Microwave-promoted synthesis of chiral pyridinium salts

Article abstract of DOI:10.1016/j.tetlet.2005.09.036

The synthesis of several chiral pyridinium salts via Zincke's reaction can be easily accomplished by domestic microwave oven irradiation. Yield enhancements, reduction of reaction time, and less racemization were observed under microwave heating when compared to conventional heating in similar conditions.

Full text of DOI:10.1016/j.tetlet.2005.09.036

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7773–7776
Microwave-promoted synthesis of chiral pyridinium salts
Gustavo H. R. Viana,a Itamar C. Santos,a Rosemeire B. Alves,a Laurent Gil,b
Christian Marazanoc and Rossimiriam P. F. Gila,*
a
ˆ ˆ
Departamento de Quı´mica, Instituto de Ciencias Exatas, Universidade Federal de Minas Gerais, Av. Antonio Carlos,
6627, 31270-901 Belo Horizonte, Brazil
bDepartamento de Quı´mica, ICEB, UFOP, Campus Morro do Cruzeiro, Ouro Preto, MG, Brazil
cInstitut de Chimie des Substances Naturelles, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Received 7 July 2005; revised 5 September 2005; accepted 7 September 2005
Available online 23 September 2005
Abstract—The synthesis of several chiral pyridinium salts via ZinckeÕs reaction can be easily accomplished by domestic microwave
oven irradiation. Yield enhancements, reduction of reaction time, and less racemization were observed under microwave heating
when compared to conventional heating in similar conditions.
Ó 2005 Elsevier Ltd. All rights reserved.
Pyridinium salts are a versatile class of compounds used
as phase transfer catalysts,1 initiators of cationic poly-
merization,2 wide range antimicrobials,3 enzyme inhibi-
tors,4 acylating agents,5 dyes, and cationic surfactants.6
Their chiral representatives, that is, pyridinium salts
containing a chiral auxiliary group linked to the ring
nitrogen, have been largely used as starting materials
in asymmetric synthesis to obtain substituted chiral
dihydropyridines,7 tetrahydropyridines,8 piperidines,9
and nitrogenated complex compounds such as natural
alkaloids10 and synthetic candidates for drugs.4b
The original ZinckeÕs reaction14 involves the attack of a
primary amine 1 on ZinckeÕs salt 2 (Eq. 1) to produce
salt 3. As the mechanism of reaction does not involve
rupture of the C–N bond, if we use a primary chiral
amine, the configuration of the stereocenter will be kept.
This idea was extensively studied by Marazano15 and
ZinckeÕs reaction became an excellent method for the
synthesis of chiral pyridinium salts.
R
NH2
R
NO2
+
Several synthesis routes for pyridinium salts are known,
but the most commonly used one is the Menschutkin
reaction, a SN2 reaction of a pyridine derivative with
an organic halide or sulfonate.6 Nevertheless, this
method in not suitable to prepare chiral pyridinium salts
with a stereocenter directly attached to the ring nitrogen
since there is a significant risk of racemization by a
competing SN1 process. There are two main methods
to obtain these kinds of salts with negligible racemiza-
tion. The first uses pyrilium salts11,12 and the second
employs ZinckeÕs salts,13 a highly electrophilic species
formed by reaction between a pyridine derivative and
1-chloro-2,4-dinitrobenzene.
_
NH2
N
Y
+
+
+
R1
_
NO2
R3
N
Y
R2
DNP
NO2
R1
R3
1
R2
2
3
4
NO2
ð1Þ
Some recent uses of ZinckeÕs reaction have been
described by Eda and co-workers4a,16 and Urban et al.17
The former adapted this reaction for solid-phase appli-
cation to achieve chiral quaternary ammonium salts
analogs of vesamicol4a and salts that could be useful
to treat cystic fribosis.16 The latter applied ZinckeÕs reac-
tion to make chiral naphthyridinium salts for the syn-
thesis of cytotoxic alkaloid manzamine A.17
Keywords: Asymmetric synthesis; Amino alcohols; Pyridines; Micro-
wave irradiation; ZinckeÕs reaction.
*
Corresponding author. Tel.: +55 3134995721; fax: +55
3134995700; e-mail: rossi@netuno.lcc.ufmg.br
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.036

