Convenient one-pot procedures for the synthesis of 2,2′:6′, 2″-terpyridine

Article abstract of DOI:10.1080/00397910600616750

One-pot reactions to produce 2,2′:6′,2″-terpyridine (tpy) under mild conditions are described under both solventless and solvent-assisted conditions. Tpy can be obtained in 32% yield in a simple one-pot reaction, which can readily be scaled-up to give large quantities of tpy. These new approaches are superior to those previously described because of the fast and efficient synthesis and purification of tpy. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600616750

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Convenient One‐Pot Procedures for the
Synthesis of 2,2′:6′,2″‐Terpyridine
a
a
a
Michael W. Cooke , Jianhua Wang , Isabelle Theobald & Garry S. Hanan
a
a
Chemistry Department, University of Montréal, Montréal, Québec, Canada
Version of record first published: 22 Aug 2006.
To cite this article: Michael W. Cooke , Jianhua Wang , Isabelle Theobald & Garry S. Hanan (2006):
Convenient One‐Pot Procedures for the Synthesis of 2,2′:6′,2″‐Terpyridine, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:12, 1721-1726
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Synthetic Communications , 36: 1721–1726, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600616750
Convenient One-Pot Procedures for the
0
0
00
Synthesis of 2,2 :6 ,2 -Terpyridine
Michael W. Cooke, Jianhua Wang, Isabelle Theobald,
and Garry S. Hanan
Chemistry Department, University of Montr e´ al, Montr e´ al, Qu e´ bec,
Canada
0
0
00
Abstract: One-pot reactions to produce 2,2 :6 ,2 -terpyridine (tpy) under mild
conditions are described under both solventless and solvent-assisted conditions.
Tpy can be obtained in 32% yield in a simple one-pot reaction, which can readily
be scaled-up to give large quantities of tpy. These new approaches are superior to
those previously described because of the fast and efficient synthesis and purification
of tpy.
Keywords: Green chemistry, heterocycles, nitrogen ligands, one-pot reactions,
terpyridine
0
0
00
Transition-metal complexes of 2,2 :6 ,2 -terpyridine (tpy) and its substituted
analogues possess interesting electrochemical, magnetic, and photophysical
[
1–7]
0
properties.
thesized and functionalized, the parent tpy ligand remains a highly utilized
Although 4 -substituted terpyridines are more easily syn-
[8–10]
component in organometallic and coordination assemblies.
Tpy itself is commercially available; however, the compound remains
relatively expensive considering the scale on which it is commonly used
and therefore is typically prepared. Two common methods to synthesize tpy
[
11–16]
involve carbon–carbon bond-forming reactions
[
and ring-forming
of which the ring-forming reaction is more prevalent. In
17–18]
reactions,
this respect, the methods developed by Hantzsch
[17]
[18]
and Potts et al.
Received in the USA December 14, 2005
Address correspondence to Garry S. Hanan, D e´ partement de chimie, Universit e´ de
Montr e´ al, 2900 Edouard-Montpetit, Montr e´ al, Qu e´ bec H3T 1J4, Canada. Tel.: 514-
343-7056; Fax: 514-343-2468; E-mail: garry.hanan@umontreal.ca
1
721

