A convenient approach for the synthesis of 2,6-diformyl- and 2,6-diacetylpyridines

Article abstract of DOI:10.1016/j.tetlet.2012.11.004

2,6-Diformyl- and 2,6-diacetylpyridines are readily accessed in good yields (60-90%) via the single-pot reaction of 2,6-pyridine dicarboxamides with LiAlH₄ or MeMgCl in THF at 0-20°C. The high efficiency of the method illustrates the significance of solubility in the reduction and alkylation of difunctionalized substrates.

Full text of DOI:10.1016/j.tetlet.2012.11.004

Accepted Manuscript
A convenient approach for the synthesis of 2,6-diformyl- and 2,6-diacetylpyri‐
dines
Pavel V. Ivchenko, Ilya E. Nifant’ev, Ivan V. Buslov
PII:
S0040-4039(12)01925-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2012.11.004
TETL 42096
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
15 August 2012
13 October 2012
1 November 2012
Please cite this article as: Ivchenko, P.V., Nifant’ev, I.E., Buslov, I.V., A convenient approach for the synthesis of
2,6-diformyl- and 2,6-diacetylpyridines, Tetrahedron Letters (2012), doi: http://dx.doi.org/10.1016/j.tetlet.
2012.11.004
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A convenient approach for the synthesis of
2,6-diformyl- and 2,6-diacetylpyridines
Pavel V. Ivchenko,* Ilya E. Nifant’ev, Ivan V. Buslov
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1
Tetrahedron Letters
journal hom epage: www.elsevier.com
A convenient approach for the synthesis of 2,6-diformyl- and 2,6-diacetylpyridines
Pavel V. Ivchenkoa,∗, Ilya E. Nifant’ev a, b, Ivan V. Buslov a
a Chemistry Department, M.V. Lomonosov Moscow State University, Moscow, Russia 119991
b A.V. Topchiev Institute of Petrochemical Synthesis RAS, 29 Leninsky prosp., Moscow, Russia 119991
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
2,6-Diformyl- and 2,6-diacetylpyridines are readily accessed in good yields (60-90%) via the
single-pot reaction of 2,6-pyridine dicarboxamides with LiAlH4 or MeMgCl in THF at 0-20 °C .
The high efficiency of the method illustrates the significance of solubility in the reduction and
alkylation of difunctionalized substrates
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
amide reduction
Grignard reagents
diacetylpyridine
pyridine-2,6-dicarbaldehyde
2,6-Diformylpyridine, 2,6-diacetylpyridine and their 4-halo
derivatives have often served as convenient starting materials for
the synthesis of physiologically active compounds,1 crown-ether-
like macrocycles,2 supramolecular coordination complexes,3
metalloenzyme analogs,4 and chemosensors.5 Arguably the most
important application of these compounds is in the preparation of
bis(arylimino)pyridine ligands, [2,6-(ArN=CR)2C5H3N], which
impart late transition metals (Fe, Co, Ni, V) with high catalytic
activities for ethylene polymerization.6 Bis(imino)pyridyl
complexes also catalyse 1,3-butadiene polymerization (Fe, Co),7
oxidation (Fe, Cu),8 hydrogenation (Fe, Co, Ru, Rh),9
hydrosilylation (Fe),9h,i hydrocarboxylation (Fe)9j and [2+2]
cycloaddition (Fe).10
The most convenient method for the synthesis of 2,6-
diacetylpyridine (2)18a and its 4-substituted analogs18b entails the
Claisen condensation of ethyl acetoacetate and dialkyl pyridine-
2,6-dicarboxylates; alternative approaches to
2 use 2,6-
pyridinedicarboxylic acid dichloride19 or dinitrile.12 2,6-Diacetyl-
4-chloropyridine was synthesized from the corresponding 4-
chloro-substituted acid dichloride.20 The reaction of amides with
MeMgX, which has found use in the synthesis of methyl aryl
ketones,21 has not previously been used to prepare 2.
Moreover, bis(arylimino)pyridines can be modified at position
4 by direct substitution using alkylmanganese(II) complexes,22
but this method has limited synthetic scope.
We
hypothesized
that
the
reactions
of
2,6-
To date, pyridine-2,6-dicarbaldehydes have been synthesized
by either the oxidation of 2,6-lutidine11 or 2,6-
bis(hydroxymethyl)pyridines,3a,12 or by the reduction of 2,6-
pyridinedicarboxylic acid chlorides13 and esters14 using relatively
expensive composite reagents. In a recent publication, substituted
2,6-diformylpyridine (1) was prepared by the reduction of 2,6-
pyridinedicarboxylic acid diamide with diisobutylaluminium
hydride;15 a high (75%) yield was achieved using a four-fold
excess of the reducing agent and by temperature control (-70 ºC,
4 h). LiAlH4, which can reduce aromatic acid amides to
aldehydes,16 has not previously been used to prepare compound
1.17
pyridinedicarboxamides with LiAlH4 or Grignard reagents would
be suitable for the preparation of pyridines 1, 2 and their 4-
substituted analogs. We chose the previously described bis-
diethylamide 3 to identify and optimize the reaction conditions.23
Aldehyde 1 was prepared in 70-75% yield (Scheme 1) by
reduction of 3 in THF24 at 0-5 ºC for 30 min using LiAlH4 pre-
dissolved25 in THF (3/LiAlH4 ~ 1:0.7).26 The use of a solution of
LiAlH4 was critically important: the addition of 3 to a suspension
of LiAlH4 in THF produced a reaction mixture with no more than
30% of 1, even after 16 hours of stirring at 20 ºC followed by
hydrolysis. In our opinion, the poor solubility of the product
———
∗ Corresponding author. Tel.: +7 495 939 4098; e-mail: inpv@org.chem.msu.ru