7774
G. H. R. Viana et al. / Tetrahedron Letters 46 (2005) 7773–7776
Faster and simpler methods are a permanent need in
organic synthesis. In 1986, Gedye18 and Giguere19 dem-
onstrated that many organic reactions could be rapidly
conducted under microwave irradiation. Since then,
microwave irradiation has been increasingly used as a
laboratory method to accelerate synthesis.20 Micro-
wave-assisted organic synthesis has several advantages
over conventional methodology: remarkable reduction
of reaction time (up to three orders of magnitude),
improved isolated product yields (when thermal decom-
position is associated with conventional heating
reactions), and sometimes, effects on chemo-, regio-,
and stereoselectivities are also achieved.21
We have used a modified domestic microwave oven,
2450-MHz General Electric JEI 1145 AWA. The oven
top was cut to accommodate a reflux condenser and a
steel ring was used to avoid microwave leakage. The
turnable dish was turned off.
A typical procedure involves irradiation of a mixture of
1 equiv of ZinckeÕs salt and 1 equiv of primary amine
using 10 mL of 1-butanol as solvent under microwave
irradiation for 5–10 min. In the end of the reaction,
the salt recovery by simple partition into water phase
from ethyl acetate allowed its complete separation from
2,4-dinitroaniline 4 (Eq. 1). Purification of the crude
products by silica gel flash chromatography furnished
the isolated salts with yields from 61% to 100% (Table
1). All salts were confirmed by 1H NMR and 13C
NMR analyses.22 All reactions were performed under
microwave and conventional heating for comparison.
The results are presented in Table 1.
Due to the important role of chiral pyridinium salts in
asymmetric synthesis and the absence of reported micro-
wave-assisted ZinckeÕs reaction, we report here a new
and efficient method for the fast synthesis of chiral
pyridinium salts from chiral primary amines.
Table 1. Synthesis of pyridinium salts under microwave and conventional heating
R
R
NH2
+
+
_
+
R1
N
_
Y
R3
N
Y
R2
R1
DNP
R3
R2
2
1
3
Entry
1
Primary amine 1
2
3
Microwave heating
Conventional heating
Time (h) Yield (%)
R
Yꢀ
Time (min)
Yield (%)
NH2
–CH3
Clꢀ
5
91
15
85
OH
H
Ph
NH2
OH
2
3
–CH3
–CH3
Clꢀ
10
10
72
57
15
68
H
Ph
NH2
OH
Clꢀ
15
29
H
NH2
H
4
5
–CH3
–CH3
Clꢀ
10
10
100
98
15
15
100
49
Ph
Me
NH2
OH
Clꢀ
OH
Me
NH2
OH
6
7
–CH3
–CH3
Clꢀ
10
10
98
98
15
15
65
72
H
H
NH2
Clꢀ
Me
Ph