1
722
M. W. Cooke et al.
produce modest yields of unsubstituted terpyridines and involve multiple
steps. More recently, Jameson reported a significant improvement in the
yield of tpy via a two-step process in which a pyridyl-enaminone is
[19]
generated first, followed by a ring-forming reaction to produce tpy.
Jameson’s synthesis has undoubtedly become the preferred method to syn-
thesize tpy; however, several factors make it less attractive than the
methods proposed herein. The preparation and purification of the required
pyridyl-enaminone and the variations in the final yield of the reaction due
to the sensitivity of the potassium t-butoxide has led us to investigate more
rapid procedures capable of producing consistently large quantities of tpy.
In our first attempts to produce a one-pot procedure to synthesize tpy, a
1,5-diketone was generated in situ from a basic methanolic solution of para-
formaldehyde, 2-acetylpyridine, and potassium hydroxide (Scheme 1). After
refluxing the mixture in the presence of ammonium acetate and filtering it
through a plug of deactivated alumina, tpy was obtained in 10% yield in a
solvent-assisted reaction (method A) and in 6% yield in a solventless
reaction (method B). Although an excess of 2-acetylpyridine should favor
the formation of the desired 1,5-diketone intermediate, 6 equiv of 2-acetylpyr-
idine gave rise to a complex mixture that contained principally a cyclohexanol
and a cyclohexanediol by-product analogous to those found for condensation
0
[20]
reactions of 4 -aryl terpyridines.
Thus, a threefold excess of 2-acetylpyri-
dine gave large amounts of the cyclohexanediol and no tpy; however, a
twofold excess was found to give a 10% yield of tpy. Although the yields
obtained are low, the reaction is very amenable to scale-up and multigram
quantities of tpy can easily be prepared.
Considering a recent report on the efficient synthesis of substituted ter-
[21]
pyridines via solventless condensation and subsequent Michael addition,
the same reaction was attempted under solventless conditions. Paraformalde-
hyde and a stoichiometric amount of 2-acetylpyridine in the presence of
potassium hydroxide were ground for 30 min, and the mixture was then
Scheme 1. Synthesis of tpy from formaldehyde. Reagents and conditions: a) formal-
dehyde (33 mmol), 2-acetylpyridine (66 mmol), KOH (102 mmol), MeOH (150 mL)
1
6 h at rt, b) NH OAc (130 mmol), AcOH, reflux, 3 h.
4

Terpy
1723
dissolved and heated to reflux in acetic acid containing ammonium acetate
for 1.5 h. The reaction mixture was then filtered through a plug of deacti-
vated alumina, and pure tpy was obtained in 6% yield. Although the yield
was low as well, the short reaction time, the simplified experimental
procedure, and the suitability of the reaction to scale-up make this a reason-
able protocol for the synthesis of tpy. The main advantage of the solvent-
assisted and solventless procedures mentioned previously is that reasonable
quantities of tpy can be obtained quickly because of the shorter reaction
times and the simplified purification procedures, filtration, and recrystalliza-
tion, as opposed to the use of column chromatography to purify the tpy.
The highest yielding one-pot procedure has been optimized using a
combination of Chichibabin and Jameson approaches (Scheme 2). As with
the Jameson method, N,N-dimethylformamide dimethylacetal is reacted
with 2-acetylpyridine to give an enaminone in situ for subsequent Michael
addition. However, the enaminone is not isolated, and the enolate of 2-acetyl-
pyridine is generated with a methanolic solution of potassium and ammonium
hydroxide. The reaction conditions are less stringent than those of the
0
0 00
Jameson reaction as anhydrous conditions are not required. Pure 2,2 :6 2 -
terpyridine is obtained in 32% yield after stirring in EtOH at reflux
for 24 h followed by column chromatography and recrystallization
(
method C). This improved one-pot reaction can also be scaled up to give
0 g of tpy following a similar protocol, albeit in a slightly lower yield
method D).
In conclusion, we have presented three different one-pot procedures for
1
(
the synthesis of tpy, a useful synthon in coordination and supramolecular
chemistry. The highest yielding reaction provides useful quantities of tpy in
one single step.
EXPERIMENTAL
The properties of tpy prepared in the following methods were identical to
11–19]
[
those reported previously.
methods with RuCl gave a homoleptic Ru(tpy) complex with properties
The reaction of tpy prepared in any of the
2
þ
3
2
[
1]
identical to those previously reported.
Scheme 2. Generation of tpy from N,N-dimethylformamide dimethylacetal. Reagents
and conditions: N,N-dimethylformamide dimethylacetal (10 mmol), 2-acetylpyridine
(
20 mmol), KOH (20 mmol), NH OH (30 mmol), EtOH (50 mL), 24 h reflux.
4

