A new pyridine synthesis from azoenamines

Article abstract of DOI:10.1016/j.tetlet.2010.09.098

Azoenamines are formed during the interaction of α-ketohydrazones with secondary amines. These compounds can be converted into pyridines when treated with acetylenedicarboxylates under basic conditions.

Full text of DOI:10.1016/j.tetlet.2010.09.098

Tetrahedron Letters 51 (2010) 6186–6188
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Tetrahedron Letters
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A new pyridine synthesis from azoenamines
⇑
Didier Coffinier, Laurent El Kaim , Laurence Grimaud, Simon Hadrot
Laboratoire Chimie et Procédés, DCSO, UMR 7652, Ecole Nationale Supérieure de Techniques Avancées, 32 Bd Victor, Paris 75015, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 June 2010
Revised 26 August 2010
Accepted 20 September 2010
Available online 25 September 2010
Azoenamines are formed during the interaction of a-ketohydrazones with secondary amines. These com-
pounds can be converted into pyridines when treated with acetylenedicarboxylates under basic
conditions.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Hydrazones
Pyridines
Enamine
Azoenamine
Hydrazones have a rich history with known reactions associ-
ated to the early development of organic synthesis at the end of
the 19th century.1 More recently, a renewal of studies devoted to
these compounds can be observed in association with organome-
tallic chemistry and the subsequent development of enantioselec-
tive processes.2 Interested by new applications of hydrazones in
heterocyclic synthesis, we disclosed a few years ago, a Mannich
in hot toluene. Under these conditions, we were pleased to observe
formation of the pyridine 3a in a moderate 40% isolated yield. The
yield could be raised to 50% by replacing DBU with diisopropyleth-
ylamine (DIPEA). This new pyridine synthesis probably involves a
formal cycloaddition of deprotonated hydrazone A followed by
elimination of aniline to form the aromatic system (Scheme 3).
Deprotonation of the hydrazone leading to enhanced nucleophilic
behavior is supported by the absence of reactivity of diphenyl acet-
ylene in this reaction (with or without base).
coupling of
a
-ketohydrazones3 and applied it to trap various
-ke-
azoalkenes to form heterocycles.4 In all these reactions, the
a
tone function appeared unreactive, presenting just an electron-
withdrawing effect associated with an easier deprotonation of
the hydrazone (Scheme 1). However, when working with pyrroli-
dine and ketohydrazone 1a, we were surprised to observe the for-
mation of an azoenamine side product 2a resulting from the
condensation of pyrrolidine with 1a (Scheme 1).
The azoenamine 2a could be obtained in quantitative yields by
simply heating 1a with 1 equiv of pyrrolidine in toluene. The par-
ticular reactivity of pyrrolidine was confirmed when the same
reaction was attempted with morpholine. Indeed, after three hours
at reflux, the ketohydrazone was recovered unreacted. The azoen-
amine 2a proved to be rather stable, as it can be purified by fast sil-
ica gel chromatography without observing hydrolysis to give back
the starting 1a. Very few azoenamines have been reported in the
literature and little is known about their chemistry.5 We envi-
sioned that these species could easily be deprotonated to form a
stabilised anion which could then behave as an electron-rich hete-
rodiene in various cycloadditions (Scheme 2).6
Substitution of the phenyl moiety of 1a by an electron-with-
drawing p-nitrophenyl group did not improve the reaction as 3a
was obtained in a reduced 21% isolated yield. As the enamine 2a
was formed quantitatively with equimolar amounts of the reac-
tants in toluene, a simplified procedure was performed from the
starting hydrazone. Under such conditions, pyridines could be ob-
tained from one-pot couplings of alkyl acetylenedicarboxylate,
substituted a-ketohydrazones and pyrrolidines (Scheme 4).
We wished to broaden the scope of this strategy to prepare pyr-
idines substituted with different amino moieties. When working
with morpholine, we were unable to obtain any efficient coupling
with 1a in refluxing toluene, even with a large excess of morpho-
line. A conversion of 25% (determined by NMR) was the best we
observed with a two-molar excess of morpholine. In spite of these
difficulties, the use of trimethylaluminum allowed us to induce the
coupling giving, after work-up, a quantitative formation of the ex-
pected enamine 2c. Enamines 2d and 2e could be similarly ob-
tained from 1a and the corresponding secondary amines (Scheme
5). These enamines are much more sensitive to hydrolysis than
2a and attempted purification on silica gel usually led to their com-
plete hydrolysis. Therefore, they were used directly after rapid
hydrolysis and an extraction. With these crude enamines in hand,
we tested the corresponding pyridine formation with either
Consequently, 2a was treated with a catalytic amount of DBU in
the presence of an excess of diethyl acetylenedicarboxylate (DEAD)
⇑
Corresponding author. Tel.: +33 145525537; fax: +33 145528322.
E-mail address: laurent.elkaim@ensta.fr (L. El Kaim).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.098

