Friedel-crafts acylation of 2(3H)-benzoxazolone: Investigation of the role of the catalyst and microwave activation

Article abstract of DOI:10.1007/PL00010199

To study the scope and limitations of the use of complexed species of AlCl₃ in Friedel-Crafts reactions, we investigated the acctylation and benzoylation of 2(3H)-benzoxazolone and 3-methyl-2(3H)-benzoxazolone varying the amide complexing agent. We replaced dimethylformamide by N-methylformamide, dimethylacetamide, pyrrolidone, N-methylpyrrolidone, tetramethylurea, and dimethylsulfoxide. However, there was no particular advantage of substituting dimethylformamide by another amide ligand. This can probably be ascribed to the fact that the complex formed between AlCl₃ and the complexing agent becomes too stable. Alternatively, a route using polyphosphoric acid and microwave activation was explored. The major advantage of running the reaction in a microwave oven was that a good yield was reached in a rather short period of time.

Full text of DOI:10.1007/PL00010199

Monatshefte f uÈ r Chemie 130, 1393±1397 (1999)
Friedel-Crafts Acylation of 2(3H)-
Benzoxazolone: Investigation of the Role
of the Catalyst and Microwave Activation
1
1
2
1;Ã
Messaoud Liacha , Sa Èõ d Yous , Jacques H. Poupaert , Patrick Depreux
and Hocine Aichaoui1
,
1
Institut de Chimie Pharmaceutique Albert Lespagnol, F-59006 Lille, France
Unit e de Chimie Pharmaceutique, Ecole de Pharmacie, Facult e de M e decine, Universit eÂ
Catholique de Louvain, B-1200 Bruxelles, Belgium
2
Summary. To study the scope and limitations of the use of complexed species of AlCl in Friedel-
3
Crafts reactions, we investigated the acetylation and benzoylation of 2(3H)-benzoxazolone and 3-
methyl-2(3H)-benzoxazolone varying the amide complexing agent. We replaced dimethylformamide
by N-methylformamide, dimethylacetamide, pyrrolidone, N-methylpyrrolidone, tetramethylurea, and
dimethylsulfoxide. However, there was no particular advantage of substituting dimethylformamide
by another amide ligand. This can probably be ascribed to the fact that the complex formed between
AlCl and the complexing agent becomes too stable. Alternatively, a route using polyphosphoric acid
3
and microwave activation was explored. The major advantage of running the reaction in a microwave
oven was that a good yield was reached in a rather short period of time.
Keywords. 2(3H)-Benzoxazolone; Friedel-Crafts reaction; AlCl -DMF complex; Microwave irra-
3
diation.
Friedel-Crafts-Acylierung von 2(3H)-Benzoxazolon: Untersuchungen zur Rolle des Katalysators
und zur Aktivierung durch Mikrowellen
Zusammenfassung. Im Zuge der Untersuchung komplexierter Spezies von AlCl im Rahmen von
3
Friedel-Crafts-Reaktionen wurde die Acetylierung und Benzoylierung von 2(3H)-Benzoxazolon und
1-Methyl-2(3H)-benzoxazolon unter Variation des komplexierenden Amidagens untersucht. Es
wurde dabei Dimethylformamid durch N-Methylformamid, Dimethylacetamid, Pyrrolidon, N-
Methylpyrrolidon, Tetramethylharnstoff oder Dimethylsulfoxid ersetzt; es konnten jedoch keine
Vorteile gegen uÈ ber Dimethylformamid beobachtet werden. Dieses Resultat beruht vermutlich darauf,
daû der Komplex zwischen AlCl und diesen Amiden zu stabil ist. Dar uÈ ber hinaus wurde auch die
3
M oÈ glichkeit, Polyphosphors aÈ ure und Mikrowellenaktivierung einzusetzen, untersucht. Der beson-
dere Vorteil liegt hiebei in den guten Ausbeuten, die bei relativ kurzen Reaktionszeiten erzielt
werden k oÈ nnen.
à Corresponding author

