Concentration-dependent chemo- and regioselective metalation of 6,6′-dibromo-2,2′-bipyridine

Article abstract of DOI:10.1055/s-2006-944192

A reliable and synthetically useful strategy for the selective single or double metalation of 6,6′-dibromo-2,2′-bipyridine via lithium-halogen exchange is discussed. Experimental conditions for the optimal formylation of the singly and doubly lithiated intermediates are outlined as well as unequivocal X-ray crystallographic evidence for the regiochemistry of a competing deprotonation pathway. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-944192

LETTER
1759
Concentration-Dependent Chemo- and Regioselective Metalation of
6
,6¢-Dibromo-2,2¢-bipyridine
C
G
hemo- and Regio
e
selective
M
n
e
talation of
n
6,6
¢
-Dibromo
a
-2,2
¢
-
bipyr
d
idine iy Ilyashenko, Rahela Choudhury, Majid Motevalli, Michael Watkinson*
School of Biological and Chemical Sciences, Queen Mary, University of London, Mile End Road, London, E1 4NS, UK
Fax +44(20)788827427; E-mail: m.watkinson@qmul.ac.uk
Received 26 February 2006
the commercially available 2,6-dibromopyridine. The
dilithiated species can then be converted to dialdehyde 3,
Abstract: A reliable and synthetically useful strategy for the selec-
tive single or double metalation of 6,6¢-dibromo-2,2¢-bipyridine via
lithium–halogen exchange is discussed. Experimental conditions
although the reported yield of 48% is perhaps a little dis-
5
for the optimal formylation of the singly and doubly lithiated inter- appointing given the efficiency of the metalation. We
mediates are outlined as well as unequivocal X-ray crystallographic were also keen to develop conditions for the selective
evidence for the regiochemistry of a competing deprotonation path-
way.
metalation of 1 to provide 4, akin to Holm’s original pro-
cedure for the desymmetrisation of 2,6-dibromopyridine.
Key words: bipyridine ligands, lithium–halogen exchange, metala- Further elaboration of the ligand structure could then be
tion, regiocontrol
affected through bromide exchange, e.g., via Suzuki cou-
pling, which would ultimately allow us to fine-tune
6
ligand structures in any active catalysts. Indeed Holm’s
Despite the fact that 2,2¢-bipyridine (bipy) was first re- original report has been used in exactly this way to devel-
th
ported in the 19 century and has subsequently been the op ligand architectures derived from 2,6-dibromopyri-
7
subject of very extensive investigations, there continues to dine, though reports have highlighted the capricious
1
be considerable interest in its chemistry. This is because nature of the reaction, including the possibility of compet-
of the enormous number of applications that have been ing but uncorroborated deprotonation pathways.8,9
found for this bidentate ligand and its derivatives, which Although the desymmetrisation of 1 via lithium–halogen
include applications in supramolecular and macromolecu- exchange has been reported, no representative procedure
1
2
10
lar chemistry, novel materials and devices, as well as in was included. Additionally, Ziessel has reported an ele-
3
asymmetric catalysis.
gant method using a palladium-catalysed carbonylation
reaction to ultimately provide the target aldehyde 5 in
Our interest in the area was stimulated by Stack’s recent
report of the efficient epoxidation of a range of alkene
substrates catalysed by a number of manganese complex-
1
1
three steps from 1 in 34% overall yield. Thus, although
our initial targets had previously been reported, the mod-
erate yield of 3, the total absence of experimental methods
for the preparation of 5 via lithium–halogen exchange and
the uncertain nature of the competing deprotonation
pathways prompted us to make a thorough investigation
2
+
es, including [Mn(bipy) ] , using peracetic acid as the
2
4
oxidant. We viewed 6,6¢-dibromopyridine (1) as an ideal
starting material for the preparation of new enantiomeri-
cally pure ligands based on the bipy core, as the material
has been reported to undergo smooth dilithiation forming
1
of this process by H NMR spectroscopy (Scheme 1).
2
in 80% yield, which can be conveniently prepared from
(iii)
(i)
Li
N
N
Br
Br
N
N
Br
Li
N
N
Li
4
1
2
(ii)
(iv), (ii)
(ii)
CHO
Br
OHC
N
N
Br
Br
N
N
OHC
N
N
CHO
5
6
3
1
Scheme 1 Reagents and conditions: Optimised conditions as judged by H NMR spectroscopy (i) 3.0 equiv n-BuLi, –80 °C, THF; (ii) DMF,
–80 °C; (iii) 1.4 equiv n-BuLi, –90 °C; (iv) 0.9 equiv n-BuLi, –90 °C.