D. Coffinier et al. / Tetrahedron Letters 51 (2010) 6186–6188
6187
NPh
H
HN NBn
NHPh
N
NHPh
NH
N
N
Me
RCHO
NBn
Me
Me
N
R
H
N
Toluene
Toluene
O
O
Δ
Δ
1a
2a
Scheme 1. Mannich reaction of
a-ketohydrazone 1a.
E
N
NPh
H
NPh
N
H
N
N
Ph
E
Me
Cycloadditions
base
H
H
H
N
N
N
?
2a
Scheme 2. Mannich reaction of a-ketohydrazone 1a.
CO2Et
N
NAr
N
EtO2C
Me
H
DIPEA 20 mol %, DEAD (2 equiv)
Toluene reflux, 3 h
H
N
N
2a (Ar=Ph)
3a
Ar = Ph
50%
DIPEA cat
DEAD
Ar= p-NO2Ph, 21%
- ArNH2
CO2Et
CO2Et
CO2Et
EtO2C
NHAr
EtO2C
N
NAr
N
N
N
Ar
EtO2C
DIPEAH
H
H
H
N
H
N
N
A
Scheme 3. Pyridine formation from enamine 1a.
NH
1)
(1 equiv)
toluene (0.5 M) reflux, 3 h
2) R3O2C CO2R3
R3O2C
R3O2C
NHPh
N
R2
N
H
N
R1
H
R2
(2 equiv)
DIPEA, reflux, 24 h
R1
O
R1 = H, 1a
R1 = allyl, 1b
3b : R1= H, R2= H, R3= Me
54%
3c : R1= H, R2= NHCO2t-Bu, R3= Et 39%
3d : R1= allyl, R2 = H, R3= Et 40%
Scheme 4. Pyridine formation from
a
-ketohydrazone 1a.
CO2R1
N
CO2R1
R1O2C
NHPh
H
N
NHPh
2 equiv
CO2R1
N
HN
X
H
Me
Et
N
X
N
X
H
DIPEA cat
Toluene
AlMe3
Toluene 80 °C
24h
O
1a
reflux, 24 h
AlMe3
HN
2c: X = O
2d: X = CHBn
Toluene
3e: R1= Et,
X = O
38%
19%
20%
Bn
80 °C, 24 h
3f: R1= Et,
CO2Et
CO2Et
NHPh
X = CHBn
N
3g: R1= Me,
X = CHBn
H
complex mixture
N
DIPEA
2e
Bn
Et
Scheme 5. Pyridine formation from six-membered cyclic amines.