1
724
M. W. Cooke et al.
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00
Method A: 2,2 :6 ,2 -Terpyridine Synthesis
In a typical reaction, paraformaldehyde (1 g, 0.033 mol) was dissolved in
methanol (150 mL) containing potassium hydroxide (5.74 g, 0.102 mol) and
2
-acetylpyridine (16.2 g, 0.132 mol). The reaction mixture was stirred at
room temperature for 16 h, after which time ammonium acetate (10 g,
.130 mol) was added, and the mixture was stirred at reflux for 3 h. The
0
methanol was removed under reduced pressure, and the remaining aqueous
residue was washed with chloroform (100 mLꢀ3). The combined organic
phases were dried, taken up in toluene, and purified by filtration through a
plug of 5% deactivated alumina using toluene as eluent and ferrous
ammonium sulfate as indicator. The desired fractions were collected and
dried under vacuum at 70 8C to remove residual 2-acetylpyridine and gave
0
0
00
2
,2 :6 ,2 -terpyridine (0.775 g, 10%) after recrystallization from hexane.
Elem. anal.: calc. C, 77.23; H, 4.75; N, 18.01; found C, 77.17; H, 4.77; N,
7.98.
1
Method B
In a typical reaction, paraformaldehyde (0.5 g, 0.0165 mol), 2-acetylpyridine
(4.03 g, 0.033 mol), and potassium hydroxide (1.87 g, 0.033 mol) were
ground in a mortar for 30 min. The resulting viscous residue was then
dissolved in acetic acid (40 mL), to which was added ammonium acetate
(5 g, 0.065 mol), and the mixture was stirred at reflux for 1.5 h. The crude
mixture was then tipped into water (400 mL) to give a fine precipitate,
which was isolated, dissolved in toluene, and purified by filtration through a
plug of 5% deactivated alumina using toluene as eluent and ferrous
ammonium sulfate as indicator. Evaporation of the combined tpy fractions
0
0
00
and recrystallization of the crude product gave 2,2 :6 ,2 terpyridine
0.235 g, 6%). Elem. anal. calc. C, 77.23; H, 4.75; N, 18.01; found C,
7.02; H, 4.75; N, 17.91.
(
7
Method C
In a typical reaction, 2-acetylpyridine (2.42 g, 0.020 mol), N,N-dimethylfor-
mamide dimethylacetal (1.19 g, 0.010 mol), potassium hydroxide (1.54 g,
0.020 mol), and ammonium hydroxide (29 mL, 0.030 mol) were combined
in absolute ethanol (50 mL). The solution was then heated to reflux for 24 h.
After cooling, the ethanol was removed under reduced pressure, and the
remaining aqueous solution was extracted with chloroform (30 mL ꢀ 3).
The combined organic phases were dried, taken up in toluene, and applied
to a short column of 5% deactivated alumina for purification using toluene
as eluent and ferrous ammonium sulfate as indicator. Evaporation of the

Terpy
1725
combined tpy fractions and recrystallization of the residue from hexane
0
0
00
affords 2,2 :6 ,2 -terpyridine (0.74 g, 32%). Elem. anal.: calc. C, 77.23; H,
.75; N, 18.01; found C, 77.08; H, 4.79; N, 17.89.
4
Method D
In a typical reaction, 2-acetylpyridine (60.6 g, 0.50 mol), N,N-dimethylforma-
mide dimethylacetal (29.8 g, 0.25 mol), potassium hydroxide (32.6 g, 85%,
0
.50 mol), and ammonium acetate (77 g, 1.0 mol) were combined in
denatured alcohol (1.0 L; ethanol/methanol ¼ 85:15). The solution was then
heated to reflux for 24 h. After cooling, the solvent was removed under
reduced pressure, and the remaining residue was extracted with chloroform
(
100 mLꢀ5). The organic phases were combined and dried, taken up in
toluene, and applied to a short column of 5% deactivated alumina for purifi-
cation using toluene as eluent and ferrous ammonium sulfate as indicator.
0
0
00
Recrystallization from hexane affords 2,2 :6 ,2 -terpyridine (10.4 g, 18%).
Elem. anal.: calc. C, 77.23; H, 4.75; N, 18.01; found C, 76.88; H, 4.87;
N, 17.76.
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