 5.0 mmol). The reaction mixture was aged for 2 hours. Electrophile
(5.5 mmol) was added. The solution was stirred for 1 hour at ^78ꢀC and then warmed to ^10ꢀC. NH4Cl saturated
aqueous solution (10 mL) was added and the mixture was warmed to rt. Separation of two phases gave toluene
solution, which was concentrated to dryness. Puri®cation by ¯ash column chromatography a€orded the desired
product.
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9. Kondo, Y.; Manabu, S.; Uchiyama, M.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1996, 1781.