A facile synthetic approach to the preparation of 3-pyridyl derivatives: Preparations and coupling reactions of 3-pyridylzinc and its analogues

Article abstract of DOI:10.1055/s-0029-1217000

A facile synthetic approach to the direct preparation of 3pyridylzinc bromide has been demonstrated using Rieke zinc with 3-bromopyridine in the presence of a catalytic amount of lithium chloride. A variety of different electrophiles have been coupled to give the corresponding cross-coupling products in moderate to good yields. Also, this methodology has been expanded to the preparation of the corresponding organozinc reagents of 3-bromopyridine analogues. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217000

PAPER
3823
A Facile Synthetic Approach to the Preparation of 3-Pyridyl Derivatives:
Preparations and Coupling Reactions of 3-Pyridylzinc and Its Analogues
P
reparation of
e
3-Pyridyl
D
u
e
rivatives ng-Hoi Kim, Tim B. Slocum, Reuben D. Rieke*
Rieke Metals Inc., 1001 Kingbird Rd., Lincoln, NE 68521, USA
E-mail: sales@riekemetals.com
Received 20 May 2009
route has limitations such as cryogenic conditions, several
side-reactions and limited functional-group tolerance.9
Abstract: A facile synthetic approach to the direct preparation of 3-
pyridylzinc bromide has been demonstrated using Rieke zinc with
3-bromopyridine in the presence of a catalytic amount of lithium
chloride. A variety of different electrophiles have been coupled to
give the corresponding cross-coupling products in moderate to good
yields. Also, this methodology has been expanded to the preparation
of the corresponding organozinc reagents of 3-bromopyridine ana-
logues.
Very few studies have reported the direct synthesis of 3-
pyridylmetallic halide reagents. Most of these reports in-
clude the treatment of 3-iodo- or 3-bromopyridine with
highly active metals (Ca, Mg, Zn).10 The subsequent cou-
pling reactions were also carried out with a limited num-
ber of electrophiles. In these studies, 3-bromopyridine
was generally used with active magnesium and calcium.
Interestingly, for the preparation of 3-pyridylzinc halide
via the direct method, 3-iodopyridine was exclusively
used. To our best knowledge, there is only one example of
the direct preparation of 3-pyridylzinc bromide utilizing
3-bromopyridine and, in this case, a very low yield was
obtained from the subsequent cross-coupling reaction.10a
Key words: 3-pyridylzinc bromide, coupling reaction, heterocyclic
derivatives
Heterocyclic compounds which contain a pyridine func-
tion have frequently been found in natural products that
have biological activity, especially in pharmaceutical,
agrochemical and medicinal chemistry.1 For example, bi-
pyridine groups were found to be a key element in antibi-
otics such as caerulomycins and collismycins.2 Other
examples are the pyridylpyrimidines, which are used as
fungicides, as well as tyrosine kinase inhibitors.3 In addi-
tion, pyridine-containing oligomers are frequently found
in liquid crystals used in material chemistry.4
In our continuing study of active zinc and cross-coupling
reactions of organozinc reagents, it has been found that
Rieke zinc, in the presence of certain additives, exhibits a
very high reactivity to 3-bromopyridine. Therefore, here
we would like to report a facile synthetic method for the
direct preparation of 3-pyridylzinc bromide and its cou-
pling reactions.
As described above, the pyridine moiety has played a very
significant role in a wide range of organic compounds.
Consequently, new practical synthetic approaches for in-
troducing pyridine rings into complex organic molecules
are of high value.
The first attempt to synthesize 3-pyridylzinc bromide
from the direct reaction of active zinc and 3-bromopyri-
dine in tetrahydrofuran at room temperature under reflux
resulted in low conversion (70%) to the organozinc re-
agent. Almost the same result was obtained after an ex-
tended reaction time (reflux, 24 h). However, as shown in
Scheme 1, a dramatic improvement in the oxidative addi-
tion of active zinc was achieved by adding 10–20 mol%
of lithium chloride to the reaction mixture. Even though
the role of the lithium chloride has not been totally ex-
plained, more than 99% conversion of 3-bromopyridine
into 3-pyridylzinc bromide was obtained in two hours at
reflux in tetrahydrofuran. As was pointed out in 1989,11
the rate-limiting step in the oxidative addition is electron
transfer. Accordingly, this process will be accelerated by
the presence of alkali salts, which can either be generated
in the reduction process of forming the active metals or by
addition of salts to the reaction mixture.12
Preparation of pyridyl derivatives are mostly performed
using transition-metal-catalyzed cross-coupling reactions
of pyridylmetallic reagents. However, the preparation of
electron-deficient aryl organometallic reagents has been a
challenging subject.
Even though there are many examples of the preparation
of 2-pyridylmetallic halides from the reaction of halopy-
ridines, only a limited number of studies have been re-
ported on the preparation of 3-pyridylmetallic halides.
3-Pyridylmagnesium,5 3-pyridylzinc,6 3-pyridylindium
halides7 and Suzuki reagents8 are the most widely used
reagents for the preparation of pyridine-containing com-
pounds.
Lithiation of 3-halopyridine followed by transmetallation
with the appropriate metals (Mg, Zn, In) have afforded the
corresponding 3-pyridylmetallic halides. However, this
Br
ZnBr
I
I2
Zn*
+
LiCl (20 mol%)
THF, reflux
THF
N
N
N
N
SYNTHESIS 2009, No. 22, pp 3823–3827
x
x.
x
x
.
2
0
0
9
Advanced online publication: 09.09.2009
DOI: 10.1055/s-0029-1217000; Art ID: M02609SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Preparation of 3-pyridylzinc bromide

