An efficient and rapid synthesis of β-carboxamide derivatives using 2,2-dimethyl-2H,4H-1,3-dioxin-4-ones by microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2003.08.118

A general, efficient and rapid method for the synthesis of various β-carboxamide derivatives using microwave irradiation is described. Excellent isolated yields were obtained in very short reaction times when conventional heating was replaced by microwave irradiation.

Full text of DOI:10.1016/j.tetlet.2003.08.118

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7957–7959
An efficient and rapid synthesis of b-carboxamide derivatives
using 2,2-dimethyl-2H,4H-1,3-dioxin-4-ones by microwave
irradiationꢀ
Bruhaspathy Miriyala and John S. Williamson*
Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, MS 38677 USA
Received 16 July 2003; revised 29 August 2003; accepted 29 August 2003
Abstract—A general, efficient and rapid method for the synthesis of various b-carboxamide derivatives using microwave
irradiation is described. Excellent isolated yields were obtained in very short reaction times when conventional heating was
replaced by microwave irradiation.
© 2003 Elsevier Ltd. All rights reserved.
The efficient and rapid synthesis of b-carboxamide
derivatives is of significant importance due to their
presence in various nitrogen containing heterocycle sys-
tems that have extensive application in medicinal chem-
istry.1–3 It is also used as yellow-dye forming image
couplers in photographic systems.4
focused our attention on replacing conventional heating
with microwave irradiation, and we now report a very
fast, simple and efficient procedure for the synthesis of
b-ketocarboxamides starting from b-diketones and pri-
mary or secondary amines.
Substituted 2,2-dimethyldioxin-4-ones were initially
synthesized from b-ketoesters after base hydrolysis fol-
lowed by the acid catalyzed cyclic adduct formation
with acetone according to established procedures.9 Sub-
sequent formation of the b-ketocarboxamides was
accomplished by microwave irradiation of 2,2-dimethyl-
dioxin-4-ones with an amine in a commercially avail-
able multimode microwave reactor dedicated for
organic synthesis. The microwave irradiated reaction
proceeds through the initial formation of a highly reac-
tive a-oxoketene intermediate via pseudopericyclic reac-
tion pathways.10 The subsequent addition of the
nucleophile (in this case, the amine) then captures the
ketene which results in the formation of the corre-
sponding b-ketocarboxamide.
b-Carboxamide derivatives were originally prepared by
heating the reaction of methyl or ethyl ketocarboxylates
with amines in high boiling solvents like xylene for
prolonged time periods.5 More recent approaches have
focused on the use of 2,2-dimethyl dioxin-4-ones in lieu
of the less reactive b-ketocarboxylates.6–8 However, the
yields of the reaction, as well as the reaction durations,
are generally unsatisfactory, especially when 5- or 6-
monosubstituted or 5,6-disubstituted dioxinones are
involved. Such inefficient syntheses necessitate the need
to develop more rapid reaction conditions.
In recent years, owing to its ability to couple directly
with the reacting molecules and bypassing thermal con-
ductivity leading to rapid rise in temperature,
microwave irradiation has been used to improve many
organic syntheses, leading to shorter reaction times,
higher yields, cleaner reaction products and easier
work-up than classical heating. In this respect, we have
Table 1. Standardization of MW irradiation time for the
synthesis of N-benzyl-3-oxo butyramide produced via
Scheme 1
E
Time (min)
Yield (%)
ꢀ Financial support for this project was provided in part by grants
from the Center for Disease Control (CDC U50-CCU418839 and
CDC UR3-CCU418652).
* Corresponding author. Tel.: 1-662-915-7142; fax: 1-662-915-5638;
e-mail: mcjsw@olemiss.edu
1
2
3
4
1.0
2.0
4.0
8.0
40
72
88
91
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.118