1394
M. Liacha et al.
Introduction
In a series of recent papers, we have reported on the AlCl -DMF complex as a
3
useful catalyst in the Friedel-Crafts (FC) reaction [1±4]. This catalyst displays a
rather unique behaviour in the acylation of electron-rich compounds which are
quite basic substrates. Using classical Lewis acid catalysts (AlCl , BF , ZnCl ,
3
3
2
TiCl , etc.), these substrates are strongly complexed; they become therefore
4
heavily deactivated in electrophilic substitution reactions such as the FC reaction,
and yields are low. When AlCl -DMF is used as a catalyst, acylation products are
3
obtained in good yields. The use of the AlCl -DMF catalyst has been exempli®ed
3
in several publications concerning the acylation of 2(3H)-benzoxazolone and
2(3H)-benzothiazolone using activated forms of carboxylic acids (acid halides or
anhydrides) [5±12].
The initial paper of the series [1] was seminal in that several other groups were
prompted to investigate the same or similar Lewis acid-base complexes such as
AlCl -DMSO, AlCl -dimethylsulfone, or AlCl -nitromethane [13±15]. The FeCl -
3
3
3
3
graphite complex can be regarded as another example of a Lewis salt used as FC
catalyst [16].
An alternative route employs polyphosphoric acid (PPA) as catalyst [17].
In all cases, regioselectivity for position 6 of the heterocycle was observed.
However, in the case of !-halogenoacids or dicarboxylic acids, PPA was not found
as satisfactory as the AlCl -DMF complex, since either the expected acylation
3
product was not formed or low yields were obtained. The problem of !-halogenoacids
has been addressed in a previous paper [3]. In an effort to further study the scope
and limitations of the use of complexed species of AlCl in the Friedel-Crafts
3
reaction, we investigated the acetylation and benzoylation of 2(3H)-benzoxazolone
(1) and 3-methyl-2(3H)-benzoxazolone (2) as pilot reactions varying the amide
complexing agent (Fig. 1). In a second part, we also brie¯y report on the use of
PPA taking advantage of the well-known potentialities offered nowadays by the use
of microwave ovens. Microwave irradiation has been shown to be a very useful
alternative to conventional heating for chemical reactions [18].
1
Fig. 1. Regioselectivity in the FC acylation of 2(3H)-benzoxazolone (1, R ˆ H) and 3-methyl-2(3H)-
1
2
2
benzoxazolone (2, R ˆ CH ); R ˆ CH or C H ; methods: (a) R COCl, AlCl -X (X ˆ complexing
3
3
6
5
3
ꢀ
2
agent), 85 C; (b) R COOH, PPA, 80±125 C
ꢀ

Friedel-Crafts Acylation of 2(3H)-Benzoxazolone
1395
Results and Discussion
As already mentioned above, the major problem in the FC acylation of electron-
rich aromatic compounds and in the particular case of 1 is the complexation of the
substrates by Lewis acids. The substrates become therefore highly deactivated. This
problem can be alleviated to some extent using AlCl -DMF as a catalyst [9]. In an
3
effort to further substantiate the effect of the complexing agent on AlCl we
3
replaced dimethylformamide (DMF) by N-methylformamide (NMF), dimethyla-
cetamide (DMA), pyrrolidone (PYR), and N-methylpyrrolidone (MPY). The ratios
DMF/substrate and AlCl /substrate were kept constant at 3.5 and 10, which are the
3
optimal values found empirically and documented in previous publications [1, 2, 5].
As can be judged from Table 1, no particular advantage arises from substituting
DMF by another amide ligand, and in the case of compounds endowed with higher
basicity, e.g., tetramethylurea (TMU), DMSO, or sulfolan the yield of benzoylation
ꢀ
of 1 (4 h at 85 C) was found to be rather low (10±15%). This can probably be
ascribed to the fact that the complex formed between AlCl and the complexing
3
agent becomes too stable.
To evaluate if there was indeed a correlation between this trend in the yields
and the basicity of the various complexing partners of AlCl , we performed
3
quantum chemical calculations using the AM1 method (Table 2) [19].
Table 1. Variation of solvent in the Friedel-Crafts reaction of 1 and 2 resulting in 3a, 3b, 4a, and 4b
3a
3b
4a
4b
Solvent
Yield Reaction
Yield Reaction
Yield Reaction
Yield Reaction
(%)
time (h)
(%)
time (h)
(%)
time (h)
(%)
time (h)
DMF
NMF
DMA
PYR
68
60
65
65
52
3.5
5
70
65
68
68
61
2.5
3.5
3
66
61
60
58
51
4
75
63
62
60
62
4.5
5
4.5
5
4.5
4.5
4.5
5
3
5.5
5.5
5.5
5
MPY
2.5
Table 2. Electron densities of the solvents used acording to AM1
calculations
Electron Density at
Solvent
Oxygen
Nitrogen
Dimethylformamide
N-Methylformamide
Dimethylacetamide
Pyrrolidinone
� 0.373
� 0.376
� 0.371
� 0.359
� 0.356
� 0.875
� 0.417
� 0.358
� 0.402
� 0.352
� 0.396
� 0.354
±
N-Methylpyrrolidinone
Dimethylsulfoxide
Tetramethylurea
� 0.364

