Silica-bound benzoyl chloride mediated the solid-phase synthesis of 4H-3, 1-benzoxazin-4-ones

Article abstract of DOI:10.3762/bjoc.5.13

The solid-phase synthesis of 4H-3, 1-benzoxazin-4-ones was achieved using silica-bound benzoyl chloride (SBBC) as dehydrating agent in reaction with 2-acylaminobenzoic acids. The silica-grafted reagent (SBBC) was simply recovered after reaction and reused several times.

Full text of DOI:10.3762/bjoc.5.13

Silica-bound benzoyl chloride mediated the
solid-phase synthesis of 4H-3,1-benzoxazin-4-ones
Kurosh Rad-Moghadam* and Somayeh Rouhi
Full Research Paper
Open Access
Address:
Beilstein Journal of Organic Chemistry 2009, 5, No. 13.
Chemistry Department, University of Guilan, P.O. Box 41335-19141,
Rasht, Iran
doi:10.3762/bjoc.5.13
Received: 20 January 2009
Accepted: 14 April 2009
Published: 23 April 2009
Email:
Kurosh Rad-Moghadam* - radmm@guilan.ac.ir
*
Corresponding author
Editor-in-Chief: J. Clayden
Keywords:
H-3,1-benzoxazin-4-one; silica-bound benzoyl chloride; solid-phase
© 2009 Rad-Moghadam and Rouhi; licensee Beilstein-Institut.
License and terms: see end of document.
4
synthesis
Abstract
The solid-phase synthesis of 4H-3,1-benzoxazin-4-ones was achieved using silica-bound benzoyl chloride (SBBC) as dehydrating
agent in reaction with 2-acylaminobenzoic acids. The silica-grafted reagent (SBBC) was simply recovered after reaction and reused
several times.
Introduction
Solid-phase approaches are gaining more and more applica- removed from the heterogeneous reaction mixture by filtration.
tions in organic synthesis mainly because reactions with a Besides functionalized organic polymers a variety of silica gel-
loaded substrate can be manually sequenced and driven to grafted reagents have also been devised for solid-phase organic
higher yields by using excess reagents, which are subsequently syntheses [10-14]. Compared with organic polymers, silica gel
removed by simple filtration [1-7]. Conventionally, solid-phase is more robust to drastic conditions and harsh reagents.
synthesis referred to approaches in which the substrate was
loaded onto the solid support and after programmed reactions 4H-3,1-Benzoxazin-4-ones are the most frequently used
the product was formed and then cleaved from the support. precursors in the synthesis of biologically active quinazolin-
However, the concept of solid-phase chemistry is now used in a 4(3H)-ones [15]. In addition, some of the 4H-3,1-benzoxazin-4-
wider sense to cover alternative solid-phase reagent chemistry. ones themselves have shown interesting biological activities
In these approaches, substrates are chemically bound to the [16-19]. As a result of these attractive features, a number of
surface of the solid-supported reagent and converted to the approaches have been developed for the synthesis of 4H-3,1-
product during liberation from the solid [8]. In another version, benzoxazin-4-ones. A literature survey regarding the synthesis
the core structure of the library molecule resides in solution and of 2-substituted 4H-3,1-benzoxazin-4-one derivatives disclosed
solid-phase reagents are added to the mixture to facilitate the a variety of methods, including cyclodehydration of N-acylan-
reaction [9]. The solid-phase reagent or its residue is then thranilic acids by acetic anhydride [20], reaction of anthranilic
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Beilstein Journal of Organic Chemistry 2009, 5, No. 13.
acid with acid chlorides [21], treatment of methyl N-aroylan- stretching vibration of the carboxyl groups while the absorbtion
thranilates or methyl 2-ureidobenzoates with concentrated of C=O stretching vibration of carbonyl chloride groups in
sulfuric acid [22], rearrangement of o-nitrophenylacetic acid in SBBC appeared at 1704 cm−1.
boiling acetic anhydride [23], condensation of 2-azidobenzoic
acid with aldehydes [24], photoisomerization of 2-arylisatogen The extent of functionalization was roughly determined gravi-
[
[
25], and cyclocondensation of anthranilic acid with orthoesters metrically by measuring the weight gain of SBBC relative to the
26]. Meanwhile, the cyclodehydration of N-acylanthranilic starting silica chloride. This measurement gave an averaged
acids in refluxing acetic anhydride has been the prevalent value of 1.1 mmol of supported benzoyl chloride per gram of
method used for production of 4H-3,1-benzoxazin-4-ones. SBBC. There is a considerable difference between the meas-
However, use of traditional dehydrating agents like acetic ured amount of immobilized benzoyl chloride functions on the
anhydride or sulfuric acid usually suffers from difficulties silica and the value of 2.3 mmol Si-Cl groups per gram of silica
encountered in their handling, separation, and recovery after the chloride as determined by Volhard’s precipitation titration [29]
reaction and may lead to environmental pollution. To eliminate of Cl− ions released on hydrolysis of 1 g silica chloride. Appar-
these disadvantages we intended to evaluate the silica-bound ently, owing to porous nature of silica chloride, a significant
benzoyl chloride (SBBC) as a solid-phase reagent for cyclode- fraction of the silyl chloride linkers remains unreacted even in
hydrating N-acylanthranilic acids 2a–f. Accordingly, we intro- treatment with excess 4-hydroxybenzoic acid during the loading
duce it here as an efficient and recyclable dehydrating agent for process. On the other hand, and for the same reason, many of
convenient synthesis of 4H-3,1-benzoxazin-4-ones.
the graft sites may be unavailable or more hindered for reaction
with the substrate molecules. In view of this we planned to
determine the optimal amount of SBBC needed in reaction with
