Institute of Organic Chemistry, Politechnika Krakowska
ul. Warszawska 24, 31-155 Krakow, Poland;
e-mail:
pcbogdal@kinga.cyf-kr.edu.pl
Abstract - Under microwave irradiation a
number of azaheterocycles (i.e., pyrrole, imidazole, pyrazole,
indole, and carbazole) react remarkably fast with alkyl halides
to give exclusively N-alkyl derivatives.
In the last few years there has been an interest in the use of microwave heating in organic synthesis.1 The use of such nonconventional reaction conditions reveals several features like: a short reaction time compared to conventional heating, ease of work-up after a reaction, and reduction in the usual thermal degradation and better selectivity.2
Reactions under "dry" conditions (i.e., in the absence of a solvent, on a solid support with or without catalysts) were originally developed in the late1980s.3 Synthesis without solvents under microwave irradiation offers several advantages.4 The absence of solvent reduces the risk of explosions when the reaction takes place in a closed vessel in an oven. Moreover, aprotic dipolar solvents with high boiling points are expensive and difficult to remove from the reaction mixtures. During microwave induction of reactions under dry conditions, the reactants adsorbed on the surface of alumina, silica gel, clay, and others absorb the microwaves whereas the support does not, nor does it restrict the transmission of microwaves. Consequently, such supported reagents efficiently induce reactions under safe and simple conditions with domestic microwave ovens instead of specialized expensive commercial microwave systems.
The N-alkylation of heterocyclic compounds bearing an acidic hydrogen atom attached to nitrogen is generally accomplished by treatment of these compounds with an appropriate base (sodium hydride or amide, or metaloorganic compounds) followed by treatment of the resulting salts with an alkylating agent.5 An alternative is to perform the reaction of such heterocyclic compounds under phase transfer catalysis (PTC) conditions, in which halides react directly with heterocyclic compounds without converting them to salts in preliminary steps.6
Since a number of heterocycles (e.g., pyrrole and indole) exhibit ambident behavior as nucleophiles, alkylation can occur at carbon as well as at nitrogen,7 and, in many instances, the major products are those derived from C-alkylation. During the past decades, several new procedures have been developed5,7 in which N-alkylation of heterocycles can be accomplished with little or no interference from C-alkylation. The PTC procedures appear to be the most useful in terms of mildness of conditions, yield, and convenience. Under PTC conditions, exclusive N-alkylation is usually observed.8
We have sought to develop a general method of the N-alkylation of heterocycles possessing an acidic hydrogen .9 Such a procedure should retain the convenience of PTC methods but should be free from some limitations related to PTC systems8 and much faster. Therefore we decided to explore the use of microwave heating under solvent free PTC conditions for N-alkylation of heterocycles.
Recently, the N-alkylation of 1,2,4-triazole and benzotriazole was achieved in the absence of solvent.10 The alkylation was performed either in basic medium under solvent free PTC conditions or in the absence of base by conventional and microwave heating. In the case of triazole alkylation, Loupy at al. claim that microwave irradiation produces specific (non-thermal) effects both on reactivity and selectivity.10 More recently, the 'dry' microwave N-alkylation of indole was attempted by Abramovitch et al.,11 but the yield of the reaction was unsatisfactory low.
We now report here the remarkable fast method of synthesis of N-alkylazaheterocycles in 'dry' media under microwave irradiation Fig.1.
Figure 1: The reactions of five-membered azaheterocycles with
alkyl halides under microwave irradiation.
The reactions were carried out by simply mixing of an azaheterocycle compound with 50% excess of an alkyl halide and a catalytic amount of tetrabutylammonium bromide (TBAB). The mixtures were adsorbed either on the mixture of potassium carbonate and potassium hydroxide or potassium carbonate and then irradiated in an open vessel in a domestic microwave oven for 1-10 min. For five-membered azaaromatic compounds the results are summarized in Table 1, while the results for the reactions of azaaromatic compounds fused with benzene rings are given in Table 2 (Fig. 2).
