Double nucleophilic addition. A new one-pot synthesis of 2-alkyl- and 2- phenyl-5-hydrazinopyridine from pyridine

Article abstract of DOI:10.1016/S0040-4039(00)00340-3

A new method for the synthesis of 2-alkyl- and 2-phenyl-5- hydrazinopyridine has been developed. Nucleophilic addition on pyridine by alkyl or phenyl lithium reagents generated a 2-substituted dihydropyridine anion that reacts with di-t-butyl azodicarboxylate to form 2,5-disubstituted dihydropyridine. Conversion of the dihydropyridines to pyridines was achieved by a mild air oxidation. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00340-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3025–3028
Double nucleophilic addition. A new one-pot synthesis of
2-alkyl- and 2-phenyl-5-hydrazinopyridine from pyridine
Lin-hua Zhang ∗ and Zhulin Tan
Chemical Development, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT 06877-0368, USA
Received 18 November 1999; revised 23 February 2000; accepted 24 February 2000
Abstract
A new method for the synthesis of 2-alkyl- and 2-phenyl-5-hydrazinopyridine has been developed. Nucleophilic
addition on pyridine by alkyl or phenyl lithium reagents generated a 2-substituted dihydropyridine anion that reacts
with di-t-butyl azodicarboxylate to form 2,5-disubstituted dihydropyridine. Conversion of the dihydropyridines to
pyridines was achieved by a mild air oxidation. © 2000 Elsevier Science Ltd. All rights reserved.
The synthesis of polysubstituted pyridines has been an active research area for many years.1 Sub-
stituted pyridines have found a number of applications, such as in biological studies,2 anticorrosion
agents,3 insecticides,4 mechanistic investigations,5 and as potential drug substances.6 The synthesis of
2-alkyl or 2-aryl-5-hydrazinopyridine (1) possess particular challenges, and has never been executed
directly from pyridine. The reported methods involve several steps and expensive intermediates such as
2-alkyl-5-bromo or 2-alkyl-5-aminopyridine (2).6 Recently, a synthesis of hydrazinopyridine from para-
nitro bromopyridine by Pd catalysis has been reported, and the conditions for deprotection have also
been studied.7 We report a useful method for synthesizing 2-alkyl or 2-aryl-5-hydrazinopyridines from
pyridine in one-pot.
It has been reported that nuleophilic addition of organolithium reagents toward pyridine takes place
at the 2-position.8 The reactions of this N-lithio-1,2-dihydropyridines with suitable electrophiles in
arylalkylation,9 alkylation,10 hydroxyalkylation,9,11 aminoalkylation,9 acylation12,13 and thiolation14
have been reported. We envisioned that 2-alkyl or aryl-5-hydrazinopyridine could be generated by this
approach if di-t-butyl azodicarboxylate (DBAD) were used as an electrophile, as depicted in Scheme 1.
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00340-3
tetl 16620

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Scheme 1. Double nucleophilic addition
The results of double nucleophilic addition were illustrated in Table 1. However, the initial experiment
of preparing substituted pyridohydrazine by this approach was not successful. When alkyl lithium reacts
with pyridine for prolonged time, the major product was 2-alkylated pyridine 4 (Scheme 2). Formation
of 4 could be caused by losing LiH or disproportionation of intermediate 3.15 To minimize the generation
of side product 4, it is important to add DBAD into the reaction mixture when the concentration of 2-
substituted dihydropyridine 3 reaches maximum before it converts to 4. Therefore, it is crucial to develop
an analytical method to follow the progress of first nucleophilic addition.
Since the lithium reagent and the active intermediate 3 formed in this reaction is highly sensitive
to air and moisture, it is difficult to follow the progress of nucleophilic addition. Initial attempts of
using HPLC or TLC methods failed to give any useful information. Finally, satisfactory results were
obtained by using 1H NMR techniques. During the reaction, a small portion of mixture was quenched by
deuterated methanol. The proton signal of pyridine at 8.6 ppm, the signal of 2-substituted pyridine at 8.5
ppm, and the dihydropyridine 3 at about 5.0 ppm were integrated and analyzed. When the concentration
of intermediate 3 reached maximum (its proton signal did not further increase by NMR analysis), DBAD
was added to execute the second nucleophilic addition.
The first nucleophilic addition, organolithium with pyridine, took place between −10°C and 20°C.
There was no reaction when the temperature was too low. At high temperature, the majority of the
product was 2-substituted pyridine. The second nucleophilic addition, dihydropyridine to DBAD, was
carried out initially at −70°C and then warmed to room temperature. This step was exothermic and fast,
the reaction temperature was controlled by slow addition of DBAD to dihydropyridine solution.
The stoichiometry of the reaction typically was one-to-one ratio of organolithium reagent to pyridine.
The use of more pyridine did not enhance the yield of dihydropyridine. DBAD was used as 1.2
equiv. to organolithium reagent. Adding more DBAD did not increase the yield of products. Other
azodicarboxylate reagents were also tried, such as diethyl azodicarboxylate (DEAD) and di-2,2,2-
trichloroethyl azodicarboxylate. The reactions worked but the yields were not as good as in the case of
DBAD. In addition, DBAD provides more readily cleavable bis-carbamate. Finally, the 2,5-substituted
dihydropyridines converted into their aromatic products by stirring at room temperature in air. Removing
the t-Boc protecting group has been executed under very mild conditions (TFA, room temperature). Some
examples of this double addition are illustrated in Table 1.
In summary, a new synthesis of 2-alkyl- and 2-phenyl-5-hydrazinopyridine has been developed. The
unique feature of this synthesis is to execute three chemical reactions, double nucleophilic addition and

3027
Table 1
Results of double nucleophilic addition
Scheme 2. Product distribution from dihydropyridine 3
aromatizing in one-pot, which provides a very attractive route to prepare 2,5-disubstituted hydrazinopy-
ridines.
General procedure. Pyridine (12 mmol) was added to a solution of organolithium reagent (12 mmol)
at −20°C under an atmosphere of argon. The resulting mixture was stirred and allowed to warm to
room temperature. The agitation was kept at room temperature for 4∼8 h. Anhydrous THF (10 ml) was
added and the resulting solution was cooled to −78°C. The solution of t-butyl azodicarboxylate (14
mmol) in anhydrous THF (15 ml) was added with syringe pump in 1.5 h. The mixture was allowed to

3028
warm to room temperature and stirred for 2 h, followed by an additional 1 h under air (for oxidation).
Saturated ammonium chloride aqueous solution (10 ml) was added and the organic layer was separated.
The aqueous layer was extracted with ethyl acetate (3×10 ml). The combined organic layer was dried
with magnesium sulfate. The solvent was removed under reduced pressure and the crude product was
purified by silica gel flash chromatography (hexane/EtOAc).
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