Results and Discussion
As is shown in Scheme 1, an approach consisting of three steps 2-acylaminobenzoic acid experimentally, and to this purpose
was employed for synthesis of SBBC through which first the the reaction with 1 mmol of 2-benzoylaminobenzoic acid in
surface of silica gel was converted to silica chloride by means refluxing dichloromethane was used as a model reaction.
of reaction with thionyl chloride [27,28]. The silica chloride Preliminary experiments employing different amounts of SBBC
was heated with 4-hydroxybenzoic acid to form the silica-bound in the model reaction showed that the best result in term of
benzoic acid (SBBA). The SBBA was washed with acetone to product yield is obtained from the optimum 2 g of SBBC. Thus,
remove excess 4-hydroxybenzoic acid. Finally, the silica-bound the reaction between 2-acylaminobenzoic acid (1 mmol) and 2 g
benzoyl chloride, SBBC, was obtained from the reaction of of SBBC in refluxing dichloromethane went to completion in
SBBA with thionyl chloride. The IR spectrum of SBBA reasonable time and in fairly good yields (Table 1).
revealed a band around 1660 cm−1 clearly indicative of C=O
Scheme 1: Three-step synthesis of silica-bound benzoyl chloride.
Table 1: Results of reaction between 2a–f and SBBC.
Product
R
Reaction time (min)
Yields (%)a
Mp/°C
Lit. mp/°C
5a
5b
5c
5d
5e
5f
CH3–
55
55
55
90
90
90
71
69
72
79
78
76
80–82
84–86
80–81b
85–86b
59–60b
123–124b
102c
CH3CH2–
CH3CH2CH2–
Ph-
58–60
120–122
99–100
146–147
2-Furyl
Ph-CH=CH-
148c
aYields of pure isolated products base on 2-acylaminobenzoic acid; b[18]; c[19].
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Beilstein Journal of Organic Chemistry 2009, 5, No. 13.
The progress of reaction was monitored by TLC using ethyl All the products are known compounds with IR, and 1H NMR
acetate-petroleum ether as eluent. After completion of reaction spectral data in good agreement with their structures as well as
the hot slurry of reaction-mixture was filtered to separate the with authentic samples prepared from the previously reported
SBBC residue. The residue was washed with dichloromethane methods.
and recovered by refluxing in thionyl chloride. Also, inter-
esting to note is that under similar conditions and reaction times Conclusion
the treatment of 2-acylaminobenzoic acids with silica chloride 1 A new solid-phase synthesis protocol has been developed for
did not furnish the corresponding benzoxazinones.
preparation of 2-substituted 4H-3,1-benzoxazin-4-ones. The
main advantages of this process are the recyclability of the solid
To investigate the recoverability of SBBC its reaction with support and self release of products from the linker as a
-benzoylaminobenzoic acid was chosen as the model. After concomitant with their formation. Therefore, good yields of the
2
completion of the model reaction the solid support was separ- products are obtained under relatively mild conditions by an
ated by filtration, washed with dichloromethane, dried in oven economically viable and environmentally friendly method.
and then refluxed in excess thionyl chloride. The recovered
SBBC was subjected to the next run of the model reaction. The Experimental
results of the first experiment and subsequent experiments were Melting points were measured on an electrothermal apparatus
almost consistent in yields after three runs (79%, 76%, 76%).
and are uncorrected. IR spectra were obtained in KBr wafers on
a Shimadzu IR-470 spectrometer. Chemicals were obtained
However we have not determined the mechanistic details of from Merck (Darmstadt, Germany) and were used without
reaction between SBBC and 2-acylaminobenzoic acids, plaus- further purification. The required 2-acylaminobenzoic acid
ible rationalizations may be advanced to explain the formation substrates 2a–f were prepared according to the reported
of benzoxazinones 5a–f (Scheme 2). Presumably, these reac- methods [18,30].
tions involve the formation of the transient mixed anhydrides
Procedure for preparation of silica-bound
3
a–f or 4a–f which undergo thermal cyclo-elimination through
intramolecular nucleophilic substitution to produce the benzoyl chloride (SBBC)
benzoxazinone products leaving SBBA aside. To 5.0 g of a well dried fine powder of silica gel 60
0.063–0.200 mm) in a flask was added 25 mL of SOCl2. The
(
SBBC is a reactive reagent and is prone to hydrolysis but in mixture was refluxed for about 3 h, and then distilled to remove
comparison with commonly used dehydrating acid chlorides the excess SOCl2. To 4.0 g of the resulting white powder of
such as acetyl chloride and benzoyl chloride which are more silica chloride, a solution of 4-hydroxybenzoic acid (2.0 g) in
hygroscopic and difficult to handle, it has negligeable vapour CH2Cl2 (30 mL) and DMF (4 mL) was added and the mixture
pressure so can be used simply. In addition, SBBC is not lost to was refluxed for about 6 h. The suspension was filtered to
environment as it easily is separated and recovered after reac- separate the SBBA powders, the precipitate was washed with
tion.
acetone (2 × 20 mL) and dried at 100 °C to give 4.43 g of
Scheme 2: Plausible mechanisms for the synthesis of benzoxazinones 5a–f.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 13.
1
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2
a–f) in dry CH2Cl2 (12 mL) was added 2 g of SBBC (ca. 2.2
mmol reagent). The mixture was refluxed according to the time
mentioned in Table 1, and then was filtered while hot. The
filtered solids were washed with CH2Cl2 (2×10 mL). The
combined CH2Cl2 fractions were evaporated and the residue
was purified by recrystallization in n-heptane or by chromato-
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