Erlenmeyer azlactone synthesis with aliphatic aldehydes under solvent-free microwave conditions

Article abstract of DOI:10.1016/j.tetlet.2006.11.174

2-Phenyl-5(4H)-oxazolone (azlactone) reacts with aliphatic aldehydes upon adsorption on neutral alumina and irradiation with microwaves (<2 min). The corresponding condensation products are obtained in good yields (62-78%), indicating the satisfactory res

Full text of DOI:10.1016/j.tetlet.2006.11.174

Tetrahedron Letters 48 (2007) 785–786
Erlenmeyer azlactone synthesis with aliphatic aldehydes
under solvent-free microwave conditions
Sosale Chandrasekhar* and Phaneendrasai Karri
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 8 September 2006; revised 22 November 2006; accepted 29 November 2006
Abstract—2-Phenyl-5(4H)-oxazolone (azlactone) reacts with aliphatic aldehydes upon adsorption on neutral alumina and irradia-
tion with microwaves (<2 min). The corresponding condensation products are obtained in good yields (62–78%), indicating the satis-
factory resolution of a long-standing problem plaguing the classical Erlenmeyer synthesis (poor results with aliphatic aldehydes).
Plausible mechanistic reasons for the success of the procedure are discussed.
Ó 2006 Elsevier Ltd. All rights reserved.
We have recently reported interesting mechanistic find-
ings on the classical Erlenmeyer azlactone synthesis,1,2
essentially suggesting that the aromaticity of the inter-
mediate azlactone anion (cf. II, Scheme 1) is the key
to the success of the reaction. The azlactone anion func-
tions as a glycine enolate equivalent, and is condensed
with aldehydes in a process related to the Knoevenagel3
and Perkin reactions.4 However, a serious limitation to
the original Erlenmeyer procedure is that it generally
fails in the case of aliphatic aldehydes,2,5–7 as these are
unstable under the reaction conditions (this possibly
applies to the products also, vide infra). We report
herein a resolution of this long-standing problem.
tion as the Erlenmeyer reaction is a general method
for the synthesis of amino acids.1,2 (A previously
reported microwave procedure for the Erlenmeyer syn-
thesis is apparently valid only for aromatic aldehydes.11)
The success of the microwave procedure has been attrib-
uted to the high temperatures that are rapidly attained
upon absorption of the radiation. In the present case,
the reasons noted below are also likely to be important.
The success of the procedure is possibly due to (i)
absence of both a strong base and a solvent that would
facilitate the self-condensation of the aldehyde; (ii)
alumina acting as a mild base to generate the azlactone
anion II; and (iii) the high temperatures attained during
irradiation that possibly facilitate diffusion of the reac-
tants on the surface of alumina, and the ensuing conden-
sation step in which water is eliminated from the
intermediate adduct I. (The pKa of azlactones is likely
to be much lower than aldehydes,1 so the selective
deprotonation of 1 is feasible.)
When a mixture of 2-phenyloxazol-5-one (azlactone, 1)
and an aliphatic aldehyde 2 was adsorbed on neutral
alumina and irradiated in a commercial microwave
oven, Erlenmeyer products 3 were obtained in good
yields (Scheme 1 and Table 1, which includes previously
reported results). The reaction residue was directly puri-
fied chromatographically, without work-up. The reac-
tion was successful in the case of several aliphatic
aldehydes, being complete within 2 min (at 300 W). Irra-
diation beyond this time led to a drastic fall in yields,
presumably because of destruction of the product.
It is also noteworthy that the Erlenmeyer synthesis with
aromatic aldehydes is possibly driven by the resonance
stabilization of the products, via conjugation of the aro-
matic ring with the newly formed double bond (cf. 3). As
this is absent in the aliphatic case, elimination of water
during the condensation possibly needs to be driven to
completion and is presumably achieved under micro-
wave conditions. (In fact, our attempts to effect the
above reaction between 1 and 2 with mild bases, e.g.
Et3N or DBU in CH2Cl2, led to only poor yields of 3
despite using molecular sieves to remove the water
formed.)
Microwave-assisted reactions are increasingly employed
in synthesis,8–10 and this method is an important addi-
Keywords: Aliphatic aldehydes; Alumina; Azlactones; Erlenmeyer
synthesis; Microwave; Oxazolone; Solvent-free.
*
Corresponding author. Tel.: +91 80 2293 2689/2402; fax: +91 80
2360 0529; e-mail: sosale@orgchem.iisc.ernet.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.174