3824
S.-H. Kim et al.
PAPER
In order to confirm the formation of 3-pyridylzinc bro-
mide, the resulting organozinc reagent was first treated
with iodine to afford 90% 3-iodopyridine and 3% pyri-
dine. The resulting 3-pyridylzinc bromide was added to a
variety of electrophiles to give the corresponding cou-
pling products in moderate to good yields. The results are
summarized in Table 1. Palladium-catalyzed cross-cou-
pling reactions with aryl iodides 2a–c (Table 1) were
complete in one hour at room temperature and gave the
corresponding 3-pyridylbenzene derivatives in good
yields (entries 1–3, Table 1). Longer reaction times were
required with aryl iodides 2d and 2e, bearing a substituent
in the 2-position (entries 4 and 5, Table 1), which is prob-
ably due to steric hindrance. With this result in hand, het-
eroaryl iodides 2f–h were also coupled with 3-pyridylzinc
bromide to afford the corresponding heteroaryls 3f–h in
good yields. Coupling reactions with heteroaryl bromides
2i and 2j required longer reaction times but also afforded
the expected coupling products 3i and 3j in 86% and 29%
isolated yields, respectively. As shown in entries 4 and 7
in Table 1, the carbon–iodine bond was selectively react-
ed in coupling reactions with the organozinc reagent 1a to
form the required carbon–carbon bond under the condi-
tions used here. Even though a low yield was obtained
from 2,6-dibromopyridine (2j), the coupling product 3j,
bearing a bromine atom, can serve as a valuable interme-
diate for the preparation of a variety of materials. Interest-
ingly, it was also possible to obtain the aromatic ketone 3k
in moderate yield from the reaction of 1a with benzoic
acid anhydride (2k) in the presence of the palladium cata-
lyst.
Table 1 Palladium-Catalyzed Coupling Reactions of 3-Pyridylzinc
Bromidea
ZnBr
Pd(PPh3)4
+
electrophile
Ar
THF
N
N
Entry Electrophile
Time Product
(h)
Yield
(%)b
CN
I
CN
1
1
65
81
N
2a
3a
OMe
I
OMe
2
1
N
2b
3b
OMe
OMe
OMe
I
3
1
63
N
OMe
2c
3c
F
Br
4
5
24
63
32
N
I
Br
F
2d
3d
I
12
N
MeS
MeS
2e
3e
I
6
7
1
1
71
62
N
N
N
N
N
In order to expand the application of 3-pyridylzinc bro-
mide, several copper-catalyzed coupling reactions were
also investigated; the results are summarized in Table 2.
SN2¢-type reactions were conducted with allyl halides to
afford the expected products 4a and 4b (Table 2) in good
to moderate yields, respectively. In the presence of
TMSCl, silyl enol ether 4c (Table 2) was obtained from
the conjugate addition intermediate. Like other general or-
ganozinc reagents, 3-pyridylzinc bromide (1a) was also
successfully used for the copper-catalyzed synthesis of
ketone compounds. As shown in Tables 2, 10 mol% of
copper(I) iodide promoted the coupling reaction with 1a
to give the ketones 3k and 4d–f in moderate yields under
the conditions described in Table 2.
2f
3f
Br
I
Br
N
2g
3g
I
8
9
1
48
48
71
86
29
S
N
S
3h
2h
S
Br
S
N
2i
3i
Br
This study was expanded to include several analogues of
3-bromopyridine. As described in Tables 3, 3-bromoquin-
oline and 3-bromoisoquinoline were treated with active
zinc along with 20 mol% of lithium chloride. It was found
that the oxidative addition of active zinc was complete in
two hours at reflux to give the corresponding organozinc
reagents 1b and 1c (Table 3). The subsequent coupling re-
actions of 1b were performed with aryl iodide (entry 1,
Table 3) and heteroaryl iodides (entries 2 and 3, Table 3)
in the presence of palladium catalyst, to afford the corre-
sponding products 5a–c in moderate to good isolated
yields. Entries 4 and 5 in Table 3 show the results of the
coupling reactions of 1c with heteroaryl iodide and allyl
10
N
N
N
Br
Br
2j
3j
O
O
O
11
12
38
Ph
O
Ph
N
2k
3k
a Reaction conditions: electrophile (0.8 equiv), Pd[P(Ph)3]4 (1 mol%),
r.t., THF.
b Isolated yield (based on electrophile).
Synthesis 2009, No. 22, 3823–3827 © Thieme Stuttgart · New York