SYNLETT 2006, No. 11, pp 1759–1761
1
2
.0
7
.2
0
0
6
Advanced online publication: 04.07.2006
DOI: 10.1055/s-2006-944192; Art ID: D06406ST
©
Georg Thieme Verlag Stuttgart · New York

1
760
G. Ilyashenko et al.
LETTER
Due to the poor solubility of 1 in THF, a relatively large Our investigations have also demonstrated that as soon as
volume of the solvent was required in all experiments, us- the number of equivalents of the organolithium reagent
ing a range of organolithium reagents. The only exception drops below two the reaction mixture is increasingly
to this was when an excess of n-BuLi (>2.0 equiv) was complex with the three aldehydes 3, 5 and 6 being
used, in which case we adopted Holm’s reverse addition produced in varying quantities. The optimal experimental
1
1
procedure. This revealed the efficacy of n-BuLi in the conditions for the chemoselective formation of 5 require
1
2
lithium–halogen exchange reaction and the reproducibili- 1.4 equivalents of n-BuLi whilst for 6 this drops to 0.9
ty of Holm’s procedure, with dialdehyde 3 being routinely equivalents (Table 1, entries 3 and 6, respectively) with
5
isolated in 50% yield. We subsequently found that by in- the regiochemistry of the deprotonation of 6 being
creasing both the concentration (from 1.6 to 2.5 M), the unequivocally established by single-crystal X-ray diffrac-
quantity of n-BuLi (from 2.0 to 3.0 equiv) and by using tion (Figure 1).13
the reverse addition procedure we could increase the iso-
lated yield of 3 to 70%, following a recrystallisation of the
5
crude reaction mixture from toluene. Simply increasing
the number of equivalents of n-BuLi (1.6 M) does not lead
to the increased yield, indicating that the success of this
procedure is highly sensitive to concentration. Similarly
by reducing the number of equivalents of n-BuLi (to 1.1)
we were able to isolate, following column chroma-
tography, the aldehydes 5 and 3 in 37% and 26% yield, re-
spectively (isolated yields are lower than the yields
1
estimated by H NMR spectroscopy due to the difficulty
of separating the aldehydes 3 and 5 from other materials Figure 1 An ORTEP representation of the single crystal structure of
with similar R values). We next undertook a systematic
investigation into the effects of varying the number of
6 unequivocally confirming the regiochemistry of the deprotonation
at the 3-position.
f
equivalents of n-BuLi with respect to dibromide 1
(
Table 1). As the data in Table 1 evidently show, both the At levels below this no aldehyde-containing materials are
chemo- and regioselectivity of the metalation are pro- formed and unreacted starting material is recovered
foundly affected by the number of equivalents of n-BuLi. slightly contaminated with 6-bromo-2,2¢dipyridine
When 2.5–3.0 equivalents of n-BuLi are used dialdehyde (<6%). Unfortunately aldehydes 5 and 6 have similar Rf
3
is exclusively formed and can be readily isolated by values, which makes their separation by column chroma-
recrystallisation. As soon as the stoichiometry of the tography difficult; however, we have found that 6 and 1
organolithium drops below this level other materials are are insoluble in dilute aqueous HCl, whilst 3 and 5 are
formed. When 2.0 equivalents of n-BuLi are added soluble, thus, the purification of these reactions mixtures
although 3 remains the only aldehyde containing species can readily be achieved.
we have identified (Table 1, entry 2) it is contaminated
In summary we have developed a reliable method for the
with 1 and other unidentified materials, and consequently
selective preparation of aldehydes 3 and 5 by lithium–
required purification by column chromatography.
halogen exchange and unequivocally confirmed the regio-
chemistry of the competing deprotonation to form 6. We
Table 1 Summary of the Effect of the Variation of the Stoichiomet-
are currently extending this methodology towards the
synthesis and application of new ligand systems for appli-
cation in asymmetric catalysis which will be reported in
due course.
ric Ratio of n-BuLi Relative to 1 on the Regio- and Chemoselectivity
of the Metalation Reaction as Judged by H NMR Spectroscopy
1
Entry
Equivalents of
n-BuLi (2.5 M)
Ratio of products
3
1
1
1
1
1
0
0
0
5
6
0
0
1
1
4
2
0
0
1
2
3
4
5
6
7
8
3.0
2.0
1.4
1.2
1.0
0.9
0.7
0.5
0
0
Acknowledgment
We are grateful to The University of London for the award of an
Elsie Idea Leas Studentship (to GI) and the EPSRC National Mass
Spectrometry Service, University of Wales, Swansea.
