Directed deprotonation-transmetallation of 4-bromopyridine: Flexible routes to substituted pyridines

Article abstract of DOI:10.1055/s-2002-25342

Halide-directed deprotonation and Li-Zn exchange of 4-bromopyridine 4 provides organozinc 6, which undergoes Pd-mediated coupling to give the 3-aryl-4-bromopyridines 7. Further substitution is achieved to provide the 3,4-disubstituted pyridines 8 and 9, a

Full text of DOI:10.1055/s-2002-25342

808
LETTER
Directed Deprotonation-Transmetallation of 4-Bromopyridine:
Flexible Routes to Substituted Pyridines
D
eprotonation-Tra
u
nsmetallation of 4-Bromo
t
pyridin
e
e
r Karig,a Nopporn Thasana,a,b,c Timothy Gallagher*a
a
School of Chemistry, University of Bristol, Bristol BS8 1TS, UK
Fax +44(117)9298611; E-mail: T.Gallagher@bristol.ac.uk
b
c
Chulabhorn Research Institute, Bangkok 10210, Thailand
Department of Chemistry, Mahidol University, Bangkok 10400, Thailand
Received 8 March 2002
reactant is commercially available as the hydrochloride
salt, but the free base is unstable and (unlike 2- or 3-
bromopyridine) is prone to rapid polymerization.
Abstract: Halide-directed deprotonation and Li-Zn exchange of
4-bromopyridine 4 provides organozinc 6, which undergoes Pd-
mediated coupling to give the 3-aryl-4-bromopyridines 7. Further
substitution is achieved to provide the 3,4-disubstituted pyridines 8
and 9, and the 3,4,5-trisubstituted variants 10.
Deprotonation of 4-bromopyridine 4 (HCl salt) was
carried out using LDA (2.2 equiv) in THF essentially as
described by Gribble,4 except that we conducted this step
at –78 °C rather than use lower temperatures (–90 °C,
Scheme 2). ZnCl2 (in THF) was added and the resulting
mixture was allowed to warm to room temperature. While
the organolithium intermediate 5 is prone to decom-
position, the corresponding organozinc derivative 6
appears to be stable at room temperature if kept under an
inert atmosphere. Exposure of 6 to an aryl iodide in the
presence of Pd(PPh3)4 (10 mol%) gave the 3-aryl-4-
bromopyridines 7a–d in 34–53% yield.5,6 These yields,
which are based on the aryl iodide, are significantly lower
than the corresponding reactions involving 2-bromo-
pyridine or 3-bromopyridine, and likely reflect the
instability associated with the 4-bromo substituent of both
4 and 7. By-products from these processes, though not
fully characterized, did incorporate diisopropylamine. A
more hindered base should suppress such side reactions,
and it is interesting to note that use of lithium 2,2,6,6-
tetramethylpiperidide (LiTMP)7 gave 7c in 46% yield
(compared to 34% with LDA).
Key words: directed lithiation, transmetallation, cross-coupling,
zinc, pyridine
We1 recently described an entry to ring substituted
pyridines based on a sequence involving (i) the halide-
directed deprotonation (ii) transmetallation to generate a
pyridyl organozinc and (iii) Pd(0)-mediated Negishi cross
coupling.2,3 This methodology is illustrated in Scheme 1
for 3-bromopyridine 1, which leads to 3, 4-disubstituted
pyridines such as 2 and 3. Similar methodology applied
to 2-bromopyridine provides access to 2,3- and also 2,4-
disubstituted heteroarenes.1
Ar
ZnCl
Br
Br
Br
1. LDA
ArX
Pd(0)
2. ZnCl2
N
N
N
1
2
Ar
Ar'
Ar'B(OH)2
Pd(0)
Furthermore, the 4-bromopyridines 7 are capable of
undergoing both Suzuki cross couplings8 and Heck
reactions to provide the 3,4-diarylpyridines 8a–c and 3-
aryl-4-alkenylpyridines 9a and 9b.
N
3
Scheme 1
The role of the C(4) bromo substituent in 4 is to assist and
direct deprotonation at C(3). With substitution to give 7
complete, the C(5) proton remains available for activation
and substitution, providing a vehicle for 3,5-diarylation.