2
Tetrahedron
formed from 3 and LiAlH4 on the surface of the latter hampers
dissolution, may be crucial in transforming an evident but
unobserved reaction into an efficient synthetic procedure.
the transfer of LiAlH4 to the solution and slows the entire
reaction.
Table 1. Preparation of pyridine-2,6-dicarbaldehydes and 2,6-
We established that commercially available MeMgCl in
THF27 reacts with 3 at 20 ºC over 1 hour to give 2 in ~80% yield
(Scheme 1).28 This reaction can also be performed with MeMgI
provided that four equivalents of the Grignard reagent are used.
The necessity of a twofold excess of MeMgI in the preparation of
2 can be attributed to the shift of the Schlenk equilibrium towards
Me2Mg observed for alkylmagnesium iodides in THF, which is
driven by the formation of poorly soluble MgI2(THF)x. 29,30
diacetylpyridines
X
N
X
N
X
b
a
H
H
N
N
N
O
O
2, 14-18
O
O
O
O
4-9
1, 10-13
Diformylpyridine,
Yield, %
Diacetylpyridine,
Yield, %
b
a
X
N
N
N
N
N
O
O
O
O
O
O
3
2, 80%
1, 70-75%
1, 76%
2, 88%
H
Scheme 1. Reaction of 2,6-pyridine dicarboxamide 3 with LiAlH4 and
MeMgCl in THF. a: (i) LiAlH4 (dissolved in THF), 0 °C, 30 min; (ii)
H+/H2O. b: (i) 2 eq. MeMgCl (THF), 0-20 °C, 1 h; (ii) H+/H2O.
10, 77%
11, 70%
12, 60%
14, 90%
15, 81%
16, 72%
Cl
Next, the synthesis of 4-substituted 2,6-diformyl- and 2,6-
diacetylpyridines was investigated. The high solubility of amide
3 hampers its isolation and purification. The newly prepared
pyrrolidine derivative 4 (Scheme 2) proved less soluble and more
reactive towards LiAlH4 and MeMgCl; therefore, we used
pyrrolidinyl amides 5-9, synthesized from previously described
acid halides to ascertain the applicability of this method to the
Br
N
O
–
17, 72%
18, 71%
synthesis
of
4-substituted
2,6-diformyl-
and
2,6-
diacetylpyridines15b,31 (Scheme 2).
13, 66%
X
X
a
Reagents and conditions: a: (i) LiAlH4 (dissolved in THF), 0 °C,
30 min; (ii) H+/H2O. b: (i) 2 eq. MeMgCl (THF), 0-20 °C, 1 h;
(ii) H+/H2O.
Hal
Hal
N
N
N
N
O
O
O
O
X = H ( ), Cl ( ), Br ( )
4
5
6
Supplementary data
X
N
b-d
X = p-tolyl
6
Supplementary data associated with this article can be found,
in the online version, at http:// These data include experimental
procedures and NMR spectra of new compounds.
N
N
1-pyrrolidinyl
PhO
O
O
7-9
References and notes
Scheme 2. Preparation of pyridine-2,6-dicarboxamides. a: pyrrolidine,
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