Synthesis of dicyanopyridines

Article abstract of DOI:10.1081/SCC-200032468

Synthesis of the title compounds in four steps using inexpensive collidine and lutidine as starting materials is described.

Full text of DOI:10.1081/SCC-200032468

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Synthesis of Dicyanopyridines
Emmanuel Roblou a b , Isabelle Sasaki a , Frédéric
Pezet a , Hassan Aït‐Haddou a & Sandrine
Vincendeau a
a Laboratoire de Chimie de Coordination (CNRS
UPR 8241) , 205 Route de Narbonne, 31077,
Toulouse, France
b Inorganic Chemistry, Department of Chemistry ,
Lund University , P.O.Box 124SE‐221 00, Lund,
Sweden
Published online: 19 Apr 2010.
To cite this article: Emmanuel Roblou , Isabelle Sasaki , Frédéric Pezet , Hassan
Aït‐Haddou & Sandrine Vincendeau (2004) Synthesis of Dicyanopyridines, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 34:20, 3743-3749, DOI: 10.1081/SCC-200032468
To link to this article: http://dx.doi.org/10.1081/SCC-200032468
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 20, pp. 3743–3749, 2004
Synthesis of Dicyanopyridines
1
Emmanuel Roblou,1,2 Isabelle Sasaki,1, Frederic Pezet,
Hassan A¨ıt-Haddou,1 and Sandrine Vincendeau1
*
´ ´
1Laboratoire de Chimie de Coordination (CNRS UPR 8241), 205 Route
de Narbonne, 31077 Toulouse, France
2Inorganic Chemistry, Department of Chemistry, Lund University,
P.O. Box 124SE-221 00 Lund, Sweden
ABSTRACT
Synthesis of the title compounds in four steps using inexpensive collidine
and lutidine as starting materials is described.
Key Words: Aldehyde; Hydrazone; Nitrile; Pyridine.
For many years, the synthesis of functionalized pyridines as versatile
synthetic intermediates in the preparation of important chemicals has been
*
Correspondence: Isabelle Sasaki, Laboratoire de Chimie de Coordination (CNRS
UPR 8241), 205 Route de Narbonne, 31077, Toulouse, France; E-mail: sasaki@lcc-
toulouse.fr.
3743
DOI: 10.1081/SCC-200032468
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

3744
Roblou et al.
the subject of numerous studies. In particular, nitriles are of great interest due
to their rich potential chemical transformations. During our ongoing studies
on the synthesis of new polyaza heterocycles,[1] we have found a simple
and efficient preparation of 2,6-dicyano-4-methylpyridine 9 and 2,6-dicyano-
pyridine 10 through the corresponding diformyl derivatives that are also
exciting intermediates. The diformyl precursors 5 and 6 were prepared from
the inexpensive 2,4,6-trimethylpyridine (collidine) 1 or 2,6-dimethylpyridine
(lutidine) 2, respectively, by initial conversion to the dibenzylidene deriva-
tives 3 and 4[2] followed by ozonolysis and reduction of the ozonides with
trialkylphosphine as outlined in Sch. 1.
In the first step, the workup of compound 4 is easy, as this product precipi-
tates in the reaction mixture after cooling and is simply isolated. On the
contrary, the yield of compound 3 is much lower because of its higher solubility
in the reaction mixture. In fact, in collidine 1, the three methyl groups present
equivalent reactivity to bases.[3] Preferential functionalization on the a pos-
itions can be achieved by introducing a benzylidene group. During the
Scheme 1.