PAPER
Preparation of 3-Pyridyl Derivatives
3825
Table 2 Copper-Catalyzed Coupling Reactiona
ZnBr
CuI
product
+
electrophile
THF
N
Entry
Electrophile
Temp (°C)
Time (h)
10 min
Product
Yield (%)b
1
2
0
0
71
50
Br
N
4a
Cl
10 min
N
Cl
Cl
4b
3c
0 to r.t.
0 to r.t.
24
48
50
N
O
OSiMe3
4c
O
COCl
4
12
12
12
12
N
3k
4d
4e
4f
O
O
O
COCl
5
6
7
0 to r.t.
0 to r.t.
0 to r.t.
69
38
50
N
N
N
COCl
COCl
S
S
a Reaction conditions: electrophile (0.8 equiv), CuI (10 mol%), THF.
b Isolated yield (based on electrophile).
c Reaction was conducted in the presence of TMSCl (1.0 equiv).
chloride. From these reactions, more new heteroaryl com- to give the corresponding cross-coupling products in
pounds 4d–e were obtained in moderate yields (Table 3). moderate to good yields. Furthermore, this methodology
has been expanded to the preparation of the corresponding
Finally, the regio-stability of 3-pyridylzinc bromide was
organozinc reagents of 3-bromopyridine analogues. Stud-
confirmed by two additional coupling reactions. These re-
ies on more applications of this methodology are currently
sults are listed in Table 4. It can be concluded that 3-py-
ridylzinc bromide prepared via direct oxidative addition
underway.
of active zinc to 3-bromopyridine was stable enough to be
used for the coupling reactions under the appropriate con-
ditions without scrambling of the organometallic position.
All reactions were performed under argon pressure. Active zinc was
prepared by a literature method.11 Other commercially available re-
agents including the solvent (THF, from Aldrich) were used without
further purification. Flash chromatography was carried out on Kie-
selgel 60 (230–400 mesh). NMR spectra were recorded at 300 or
500 MHz using CDCl3 (TMS). All melting points are uncorrected.
In conclusion, a facile synthetic approach to the direct
preparation of 3-pyridylzinc bromide has been demon-
strated. The reaction was easily performed using Rieke
zinc with 3-bromopyridine, in the presence of a catalytic
amount of lithium chloride. With the resulting 3-pyridyl-
zinc bromide, a variety of electrophiles have been coupled
Preparation of 3-Pyridylzinc Bromide (1a)
An oven-dried 100 mL round-bottomed flask was charged with ac-
tive Zn (3.3 g, 50 mmol) in THF (30 mL) and LiCl (0.2 g, 20 mol%)
Synthesis 2009, No. 22, 3823–3827 © Thieme Stuttgart · New York

3826
S.-H. Kim et al.
PAPER
Table 3 Preparation of Quinoline and Isoquinoline Derivatives via Heteroarylzinc Reagentsa
Entry
1
Organozinc
Electrophile
Catalyst
Temp
r.t.
Product
Yield (%)b
CN
ZnBr
ZnBr
ZnBr
CN
Pd(PPh3)4
70
N
I
N
N
1b
5a
5b
2
3
Pd(PPh3)4
Pd(PPh3)4
r.t.
r.t.
65
53
N
N
N
I
1b
S
I
N
S
N
1b
5c
ZnBr
N
N
4
5
Pd(PPh3)4
r.t.
37
35
N
N
I
1c
1c
5d
5e
ZnBr
N
CuIc
0 °C to r.t.
Cl
N
a Reaction conditions: electrophile (0.8 equiv), catalyst (1 mol%), 1 h, THF.
b Isolated yield (based on electrophile).
c 10 mol% catalyst used.
Table 4 Comparison of Physical Dataa
Entry
Organozincb
Electrophile
Product
Result
Mp (°C)
3-pyridylzinc bromide
1a
OMe
1
2b
orange solid
56–58
N
3b
oil at r.t.
(68%)c
OMe
2
3
4
2-pyridylzinc bromide
2b
2i
–
–
N
3bb
S
S
3-pyridylzinc bromide
1a
oil at r.t.
N
3i
off-white solid
(68%)c
2-pyridylzinc bromide
2i
61–62
N
3ii
a Reaction conditions: electrophile (0.8 equiv), Pd(PPh3)4 (1 mol%), r.t., THF.
b Prepared using active zinc.
c Isolated yield (based on electrophile).
Synthesis 2009, No. 22, 3823–3827 © Thieme Stuttgart · New York