1396
M. Liacha et al.
The electron density at the oxygen atom was found to be rather constant for all
amide complexing agents (ca. � 0.36). However, as expected, the electron density
at the oxygen atom is signi®cantly higher for TMU (� 0.417) and DMSO (� 0.875),
thus re¯ecting higher basicity and, consequently, higher complex stability. As the
sign of the electron density at the nitrogen atom was found to be negative it can be
inferred that this atom is also involved in complexation, which is in agreement with
the empirical ®nding that the ratio AlCl /DMF had to be higher than one to induce
3
catalytic activity.
When using a Br oÈ nsted acid, the protic acid chosen must be suf®ciently acidic
to promote the formation of the acylium ion; it should not be too acidic, however,
so as to only slightly protonate the substrate. An optimal choice in accordance with
this balance appears to be PPA which offers the additional bonus of scavenging
water either by clustering or hydrolysis of PPA itself.
The FC reaction of 1 with benzoic acid using PPA and thermal activation has
ꢀ
been thoroughly studied. This reaction (120 C, 120 min) is generally performed
employing a considerable excess of PPA (ꢁ1200 g PPA/mol of carboxylic acid)
which may represent a drawback when the reaction has to be run on a large scale.
We therefore investigated the preparation of 4b using 350 g of PPA (84% of P 0 )/
2
5
mol of the carboxylic acid. After several unsuccessful attempts, good conditions
were found involving short microwave irradiation times at partial power values.
The reaction performed in a microwave oven proceeds in good yield (65%) in
2.5 min (Table 1) and, as previously observed under classical thermal conditions,
yields exclusively the 6-acyl derivative 4b.
Experimental
A Normatron 112 microwave oven from Normalab was used for the microwave activation
experiments. Melting points (uncorrected) were determined in open capillary tubes using a B uÈ chi
SMP 20 melting point apparatus. IR spectra were recorded using a dispersion of the product in KBr
1
disks by means of a Perkin-Elmer Model 297 spectrometer. H NMR spectra were recorded using a
AC 300 P Bruker spectrometer at ambient temperature with TMS as internal reference (ꢀ scale).
Elemental analyses were obtained from the Service Central d' Analyses du C.N.R.S. at Solaise
1
13
Vernaison, France. All compounds reported here had IR, H and C NMR, and MS, data consistent
with their structure. The experimental elemental analysis values were found within 0.4% of the
calculated values. Thin layer chromatography analyses were performed on Merck TLC plates (silica
gel, 60 F 254, E. Merck, Darmstadt, Ref. 5735). All compounds reported here were found
chromatographically homogenous in standard solvents, i.e. acetone/toluene/cyclohexane (5:2:3, v/v/
3
v). HPLC conditions were as follows: C-18, methanol:water (75:25, v/v), 1.5 cm /min. All
compounds were found to be homogenous under these conditions.
General procedure for the FC acylation of 2(3H)-benzoxazolone (1)
and 3-methyl-2(3H)-benzoxazolone (2)
3
3.3 g (0.4 mol) of AlCl were placed in a three neck round bottom ¯ask (250 cm ). The ¯ask was
5
3
then equipped with a re¯ux condenser with a CaCl tube, a mechanical stirrer, and a pressure
2
equilibrating dropping funnel. DMF or the complexing agent (0.115 mol) was added dropwise over
ꢀ
1
0
0 min. The ¯ask was then placed in an oil bath thermostatized at 45 C, and the substrate (1 or 2;
.04 mol) was added in portions over 5 min. Care was taken during this addition to ensure the

Friedel-Crafts Acylation of 2(3H)-Benzoxazolone
1397
formation of an homogeneous paste. The acylating agent (acetyl chloride or benzoyl chloride,
0
8
.06 mol) was then added dropwise over 10 min, and the temperature was subsequently raised to
ꢀ
ꢀ
5 C in the case of acetyl chloride and to 95 C in the case of benzoyl chloride. The reaction time is
3
reported in Table 1. The products were isolated by addition of ice water (1 dm ). The precipitate was
stirred for 1 h, collected on a B uÈ chner funnel, dried, and recrystallized from ethanol. The yields are
1
reported in Table 1. The physical properties (m.p., IR, H NMR) are in accordance with published
data [9, 17].
Preparation of 3-methyl-6-benzoyl-2(3H)-benzoxazolone (4b) using PPA and microwave activation
3
ꢀ
In a 250 cm round bottomed ¯ask, 100 g of PPA were preheated at 65 C. Under mechanical stirring,
an intimate mixture (mortar ground) of 12.2 g of benzoic acid (0.1 mol) and 14.9 g of 2 was added in
portions over 5 min. When a homogenous paste was obtained, a magnetic stirring bar was placed in
the ¯ask that was transferred to the micro wave oven. Under magnetic stirring, the reaction medium
was heated for 2.5 min at 25% of the maximum power (corresponding to 275 W) and allowed to
3
stand for additional 20 min after which time it was diluted by 1 dm of ice water. The resulting
precipitate was ®ltered over a B uÈ chner funnel, dried, and recrystallized from ethanol to yield 65% of
the tittle compound.
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Received March 12, 1999. Accepted (revised) April 7, 1999