Synthesis of Dicyanopyridines
3745
course of the reaction, the nitrogen atom of the pyridine ring favors the reactiv-
ity on the a methyl groups leading to 3 as the major product in the presence of
the tribenzylidene derivative (R ¼ CH55CHPh in Sch. 1) which is difficult to
separate from 3. After two successive chromatographies on silica gel, com-
pound 3 was finally obtained pure with no more traces of the tribenzylidene
derivative as checked by mass spectrometry (see Experimental section).
After a short ozonolysis[4] of 3 and 4, the corresponding diformyl deriva-
tives 5[5] and 6[6] were obtained in good yields (by using methyl sulfide in the
reduction of the ozonide as described by Ref.[7], we obtained the formyl
derivatives with a much lower yield). Compound 6 was also prepared from
the commercially available and expensive 2,6-dihydroxymethylpyridine by
MnO2 oxidation with moderate yields. The last step deals with a recent
method describing the conversion of aldehydes to nitriles via their N,N-
dimethylhydrazones[8] and was performed on compounds 5 and 6 leading to
9 and 10, respectively. Compound 9 was just cited in one article[9] without
any experimental characterization, whereas 10 has been described[10] and
already obtained by different methods in moderate yields. Cyano derivatives
of pyridines were usually prepared by nucleophilic substitution with the
cyanide anion on the bromo derivative or by using the Reissert–Henze reac-
tion including the corresponding diformyl derivatives as intermediates.
Recently, dehydration of the corresponding diamide was described by
Drew[11] to obtain 10 as the starting material for the synthesis of triazines.[12]
In conclusion, we described a simple and efficient synthesis of cyano
derivatives of pyridines from commercially available methyl pyridines.
EXPERIMENTAL
Preparation of 2,6-Dibenzylidene-4-methylpyridine: 3
A solution of 1.32 mL (10 mmol) of collidine, 5.1 mL (50 mmol) of freshly
distilled benzaldehyde, and 9.4 mL (100 mmol) of acetic anhydride was heated
to 1708C for 41 h. After cooling, most of the acetic anhydride was distilled off,
and 10 mL of 5% aqueous sodium hydroxide were added, and the mixture was
stirred at room temperature for 3 h. Organic material was extracted three times
by dichloromethane, and the gathered organic phases were dried on magnesium
sulfate, filtered, and evaporated to dryness under reduced pressure. The dark-
brown oil was adsorbed on silica gel and purified through two successive flash
column chromatographies (eluent: 90% pentane–10% ethylacetate) to afford
0.47 g of 3 (16%) as white needles. Mp ¼ 130–1318C. CAUTION: we have
observed spontaneous ignition of the pentane phase in the presence of
the dibenzylidene derivative after moderate heating. 1H-NMR (250 MHz,

3746
Roblou et al.
CDCl3): d 7.70 (d, 2H, J ¼ 16.1 Hz, HC55CH); 7.61 (dd, 4H, J ¼ 7.1 and 1.4 Hz,
ortho Hbz); 7.42–7.30 (m, 6H, meta and para Hbz); 7.19 (d, 2H, J ¼ 16.1 Hz,
HC55CH); 7.13 (s, 2H, Hpy); 2.37 (s, 3H, CH3); 13C-NMR (62.9 MHz,
CDCl3): d 155.3; 147.8; 136.8; 132.6; 128.7; 128.3; 128.0; 127.1; 121.5; 21.0;
MS (DCI/NH3): m/z 298 (M þ H)þ; elemental analysis: found (calculated) C:
88.66 (88.85); H: 6.15 (6.44); N: 4.59 (4.71). A second fraction of the chromato-
graphy afforded a mixture of the dibenzylidene and of the tribenzylidene deriva-
tives which could not be separated and were evidenced by mass spectrometry.
2,6-Dibenzylidene-pyridine: 4
A solution of 2.3 mL (20 mmol) of lutidine in 10.2 mL (100 mmol) of
benzaldehyde and 18.9 mL (200 mmol) of acetic anhydride were heated at
1808C for 41 h. After cooling, the precipitate was filtered off and rinsed
1
with pentane to yield 2.8 g (49%) of a beige powder. Mp ¼ 1708C; H-
NMR (250 MHz, CDCl3): d 7.71 (d, 2H, J ¼ 16.1 Hz, HC55CH); 7.62 (dd,
4H, J ¼ 7.4 and 1.8 Hz); 7.42–7.29 (m, 9H); 7.21 (d, 2H, J ¼ 16.1 Hz,
HC55CH); 13C-NMR (62.9 MHz, CDCl3): d 155.4; 137.0; 136.7; 132.9;
128.7; 128.3; 127.2; 120.5; MS (DCI/NH3): m/z 286 (M þ H)þ; elemental
analysis: found (calculated); C: 88.50 (89.01); H: 5.80 (6.05); N: 4.84 (4.94).
2,6-Diformyl-4-methylpyridine: 5
A solution of 8.35 g (28 mmol) of 4 in 300 mL of a mixture 1/1 dichloro-
methane/methanol was ozonolysed at 2708C for 0.5 h. After bubbling oxygen
then argon, the mixture was abandoned at room temperature. Tricyanoethyl-
phosphine (500 mg per mmol) was added, and the solution was left overnight.
After filtration, the solvents are evaporated off and the crude product was chro-
matographied on silica gel and eluted with 90% pentane-10% ethylacetate.
3.93 g (94%) of a white solid was obtained. Mp ¼ 1628C; 1H-NMR
(250 MHz, CDCl3): d 10.13 (s, 2 H); 7.97 (s, 2 H); 2.53 (s, 3 H). 13C-NMR
(62.9 MHz, CDCl3): d 192.6; 152.9; 150.3; 126.1; 21.1; MS (DCI,NH3): 150
(M þ H)þ; 167 (M þ NH4)þ; elemental analysis: found (calculated), C:
64.53 (64.42); H: 4.33 (4.73); N: 9.18 (9.39).
2,6-Diformylpyridine: 6
Compound 6 was synthesized according to the procedure used for 5. Yield
98%; Mp ¼ 1248C.