This has been achieved, and exposure of 7d to LDA at
–78 °C, followed by ZnCl2 (–78 °C to r.t.) and Pd(0)-
mediated coupling with either 1-iodo-4-nitrobenzene or
iodobenzene gave 4-bromo-3-(4-nitrophenyl)-5-phenyl-
pyridine 10a and 4-bromo-3,5-diphenylpyridine 10b in
34% and 44% yields respectively (Scheme 3).9,10
In this paper we describe the application of this directed
deprotonation, transmetallation, cross coupling sequence
to 4-bromopyridine 4.4 This is significant because this
substrate complements 3-bromopyridine in terms of the
substitution and reactivity profiles that are available. In
addition, we have found that 4 undergoes sequential
substitution at C(3) and then C(5) to provide 3,4,5-
trisubstituted pyridines. These transformations are
illustrated, together with the products obtained, in
Schemes 2 and 3. It is also pertinent to recognize the
issues associated with use of 4-bromopyridine. This
In summary, we have extended the scope of the directed
deprotonation-transmetallation of bromopyridines to
include 4-bromopyridine 4. The instability of the 4-bromo
moiety is a complication that does not apply to the other
bromopyridines, nevertheless the 3-pyridyl zinc inter-
mediate 6 is available and undergoes Negishi coupling to
Synlett 2002, No. 5, 03 05 2002. Article Identifier:
1437-2096,E;2002,0,05,0808,0810,ftx,en;D05402ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Deprotonation-Transmetallation of 4-Bromopyridine
809
References
Br
Br
Br
N
M
(1) Karig, G.; Spencer, J. A.; Gallagher, T. Org. Lett. 2001, 3,
835.
(2) (a) For comprehensive reviews on the metallation of
pyridines and diazines, see: Turck, A.; Plé, N.; Mongin, F.;
Quéguiner, G. Tetrahedron 2001, 57, 4489. (b) Mongin, F.;
Quéguiner, G. Tetrahedron 2001, 57, 4059.
(3) For other recent and related examples of Li-Zn
transmetallations, see: (a) Gros, P.; Fort, Y. Synthesis 1999,
754. (b) Kristensen, J.; Begtrup, M.; Vedsø, P. Synthesis
1998, 1604. (c) Felding, J.; Uhlmann, P.; Kristensen, J.;
Vedsø, P.; Begtrup, M. Synthesis 1998, 1181.
(4) (a) Gribble, G. W.; Saulnier, M. G. Heterocycles 1993, 35,
151. (b) See also: Numata, A.; Kondo, Y.; Sakamoto, T.
Synthesis 1999, 306.
Ar
iii
i
N
N
4
5 M=Li
7a Ar=C6H4-4-NO2 34%
7b Ar=C6H4-4-OMe 48%
7c Ar=3-pyridyl 34%
7d Ar=C6H5 53%
ii
(HCl salt)
6 M=ZnCl
CO2Et
Ar'
Br
Ar
Ar
Ar
N
iv or v
N
N
N
(5) All new compounds have been fully characterized by IR, 1H
and 13C NMR, and HRMS. Selected data are presented
below. It is noteworthy that the bromo moiety of 6 does not
participate in a ‘homocoupling’ process [i.e. a Pd(0)-
mediated dimerization of 6], and only the cross coupled
product 7 is observed. Furthermore, in addition to aryl
iodides, organozinc 6 has also been coupled successfully to
vinyl triflates.
8
7
9
OMe
NO2
Ph
N
Ph
N
N
8b 27%
8a 49%
8c 35%
N
(6) We used an excess (2.5 equiv as compared to the aryl iodide)
of 4-bromopyridine and yields are based on the aryl iodide
component. A solution of LDA [from diisopropylamine (1.4
mL, 10 mmol), n-BuLi (4 mL, 2.5 M in hexanes, 10 mmol)
in THF (5 mL)] was transferred to a solution of 4-bromo-
pyridine hydrochloride (970 mg, 5 mmol) in THF (5 mL) at
–78 °C and stirred for 30 min. Dry ZnCl2 (700 mg, 5 mmol)
in THF (5 mL) was added. A precipitate was formed and the
mixture was allowed to warm to room temperature. Aryl
iodide (2 mmol) and Pd(PPh3)4 (0.06 g, 0.05 mmol) were
added and the reaction mixture was heated to reflux for 3
hours. After cooling, sat. aq NH4Cl was added, and the
product was extracted with EtOAc, the extracts were washed
with water, dried (MgSO4), and evaporated under reduced
pressure. Purification by silica gel flash chromato-graphy
gave the 3-aryl-4-bromopyridines 7.