10
3
References and Notes
8
(1) Newkome, G. R.; Patri, A. K.; Holder, E.; Schuber, U. S.
Eur. J. Org. Chem. 2004, 235.
1
(
2) For example: Welter, S.; Brunner, K.; Hofstraat, J. W.; De
Cola, L. Nature (London) 2003, 421, 54.
0
(
(
3) Chelucci, G.; Thummel, R. P. Chem. Rev. 2002, 102, 3129.
4) Murphy, A.; Pace, A.; Stack, T. D. P. Org. Lett. 2004, 6,
0
3119.
Synlett 2006, No. 11, 1759–1761 © Thieme Stuttgart · New York

LETTER
Chemo- and Regioselective Metalation of 6,6¢-Dibromo-2,2¢-bipyridine
1761
(
5) Preparation of 6,6¢-Diformyl-2,2¢-bipyridyl (3).
A warm solution (ca. 50 °C) of 6,6¢-dibromo-2,2¢-bipyridyl
1.0 g, 3.18 mmol) in THF (50 mL) was slowly added to a
complete, the mixture was stirred until its temperature was
–30 °C, at which point aq HCl (5%, 2.0 mL) was added and
the mixture was allowed to reach r.t. THF was removed and
the aqueous layer basified with KOH (pH ca. 14). The
product was then extracted with EtOAc (3 × 30 mL). The
organic extracts were combined, washed with brine (3 × 50
(
solution of 2.5 M n-BuLi (3.84 mL, 9.6 mmol, 3.0 equiv) in
THF (60 mL) at –78 °C at such a rate that precipitation was
avoided and the temperature did not increase above –70 °C.
The resultant dark red solution was stirred below –75 °C for
mL) and dried over MgSO . The solvent was removed in
4
45 min before quenching with DMF (0.74 mL, 9.6 mmol, 3.0
vacuo. This solid was purified by flash chromatography on
equiv). The solution was allowed to warm to –30 °C where
upon aq HCl (4 M, 20 mL) was added. The reaction mixture
was then allowed to reach r.t. and the aqueous layer was
separated from the organic phase. The aqueous layer was
basified to pH 14 with sat. KOH solution and washed with
silica gel eluting with light PE–EtOAc (99:1) to give 5
(0.030 g, 37%) as a white solid R = 0.16 (light PE–EtOAc,
f
99:1). All analytical and spectroscopic data were consistent
with those previously reported by: El-ghayoury, A.; Ziessel,
R. J. Org. Chem. 2000, 65, 7757.
warm (ca. 40 °C) CHCl (2 × 30 mL). The combined organic
(12) Preparation of 6,6¢-Dibromo-[2,2¢]bipyridinyl-5-
3
extracts were washed with brine (2 × 100 mL), dried over
carbaldehyde (6).
MgSO and concentrated in vacuo. The resultant solid was
Although the stoichiometric ratio for optimal yield of the
4
1
triturated with MeOH (20 mL), the solid collected by
aldehyde as judged by H NMR is as given in Table 1, it was
filtration and recrystallised from toluene to give 3 (0.41 g,
found that the following procedure gave the highest isolated
yield: n-BuLi (2.5 M, 0.14 mL, 0.35 mmol, 1.1 equiv) was
added dropwise to a solution of 6,6¢-dibromo-2,2¢-bipyridyl
(0.10 g, 0.32 mmol, 1.0 equiv) in dry THF (40 mL) at
–90 °C. After the addition was complete the reaction was
allowed to warm to –80 °C and the temperature was
maintained for a further 15 min. Dry DMF (0.028 mL, 0.38
70%). All analytical and spectroscopic data were consistent
with those reported. See: Parks, J. E.; Wagner, B. E.; Holm,
R. H. J. Organomet. Chem. 1973, 56, 53.
(
(
(
(
6) Tsuji, J. In Palladium Reagents and Catalysts; Wiley:
Chichester, 2004.