7958
B. Miriyala, J. S. Williamson / Tetrahedron Letters 44 (2003) 7957–7959
Scheme 1.
The experimental procedure for the formation of b-car-
boxamides was very simple: the 2,2-dimethyldioxin-4-
one derivatives (1 mmol) was mixed with the amine
(2–3 mmol) in a closed glass container and subjected to
microwave irradiation for a specific time with stirring.
The resulting amide product was taken in ethyl acetate
and washed sequentially with water and aqueous HCl
to remove excess amine. The organic layer was sepa-
rated, dried over magnesium sulfate, concentrated, and
purified chromatographically over silica gel to yield the
required b-ketocarboxamide.
microwave-assisted chemical reactions due to its high
dielectric loss tangent (tan l), chemical stability and
boiling point.12 All subsequent reactions were per-
formed using 2–3 equivalents of amine as solvent,
except in the case of low boiling amines such as diiso-
propylamine where a 1:1 mixture of 1,2-dichlorobenz-
ene and amine was used.
Since a wide range of b-ketoesters are either commer-
cially available or easily accessible as substrates for this
reaction, we have divided our validation methodology
into three groups: the simple alkyls (methyl), the ali-
cyclics (cyclohexyl), and the aromatics (phenyl). The
2,2-dimethyldioxin-4-one derivatives in each of the
three groups were successfully reacted with a variety of
primary and secondary amines, as shown in Tables 3–5,
resulting in good yield of the desired b-ketocarboxam-
ide in all cases.
For an initial evaluation of the method, 2,2,6-trimethyl
dioxin-4-one was selected as a suitable representative
example. The diketone was mixed with benzylamine in
1,2-dichlorobenzene and irradiated. Based on a similar
procedure for the synthesis of b-enaminoketones,11
microwave power was set at 200 watts and the temper-
ature was controlled by selecting a maximum of 178°C.
As evident from Table 1, 2,2,6-trimethyl dioxin-4-one
reacts rapidly with benzylamine. Optimum results were
obtained when the reaction mixture was irradiated for 4
min. A cursory examination of solvent effects suggested
that the absence of non-reactive solvent appears to
hasten the completion of the reaction as is indicated in
Table 2. This was somewhat surprising given that 1,2-
dichlorobenzene is the most commonly used solvent for
Table 4. Synthesis of b-carboxamide derivatives from 2,2-
dimethyl-6-phenyl-[1,3]dioxin-4-one
Entry
Time (min) R3
R4
Yield (%)
1
2
3
4
5
6
3
1
2
2
2
3
H
H
H
C6H5
-(CH2)-C6H5
-(CH2)2-C6H5
82
96
88
90
88
85
-(CH2)2-O-(CH2)2-
-(CH2)4-
-CH(CH3)2
-CH(CH3)2
Table 2. Effect of solvent for the synthesis of N-benzyl-3-
oxo butyramide by MW irradiation
E
Time (min)
Solvent
Yield (%)
Table 5. Synthesis of b-carboxamide derivatives from 2,2-
dimethyl-5,6,7,8-tetrahydro-benzo[1,3]dioxin-4-one
1
2
3
4
10
5
3
1,2-Dichloroethane
Xylene
1,2-Dichlorobenzene
Neat
62
75
88
95
Entry
Time (min) R3
R4
Yield (%)
1
1
2
3
4
5
6
3
1
2
2
2
3
H
H
H
C6H5
-(CH2)-C6H5
-(CH2)2-C6H5
78
92
88
90
85
80
Table 3. Synthesis of b-carboxamide derivatives from
-(CH2)2-O-(CH2)2-
-(CH2)4-
-CH(CH3)2
2,2,6-trimethyl-[1,3]dioxin-4-one
-CH(CH3)2
Entry
Time (min) R3
R4
Yield (%)
1
2
3
4
5
6
3
1
2
2
2
3
H
H
H
C6H5
-(CH2)-C6H5
-(CH2)2-C6H5
79
95
89
90
87
85
The presence of substitution at position 5 or alicyclic
substitution at position 5 and 6 of 2,2-dimethyldioxin-
4-one did not influence its reactivity to either primary
or secondary amines. Aniline, the least nucleophilic of
the amines, produced slightly low yields as compared to
other amines. The reactivity of various 2,2-dimethyl
-(CH2)2-O-(CH2)2-
-(CH2)4-
-CH(CH3)2 -CH(CH3)2

B. Miriyala, J. S. Williamson / Tetrahedron Letters 44 (2003) 7957–7959
7959
dioxi-4-ones was rapid with benzylamine, morpholine
and pyrrolidine. Even though the yields obtained using
diisopropylamine and phenethylamine were satisfac-
tory, the reaction times were longer owing to their low
reactivity. Steric factors associated with amines
appeared to have little effect on the nature of the
reaction.
2. Grosche, P.; Holtzel, A.; Walk, T. B.; Trautwein, A. W.;
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Chem. Soc. 1998, 120, 2493–2500.
In conclusion, microwave irradiation offers an efficient
and rapid methodology for the formation of a consider-
able range of b-ketocarboxamide derivatives using sub-
stituted 2,2-dimethyl dioxin-4-ones, which are prepared
from commercially available b-diketones and a variety
of primary and secondary amines. Presently, efforts to
extend the scope of this procedure to other nucleophilic
groups is underway.
6. Carroll, M. F.; Bader, A. R. J. Am. Chem. Soc. 1953, 75,
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