CO2Et
CO2Et
OMe
NO2
9a 56%
9b 61%
N
N
Scheme 2 Reagents: i, LDA (2.2. equiv), THF, –78 °C; ii, ZnCl2 (in
THF), –78 °C to r.t.; iii, ArX (X = I or Br), Pd(PPh3)4, THF, reflux;
iv, Suzuki: Ar B(OH)2, Pd(PPh3)4, Na2CO3, PhMe, EtOH, reflux; v,
Heck: CH2=CHCO2Et, Pd(OAc)2, NEt3, P(o-Tol)3, MeCN, reflux.
Br
Br
Br
Ph
M
Ph
Ar
Ph
i
iii
Selected data for 3-aryl-4-bromopyridines: 7a: mp 169 °C
(EtOAc–hexane); 1H NMR (300 MHz, CDCl3) 7.63 (2 H,
d, J = 8.8 Hz, CH2 ,6 ), 7.68 (1 H, d, J = 5.3 Hz, CH5), 8.36
(2 H, d, J = 8.9 Hz, CH3 ,5 ), 8.46 (1 H, d, J = 5.3 Hz, CH6),
8.53 (1 H, s, CH2). 7b: mp 60-62 °C (EtOAc–hexane); 1H
NMR (300 MHz, CDCl3) 3.87 (3 H, s, OCH3), 7.01 (2 H,
d, J = 8.8 Hz, CH3 ,5 ), 7.37 (2 H, d, J = 8.8 Hz, CH2 ,6 ),
7.61 (1 H, dd, J = 0.4, 5.3 Hz, CH5), 8.33 (1 H, d, J = 5.3 Hz,
CH6), 8.50 (1 H, s, CH2). 7c: mp 69–70 °C (EtOAc:hexane);
1H NMR (300 MHz, CDCl3) 7.43 (1 H, dd, J = 5.1, 7.9, Hz,
CH5 ), 7.67 (1 H, d, J = 5.3 Hz, CH5), 7.79 (1 H, d, J = 7.9
Hz, CH4 ), 8.44 (1 H, d, J = 5.2 Hz, CH6), 8.53 (1 H, s,
CH2), 8.70 (2 H, s, CH2 ,6 ). 7d: oil 1H NMR (300 MHz,
CDCl3) 7.44 (5 H, m, PhH), 7.61 (1 H, dd, J = 0.5, 5.3 Hz,
CH5), 8.33 (1 H, d, J = 5.3 Hz, CH6), 8.51 (1 H, s, CH2).
(7) LiTMP has found valuable application in the metallation of
diazines: (a) Mojovic, L.; Turck, A.; Plé, N.; Dorsy, M.;
Ndzi, B.; Quéguiner, G. Tetrahedron 1996, 52, 10417.
(b) Plé, N.; Turck, A.; Heynderickx, A.; Quéguiner, G.
Tetrahedron 1998, 54, 9701. (c) Turck, A.; Plé, N.;
Lepretre-Gaquere, A.; Quéguiner, G. Heterocycles 1998, 49,
205. (d) Also, LiTMP and zincate-based derivatives
influence the regiochemisty of the deprotonation of 2-
bromopyridines. See ref.1 and: Imahori, T.; Uchiyama, M.;
Sakamoto, T.; Kondo, Y. Chem. Commun. 2001, 2450.
N
N
N
10a Ar=C6H4-4-NO2 34%
10b Ar=Ph 44%
M=Li
7d
ii
M=ZnCl
Scheme 3 Reagents: i, LDA (1.1 equiv), THF, –78 °C; ii, ZnCl2 (in
THF), –78 °C to r.t.; iii, ArI (see text), Pd(PPh3)4, THF, reflux.
give a range of 3,4-disubstituted derivatives, com-
plementing the regiochemistry available for 3-bromo-
pyridine (compare 3 and 8). Furthermore, substitution at
both C(3) and C(5) can be accomplished in a stepwise
manner leading to more highly substituted pyridines, such
as 10.
Acknowledgement
We thank the Biomolecular Sciences Panel (BBSRC/EPSRC), and
NT thanks the Thailand Research Fund for award of a Royal Golden
Jubilee Scholarship through Professor Somsak Ruchirawat.
Synlett 2002, No. 5, 808–810 ISSN 0936-5214 © Thieme Stuttgart · New York

810
G. Karig et al.
LETTER
in THF (2 mL) at –78 °C and stirred for 30 min. ZnCl2
(8) General procedure for Suzuki coupling of 7 to give 8: To the
4-bromo-3-arylpyridines 7 (0.2 mmol) in toluene (9 mL) and
EtOH (1 mL) were added aryl boronic acid (0.25 mmol),
Pd(PPh3)4 (0.02 g, 0.017 mmol) and 10% aq Na2CO3
(3 mL). The mixture was heated at reflux for 3 hours, then
cooled, filtered, and extracted with EtOAc. The extracts
were washed with water, dried (MgSO4), concentrated and
the product was isolated following flash chromatography.