786
S. Chandrasekhar, P. Karri / Tetrahedron Letters 48 (2007) 785–786
OH
O
O
O
H
R
R
i
i
H
O
O
+
RCHO
H
O
N
N
(-H2O)
N
Ph
Ph
1
Ph
2
3
I
(62-78%)
O
H
1
2
(i) (1.0 eq.) + (1.2-3.0 eq.)
adsorbed on Al2O3; irradiated
with microwaves at 300 W
CHO
'TCPM'-CHO
O
N
II
Ph
Scheme 1. The Erlenmeyer azlactone synthesis effected with azlactone 1 and aliphatic aldehydes 2 in the presence of alumina and microwave
irradiation.
Table 1. Percentage yields of products 3 in the Erlenmeyer synthesis
7.90 (2H, m, ArH), 7.70–7.30 (3H, m, ArH), 6.96 (1H,
t, J 8.8 Hz, C@CH), 2.75–2.64 (2H, ‘quintet’, J 8.7 Hz,
between azlactone 1 and aliphatic aldehydes 2 (cf. Scheme 1)a
Entry
‘R’ in 2/3b
Yield of 3 (%)
MeCH2CH@C), 1.18 (3H, t, J 8.8 Hz, CH3CH2); dC
(75 MHz, CDCl3) 162.6 (C@O), 141.0 (C@N), 135.7
(ArC), 133.0 (ArC), 132.9 (ArC), 128.8 (ArC), 128.1
(CH@Cazlactone), 125.6 (CH@C), 22.2 (C@C–C), 12.9
(MeC); HRMS found 202.0868 (calcd for M+H
C12H12NO2 202.0865).12
This study
Reported
1
2
3
4
5
6
Et (3)
62
65
71
74
78
69
457
205
317
—
Prn (3)
Pri (3)
Bui (2)
n-C6H13 (1.5)
TCPM (1.2)c
05
—
Acknowledgement
a Products 3 were identified by mp (if crystalline) and spectral data
(vide infra), including HRMS.
b Number of molar equivalents of 2 employed is parenthesized, excess
being needed to offset evaporation during irradiation.
c TCPM = (1,5,5-trimethylcyclopent-1-en-4-yl)methyl (cf. Scheme 1).
We are most grateful to Professor S. Chandrasekaran
for granting permission to use the microwave apparatus
in his laboratory, without which this study would not
have been possible.
In conclusion, we have described a successful extension
of the Erlenmeyer azlactone synthesis to aliphatic
aldehydes, in a novel microwave-induced, solvent-free
process that is also remarkably rapid. This not only
removes a serious limitation of the classical Erlenmeyer
synthesis, but also adds to the growing list of micro-
wave-induced organic reactions.
References and notes
1. Chandrasekhar, S.; Karri, P. Tetrahedron Lett. 2006, 47,
5763–5766.
2. Rosen, T. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Heathcock, C. H., Eds.; Oxford: Perag-
mon, 1991; Vol. 2, pp 402–407, and references cited
therein.
3. Tietze, L. F.; Beifuss, U. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Heathcock, C. H.,
Eds.; Oxford: Pergamon, 1991; Vol. 2, pp 341–394, and
references cited therein.
4. Chandrasekhar, S.; Karri, P. Tetrahedron Lett. 2006, 47,
2249–2251, and references cited therein.
5. Crawford, M.; Little, W. T. J. Chem. Soc. 1959, 729–731,
and references cited therein.
6. Mukerjee, A. K. Heterocycles 1987, 26, 1077–1097, and
references cited therein.
7. Finar, I. L.; Libman, D. D. J. Chem. Soc. 1949, 2726–
2728.
8. Kappe, C. O. Chimia 2006, 60, 308–312.
9. El Ashry, E. H.; Kassem, A. A. ARKIVOC 2006, ix, 1–
16.
10. Hayes, B. L. Microwave synthesis; Chemistry at the Speed
of Light; CEM: Matthews (NC, USA), 2002.
11. Mogilaiah, K.; Prashanthi, M.; Reddy, S. C. Indian J.
Chem. 2003, 42B, 2126–2128.
12. Spectral assignments: cf. Kemp, W. Organic Spectroscopy,
3rd ed.; Macmillan: London, 1991; p 177–202.
Typical procedure: (Azlactone 1 was prepared as
reported2 and aldehydes 2 were procured commercially;
microwave irradiation was performed on a BPL-800T
apparatus manufactured by BPL-Sanyo India Ltd.)
Caution: Occasionally, sparks were observed during irra-
diation. An intimate mixture of azlactone 1 (1.0 mmol),
aldehyde 2 (1.2–3.0 mmol, cf. Table 1) and neutral
Al2O3 was prepared in a 10 ml round-bottomed flask,
by trituration in CH2Cl2 followed by the removal of vol-
atiles in vacuo. The flask (with residue) was fitted with a
septum that had been punctured (to release pressure),
and irradiated in a microwave oven at 300 W for
2 min. After cooling, the residue was chromatographed
directly on a silica gel column eluting with hexane–
EtOAc (9:1) to afford pure condensation product 3.
These were crystalline solids in three cases, but waxy
in the other; R (mp/°C): Et (81), Prn (57), Pri (84). Typ-
ical spectral characteristics (R@Et): vmax (film)/cmÀ1
2961, 2930, 1800, 1673; dH (300 MHz, CDCl3) 8.15–