Since the shape and size of the reaction vessel are important
factors for the heating of dielectrics in a microwave oven, the
preferred reaction vessel is a tall beaker of much larger capacity
than the volume of
Table 1. The reactions of five-membered azaheterocycles with alkyl halides under irradiation
in a microwave oven.
| Compound | R-X | Product | Time
[s] | Power
[W] | Yield
[%] | mp/bp
[C]/[C/Torr] | References |
|
| Benzyl chloride
1-Chlorodecane 1-Bromopentane |
| 50
60 34 | 300 300 300 | 77 74 58 | 120-2/10 142-5/10 75-87/10 | 14 |
| Benzyl chloride
1-Chlorodecane 1-Bromopentane |
| 40
40 28 | 300 300 300 | 89 85 73 | 71-72 148-51/10 91-93/10 | 15 17 |
| Benzyl chloride
1-Chlorodecane 1-Bromopentane |
| 35
50 25 | 300 300 300 | 89 84 61 | oil 142-4/10 100-2/30 | 16 16 16 |
Reagents ratio: heterocyclic compound (5 mmol), alkyl halide (7.5
mmol), tetrabutylammonium bromide (0.5 mmol), K2CO3
(20 mmol), KOH (20 mmol).
the reaction mixture, and bearing a loose cover. A large Erlenmeyer flask with a funnel as a loose top cap can be used in place of the beaker. Superheating of liquids is common under microwave irradiation, thus
the strategy of the reactions is to keep the reaction temperature substantially below the boiling point of
each compound used for the reaction. Since it is difficult to measure temperature in a household
microwave oven, one of the best solutions is to repeat an experiment several times increasing the power slowly so that vapours do not escape outside of the flask.
Figure 2: The reactions between five-membered azaheterocycles fused with benzene rings and alkyl halides under microwave irradiation.
After the reaction, the work-up procedure is reduced a to treatment
with an appropriate solvent (e.g., THF or CH2Cl2),
purification by distillation in a Kugelrohr apparatus or recrystallization.
If necessary before recrystallization, compounds can be separated
from starting materials by means of flash chromatography. Melting
and boiling points of all the compounds are in good agreement
with literature data. The reaction procedures are not optimised
yet.
Table 2. The reactions of five-membered azaheterocycles fused with benzene rings with alkyl halides under irradiation in a microwave oven.
| Compound | R-X | Product | Time
[ s] | Power
[W] | Yield
[%] | mp/bp
[C]/[C/Torr] | References |
|
| Benzyl chloride
1-Chlorodecane 1-Bromopentane 3-Chloropropene |
| 30
45 27 38 | 300 300 300 300 | 94 88 86 83 | 43-45 oil 138-40/10 119-21/10 |
12 12 13 |
| Benzyl chloride 1-Chlorodecane 1-Bromopentane |
| 55 65 35 | 300 300 300 | 78 64 75 | 115-117 oil oil | 14 14 |
| Benzyl chloride
1-Chlorodecane
1-Bromobutane 1-Bromopentane |
| 240*
600*
420* 300* | 450
450
450 450 | 95
82
85 79 | 116-120
18-20
57-59 51-53 | 18, 19
18, 19 18 |
Reagents ratio: heterocyclic compound (5 mmol), alkyl halide (7.5
mmol), tetrabutylammonium bromide (0.5 mmol), K2CO3
(20 mmol), KOH (20 mmol); * heterocyclic compound (5 mmol),
alkyl halide (7.5 mmol), tetrabutylammonium bromide (0.5 mmol),
K2CO3 (20 mmol).
In conclusion, we have developed a simple and economical method for the N-alkylation of azaheterocycles that occurs remarkable fast under mild conditions using inexpensive reagents and a household microwave oven as the irradiation source. Moreover, the procedure is alternative to those which rely on the use of dipolar aprotic solvents, thallium salts of heterocycles, and several procedure that rely on "standard" PTC methods.
REFERENCES