Selected data for 3,4-diarylbromopyridines: 8a mp 124–125
°C (EtOAc–hexane); 1H NMR (300 MHz, CDCl3) 7.13 (2
H, m, CH3 ,5 ), 7.31 (3 H, m, CH2 ,4 ,6 ), 7.33 (2 H, d, J
= 8.9 Hz, CH2 ,6 ), 7.40 (1 H, d, J = 4.9 Hz, CH5), 8.15 (2
H, d, J = 8.9 Hz, CH3 ,5 ), 8.66 (1 H, s, CH2); 8.71 (1 H,
br.d, J = 4.0 Hz, CH6). 8b mp 110–111 °C (EtOAc–hexane);
1H NMR (300 MHz, CDCl3) 3.80 (3 H, s, OCH3), 6.81 (2
H, d, J = 8.6 Hz, CH3 ,5 ), 7.07 (2 H, d, J = 8.6 Hz, CH2 ,6 ),
7.17 (2 H, m, CH3 ,5 ), 7.28 (3 H, m, CH2 ,4 ,6 ), 7.33 (1
H, d, J = 5.1 Hz, CH5), 8.60 (1 H, br.d, CH6); 8.62 (1 H, br.s,
CH2). 8c mp 133–134 °C (EtOAc–hexane); 1H NMR (300
MHz, CDCl3) 7.21–7.25 (2 H, m, CH5 ,5 ), 7.41 (1 H, dd,
J = 0.7, 4.6 Hz, CH5), 7.44 (2 H, m, CH4 ,4 ), 8.46 (2 H, m,
CH2 ,2 ), 8.57 (2 H, m, CH6 ,6 ), 8.70 (1 H, br.s, CH2);
8.75 (1 H, d, J = 4.6 Hz, CH6).
(138 mg, 1 mmol) in THF (2 mL) was added. A precipitate
was formed and the mixture was allowed to warm to room
temperature. 1-Iodo-4-nitrobenzene (or iodobenzene)
(1 mmol) and Pd(PPh3)4 (0.015 g, 0.01 mmol) were added
and the reaction mixture was heated at reflux for 3 hours.
After cooling, saturated aqueous NH4Cl was added, and the
product was extracted with EtOAc, the extracts were washed
with water, dried (MgSO4), and evaporated under reduced
pressure. Purification by silica gel flash chromatography
gave the 3,5-diaryl-4-bromopyridines 10.
Selected data for 3,5-diaryl-4-bromopyridines: 10a mp 153–
154 °C (EtOAc–hexane); 1H NMR (300 MHz, CDCl3)
7.48 (5 H, m, PhH), 7.53 (2 H, d, J = 9.0 Hz, CH3 ,5 ), 8.36
(2 H, d, J = 9.0 Hz, CH2 ,6 ), 8.45 (1 H, s, CH2); 8.53 (1 H,
s, CH6); 13C NMR (75 MHz, CDCl3) 123.6 (CH), 128.4
(CH), 128.6 (CH), 129.5 (CH), 130.8 (CH), 133.0 (C), 137.2
(C), 137.3 (C), 139.4 (C), 144.3 (C), 147.8 (C),148.8 (CH),
150.5 (CH). 10b mp 116–117 °C (EtOAc–hexane); 1H NMR
(300 MHz, CDCl3) 7.48 (10 H, m, PhH), 8.45 (2 H, s, CH2,
6); 13C NMR (75 MHz, CDCl3) 128.3 (CH), 128.4 (CH),
129.6 (CH), 133.4 (C), 137.9 (C), 139.1 (C), 149.4 (CH).
(10) 3,5-Diaryl-4-bromopyridines have been reported in two
previous publications: (a) West, S. D. J. Agric. Food Chem.
1978, 26, 644. (b) Taylor, H. M.; Suhr, R. G. US Pat. Appl.
4174209, 1979; Chem. Abstr. 1980, 92, 76309c..
(9) A solution of LDA [from diisopropylamine (0.35 mL, 2
mmol), n-BuLi (1 mL, 2.0 M in hexanes, 2 mmol) in THF (2
mL)] was transferred to a solution of 7d (250 mg, 1 mmol)
Synlett 2002, No. 5, 808–810 ISSN 0936-5214 © Thieme Stuttgart · New York