6188
D. Coffinier et al. / Tetrahedron Letters 51 (2010) 6186–6188
5. McNab, H.; Murray, E. A. J. Chem. Soc., Chem. Commun. 1981, 722; McNab, H.;
Murray, E. A. J. Chem. Soc., Perkin Trans. 1 1989, 583; Machaeek, V.; Eegan, A.;
Halama, A.; Rozoavska, O.; Sirba, V. Collect. Czech. Chem. Commun. 1995, 60,
1367.
dimethyl or diethyl acetylenedicarboxylate. The yields were lower
than those obtained with pyrrolidines. The reaction seems to be
limited to the use of cyclic amines as shown by the behavior of
2e which gave a complex mixture when treated with the alkyne.
In conclusion, we have developed a new pyridine synthesis
6. For a related access to pyridines by a [4+2] cycloaddition of
a,b-unsaturated
hydrazones see: Dolle, R. E.; Armstrong, W. P.; Shaw, A. N.; Novelli, R.
Tetrahedron Lett. 1988, 29, 6349–6352.
7. Typical procedure for 3d: To a solution of 100 mg of hydrazone 1b (0.5 mmol) in
from
a
-ketohydrazones.7 Improved access to this heterocyclic
1 mL of dry toluene was added 40
mixture was stirred at 100 °C for 2 h. Then, 160
carboxylate (1 mmol, 2.0 equiv) and 18 of N-ethyldiisopropylamine
l
l of pyrrolidine (0.5 mmol, 1.0 equiv) and the
family is important as pyridines display important biological
activities.8 This reaction involves the formation of intermediate
azoenamines whose reactivity has been poorly studied. Even if
the final yields are moderate, this synthesis is of interest as the
procedure is very simple and the starting hydrazones are readily
prepared using the Japp–Klingemann reaction between b-keto
acids and diazonium salts.9
l
l of diethyl acetylenedi-
ll
(0.1 mmol, 0.2 equiv) were added, and the mixture was further heated at
100 °C for 24 h. Flash chromatography on silica gel (Et2O/petroleum ether,
50:50) gave the desired product 3d as a yellow oil (66 mg, 40%). 1H NMR
(400 MHz, CDCl3) d 8.22 (s, 1H), 6.00 (tdd, J = 6.6, 10.1, 16.7 Hz, 1H), 5.12–5.04
(m, 2H), 4.39–4.28 (m, 4H), 3.58 (d, J = 6.6, 4H), 2.00–1.95 (m, 4H), 1.38 (t,
J = 7.1 Hz, 3H), 1.37 (t, J = 7.1 Hz, 3H). 13C NMR (100.6 MHz, CDCl3) d 168.1,
167.9, 143.7, 139.8, 138.2, 136.3, 127.0, 122.8, 116.5, 62.4, 62.2, 50.2, 40.1, 26.2,
14.5, 14.4. IR (thin film) 2985, 1729, 1569, 1472, 1464, 1410, 1376, 1275 cmÀ1
.
Acknowledgements
HRMS calcd for C18H24N2O4: 332.1736, found: 332.1737. Typical procedure for
3e: To a solution of 320 mg of hydrazone 1a (2 mmol) in 2 mL of dry toluene at
0 °C were added AlMe3 (1 ml, 2 mmol, 1 equiv as a 2 M solution in toluene) then
D.C. thanks GlaxoSmithKline and the Centre National pour la
Recherche Scientifique for a fellowship. The financial support was
provided by ENSTA.
morpholine (190 ll, 2.2 mmol, 1.1 equiv). The mixture was heated at 100 °C
under an argon atmosphere for 24 h. The addition at room temperature of a
saturated solution of sodium tartrate, followed by stirring for 15 min afforded,
after extraction (CH2Cl2), crude 2c which was further reacted with
diethylacetylene dicarboxylate as for 3b. Flash chromatography on silica gel
(Et2O/petroleum ether, 60:40) afforded the desired product 3e as a yellow oil
(230 mg, 38%). 1H NMR (400 MHz, CDCl3) d 9.01 (s, 1H), 8.67 (s, 1H), 4.47 (q,
7.1 Hz, 2H), 4.41 (q, J = 7.1 Hz, 2H), 3.85–3.80 (m, 4H), 3.13–3.10 (m, 4H), 1.44 (t,
J = 7.1 Hz, 3H), 1.41 (t, J = 7.1 Hz, 3H). 13C NMR (100.6 MHz, CDCl3) d 167.0,
164.5, 148.2, 147.3, 145.4, 140.3, 123.5, 67.6, 62.4, 62.3, 53.5, 14.6, 14.5. IR (thin
film) 2985, 1726, 1595, 1577, 1472, 1452, 1419, 1368, 1275 cmÀ1. HRMS calcd
for C15H20N2O5: 308.1372, found: 308.1370.
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