G. H. R. Viana et al. / Tetrahedron Letters 46 (2005) 7773–7776
7775
Table 1 (continued)
Entry
Primary amine 1
2
3
Microwave heating
Time (min) Yield (%)
Conventional heating
R
Yꢀ
Time (h)
Yield (%)
NH2
8
–H
SDSa
10
10
10
10
61
67
93
86
15
15
15
15
48
H
OH
OH
Ph
NH2
Clꢀ
70
92
75
H
9
10
11
–H
Ph
NH2
Clꢀ
Me
–H
Ph
H
NH2
Clꢀ
H
Ethyl
OH
Ph
a SDS = dodecylsulfate.
ZinckeÕs salts were easily prepared by reaction of com-
mercially available pyridine, 3-picoline, and 3-ethylpyri-
dine (1 equiv of each) and 1 equiv of 1-chloro-2,4-
dinitrobenzene under acetone reflux for 15 h. The
selected primary amines were (R)-(ꢀ)-phenylglycinol,
(S)-(+)-, (S)-(ꢀ)-phenylalaninol, (S)-(+)-isoleucinol,
(R)-(+) and (S)-(ꢀ)-a-methylbenzylamine, and the achi-
ral amine serinol.
racemization than by conventional heating methods.
These results confirm the applicability of microwave
heating to the improvement of classic reactions.
Acknowledgements
The authors thank Conselho Nacional de Desenvolvi-
´
´
mento Cientıfico e Tecnologico (CNPq), for the fellow-
ship of G.H.R.V.
From Table 1, it can be seen that the reaction time was
reduced by several times under microwave irradiation
when compared with reactions performed under conven-
tional heating. Marazano established that the ideal con-
dition for this reaction under conventional heating was
1-butanol refluxing as solvent for 15 h. We have found
similar results for conventional heating; however, for
microwave heating, the reaction time is never larger than
10 min. Furthermore, the yield of microwave heating
reactions after purification was greatly increased. It is
very interesting to observe that under microwave irradi-
ation, pyridinium salts were obtained with less racemiza-
tion than by the methods described until today, possibly
References and notes
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333, 296.
due to the much shorter reaction times. For example, for
20
the compound of the table entry 9, the value of ½aꢁD re-
ported for the solution conventional method9 was ꢀ44°.
Under solid-phase4a Zincke conditions, the same com-
20
pound was obtained with ½aꢁD ꢀ50, and by microwave
irradiation, the value recorded was ꢀ53.4° (CH3OH,
c 2.95). In addition, we also report the values of
ꢀ25.9° (CH3OH, c 1.20) for the specific rotation of the
compound derived from (S)-(ꢀ)-a-methylbenzylamine
(entry 7) for conventional heating and ꢀ32.3° (CH3OH,
c 1.05) for microwave heating. This success led to the
preparation of other chiral derivatives by microwave-
promoted ZinckeÕs reaction.
´
In summary, we have developed an operationally simple
and efficient method for the synthesis of chiral pyridi-
nium salts by microwave-promoted ZinckeÕs reaction.
The conditions employed furnished good yields and less

7776
G. H. R. Viana et al. / Tetrahedron Letters 46 (2005) 7773–7776
15. Genisson, Y.; Marazano, C.; Mehmandoust, M.; Gnecco,
D.; Das, B. C. Synlett 1992, 431–434.
16. Eda, M.; Kurth, M. J.; Nantz, M. H. J. Org. Chem. 2000,
65, 5131–5135.
17. Urban, D.; Duval, E.; Langlois, Y. Tetrahedron Lett.
2000, 41, 9251–9256.
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19. Giguerre, R. J.; Bray, T. L.; Duncan, S. M.; Majetich, G.
Tetrahedron Lett. 1986, 27, 4945–4948.
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2608.
(0.259 g, 2.41 mmol) and ZinckeÕs salt (R = CH3,
Y = Clꢀ) (0.633 g, 2.14 mmol) in 1-butanol (10 mL)
was irradiated with microwave for 10 min. After evapo-
ration, the residue was solubilized in water, and to
this solution was added ammonium hydroxide until
pH 10. The next step was a simple partition in water
phase from ethyl acetate. The aqueous phase was
evaporated and the residue was chromatographed
(CHCl3/CH3OH 100/1, 94/6, 90/10, 83/17, 50/50).
Pyridinium salt (entry 7, 0.490 g, 98%) was obtained as a
yellow oil: ½aꢁD ꢀ32.3 (CH3OH, c 1.05); H NMR (D2O,
200 MHz): d 1.97 (3H, t, J = 7.1 Hz); 2.41 (3H, s); 5.99
(1H, q, J = 7.0 Hz); 7.37–7.46 (5H, m); 7.82 (1H,
t, J = 7.4 Hz); 8.25 (1H, d, J = 7.9 Hz); 8.62–8.75 (2H,
m); 13C NMR (D2O, 50 MHz): d 18.09; 20.12; 70.89;
127.82; 128.00; 129.82; 130.17; 137.37; 140.62; 142.84;
146.85.
20
1
22. A representative procedure to obtain pyridinium salts is as
follows:
A
solution of (S)-(ꢀ)-a-methylbenzylamine