Synthesis of Dicyanopyridines
2,6-bis(N,N-Dimethyl)hydrazono-4-methylpyridine: 7
3747
To a solution of 1.78 g of 6 (12 mmol) in 84 mL methanol were added
5.1 mL (67 mmol) of N,N-dimethylhydrazine. After stirring at room tempera-
ture for 12 h, the mixture was evaporated to dryness. An addition of ethyl
acetate gave the product as 2.5 g (89%) of a yellow precipitate. Mp ¼ 738C;
1H-NMR (250 MHz, CDCl3): d 7.45 (s, 2H); 7.28 (s, 2H); 3.02 (s, 12H);
2.31 (s, 3H). 13C-NMR (62.9 MHz, CDCl3): d 150.8; 147.2; 132.2; 117.4;
42.6; 21.1; MS (DCI, NH3): 234 (M þ H)þ; elemental analysis: found (calcu-
lated), C: 61.77 (61.83); H: 8.21 (8.12); N: 30.02 (28.75).
2,6-bis(N,N-Dimethyl)hydrazonopyridine: 8
To a solution of 2.31 g (17 mmol) of 2,6-diformylpyridine in 50 mL
methanol were added 5.2 mL (68 mmol) of N,N-dimethylhydrazine, and the
reaction was stirred at room temperature for 12 h. After evaporation, 3.67 g
(98%) of pale yellow product were obtained. Mp ¼ 1258C. 1H-NMR
(250 MHz, CDCl3): d 7.55 (m, 3 H); 2.99 (s, 12 H, CH3); 13C-NMR
(62.9 MHz, CDCl3); d 135.5; 130.7; 115.7; 41.9; 40.3; MS (DCI,NH3): 220
(M þ H)þ; elemental analysis: found (calculated), C: 60.10 (60.25); H: 7.22
(7.81); N: 32.00 (31.94).
Preparation of the Dicyanopyridines: 9 and 10
2,6-Dicyano-4-methylpyridine: 9
To a solution of 7 (2.5 g, 11 mmol) in 70 mL of acetonitrile, were added
dimethylsulfate (5.25 mL, 56 mmol) and potassium carbonate (3.82 g,
28 mmol). The reaction mixture was heated to reflux for 16 h. After cooling,
potassium carbonate was filtered off, and the filtrate was evaporated to
dryness. The solid was adsorbed on silica gel and eluted with a mixture of
pentane/ethylacetate (50/50). An amount of 1.46 g (95%) was obtained
after evaporation of the solvent. mp: 138–1408C. 1H-NMR (250 MHz,
CDCl3): d 7.73 (s, 2H); 2.53 (s, 3H). 13C-NMR (62.9 MHz, CDCl3): d
151.3; 135.0; 131.9; 115.6; 20.9; MS (DCI,NH3): m/z 178 (MN2Hþ7 ); elemen-
tal analysis: found (calculated), C: 66.77 (67.13); H: 3.25 (3.52); N: 28.98
(29.35).

3748
Roblou et al.
2,6-Dicyanopyridine: 10
Compound 10 was prepared from 8 as described for 9 (Yield: 90%.
Mp ¼ 1148C).
ACKNOWLEDGMENTS
We thank CNRS (Centre National de la Recherche Scientifique) for
financial support.
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Synthesis of Dicyanopyridines
3749
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Received in the UK January 19, 2004