7) Charbonnière, L. J.; Ziessel, Z. Tetrahedron Lett. 2003, 44,
6
305.
8) Cai, D.; Hughes, D. L.; Verhoeven, T. R. Tetrahedron Lett.
996, 37, 2537.
mmol, 1.2 equiv) in Et O (10 mL) was then slowly added to
2
the reaction. After the addition was complete, the mixture
was stirred until its temperature was –30 °C, at which point
aq HCl (5%, 2.0 mL) was added to it and the reaction was
allowed to warm to r.t. Then, THF was removed in vacuo
and the resultant white solid was collected by filtration and
dried in vacuo. This solid was purified by flash
1
9) Mase, T.; Houpis, I. N.; Akao, A.; Dorziotis, I.; Emerson, K.;
Hoamg, T.; Iida, T.; Itoh, T.; Kamei, K.; Kato, S.; Kato, Y.;
Kawasaki, M.; Lang, F.; Lee, J.; Lynch, J.; Maligres, P.;
Molina, A.; Nemoto, T.; Okada, S.; Reamer, R.; Song, J. Z.;
Tschaen, D.; Wada, T.; Zewge, D.; Volante, R. P.; Reider, P.
J.; Tomimoto, K. J. Org. Chem. 2001, 66, 6775.
chromatography on silica gel eluting with light PE–EtOAc
(99:1) to give the aldehyde 6 (14 mg, 26%) as a white solid;
(
(
10) Horiuchi, Y.; Taniguchi, T.; Oshima, K.; Utimoto, K.
Tetrahedron Lett. 1994, 35, 7977.
R = 0.24 (light PE–EtOAc 99:1); mp 188–189 °C. IR: 1682
(s, C=O), 1574 (m, arom. C=N), 1531 (m, arom. C=C). H
f
1
11) Preparation of 6-Bromo-6¢-formyl-2,2¢-bipyridyl (5).
NMR (400 MHz): d = 7.52 [dd, 1 H, J = 7.88, 0.77 Hz,
N=C(Br)CH], 7.66 [t, 1 H, J = 7.80 Hz, N=C(Br)CHCH],
8.21 [d, 1 H, J = 8.01 Hz, C(CHO)CHCH], 8.40 (dd, 1 H,
J = 7.70, 0.77 Hz, N=C(Br)CHCHCH], 8.46 [dd, 1 H,
J = 7.95 0.60 Hz, C(CHO)CHCH], 10.31 (d, 1 H, J = 0.68
Although the stoichiometric ratio for optimal yield of the
1
aldehyde as judged by H NMR is as given in Table 1, it was
found that the following procedure gave the highest isolated
yield: n-BuLi (2.5 M, 0.14 mL, 0.35 mmol, 1.1 equiv) was
added dropwise to a solution of 6,6¢-dibromo-2,2¢-bipyridyl
1
3
Hz). C NMR: d = 120.7 (CH), 121.3 (CH), 129.7 (CH),
130.4 (i-C), 139.0 (CH), 139.4 (CH), 142.0 (i-C), 144.7 (i-
C), 154.3 (i-C), 159.2, 190.8 (CHO). MS (EI): m/z (%) = 298
(0.10 g, 0.32 mmol, 1.0 equiv) in dry THF (40 mL) at
–90 °C. After the addition was complete the reaction was
+
+
allowed to warm to –80 °C and was kept at this temperature
for a further 15 min. During the addition the reaction became
a clear red colour. Note: If precipitation occurs during this
addition the yield is dramatically decreased. Dry DMF
(5) [M – CHO] , 262 (10) [M – Br] , 234 (10) [M – CHO
+
+
+
– Br] , 181 (12) [M – 2Br] , 105 (35), [C H NCHO] , 76
(100) [C H N] . HRMS (EI): m/z calcd for C H Br N O
( Br): 339.8841; found: 339.8839.
5
3
+
5
3
11
6
2
2
7
9
(
0.030 mL, 0.38 mmol, 1.2 equiv) in Et O (10 mL) was then
(13) The X-ray data have been deposited at the Cambridge
Crystallographic Database: CCDC 299072.
2
slowly added to the reaction mixture. After the addition was
Synlett 2006, No. 11, 1759–1761 © Thieme Stuttgart · New York