PAPER
Preparation of 3-Pyridyl Derivatives
3827
under a positive pressure of argon gas. 3-Bromopyridine (3.9 g, 25
mmol) was added to the solution of active zinc at r.t. and the result-
ing mixture was then stirred at reflux for 2 h. After cooling to r.t.,
the supernatant was used for the subsequent coupling reactions.
(3) (a) Hargreaves, S. L.; Pilkington, B. L.; Russell, S. E.;
Worthington, P. A. Tetrahedron Lett. 2000, 41, 1653.
(b) Zimmermann, J.; Buchdunger, E.; Mett, H.; Meyer, T.;
Lydon, N. B. Bioorg. Med. Chem. Lett. 1997, 7, 187.
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Lydon, N. B. Bioorg. Med. Chem. Lett. 1996, 6, 1221.
(4) Getmanenko, Y. A.; Twieg, R. J. J. Org. Chem. 2008, 73,
830.
Palladium-Catalyzed Cross-Coupling Reactions; Typical Pro-
cedure
3-(4-Methoxyphenyl)pyridine (3b)
A 50 mL round-bottomed flask equipped with a stirring bar, a ther-
mometer and a septum, was charged with Pd(PPh3)4 (0.1 g) and then
a solution of 3-pyridylzinc bromide (0.5 M in THF, 20 mL 10
mmol) was added into the flask via a syringe. Next, whilst being
stirred at r.t., 4-iodoanisol (1.8 g, 8 mmol) in THF (5.0 mL) was
added. After stirring at r.t. for 1.0 h, the reaction mixture was
quenched with sat. NH4Cl (20 mL), then extracted with Et2O
(3 × 20 mL), washed with sat. Na2S2O3 (50 mL) and brine (50 mL),
then dried over MgSO4. The mixture was purified by flash column
chromatography on a silica gel column (EtOAc–heptanes, 10%) to
afford 2b as a light-orange solid (1.2 g, 81% isolated yield).
(5) (a) Furukawa, N.; Shibutani, T.; Fujihara, H. Tetrahedron
Lett. 1987, 28, 5845. (b) Berillon, L.; Lepretre, A.; Turck,
A.; Ple, N.; Queguiner, G.; Cahiez, G.; Knochel, P. Synlett
1998, 1359. (c) Trecourt, F.; Breton, G.; Mongin, F.;
Marsais, F.; Queguiner, G. Tetrahedron Lett. 1999, 40,
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Berillon, L.; Dehmel, F.; Rottlander, M.; Knochel, P. J. Org.
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Copper-Catalyzed Cross-Coupling Reactions; Typical Proce-
dure
Cyclohexyl 3-Pyridyl Ketone (3d)
A 50 mL round-bottomed flask equipped with a stirring bar, a ther-
mometer and a septum, was charged with CuI (0.2 g, 10 mol%) and
a solution of 3-pyridylzinc bromide (0.5M in THF, 20 mL, 10
mmol). The flask was cooled to 0 °C and, whilst being stirred at
0 °C, cyclohexanecarbonyl chloride (1.16 g, 8 mmol) was added via
syringe. The resulting mixture was allowed to warm gradually and
then stirred at r.t. for 12 h. The reaction mixture was quenched with
sat. NH4Cl (20 mL) and then extracted with Et2O (3 × 20 mL). The
combined organic plases were washed with 7% NH4OH (50 mL),
sat. Na2S2O3 (50 mL), NaHCO3 (50 mL) and brine (50 mL), then
dried over MgSO4. The mixture was purified by flash column chro-
matography on a silica gel column (EtOAc–heptanes, 5%) to afford
3d as a light-yellow oil (1.3 g, 69% isolated yield).
(7) (a) Font-Sanchis, E.; Cespedes-Guirao, F. J.; Sastre-Santos,
A.; Fernandez-Lazaro, F. J. Org. Chem. 2007, 72, 3589.
(b) Lee, P. H.; Seomoon, D.; Lee, K. Org. Lett. 2005, 7, 343.
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and 5f.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
(10) (a) Sakamoto, T.; Kondo, Y.; Murata, N.; Yamanaka, H.
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Synthesis 2009, No. 22, 3823–3827 © Thieme Stuttgart · New York