PhCOCI-Py/basic alumina as a versatile reagent for benzoylation in solvent-free conditions

Article abstract of DOI:10.3390/80400374

A solvent-free procedure using PhCOCl-Py/basic alumina under microwave irradiation has been developed for N-, O- and S-benzoylation.

Full text of DOI:10.3390/80400374

Molecules 2003, 8, 374-380
molecules
ISSN 1420-3049
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PhCOCl-Py/Basic Alumina as a Versatile Reagent for
Benzoylation in Solvent-Free Conditions
Satya Paul *, Puja Nanda and Rajive Gupta
Department of Chemistry, University of Jammu, Jammu-180 006, India.
*Author to whom correspondence should be addressed; E-mail: paul7@rediffmail.com; Phone: (+91)
191-2673841; Fax: (+91) 191-2505086.
Received: 9 December 2002; in revised form: 13 January 2003/ Accepted: 31 March 2003 / Published:
30 April 2003
Abstract: A solvent-free procedure using PhCOCl-Py/basic alumina under microwave
irradiation has been developed for N-, O- and S-benzoylation.
Keywords: Benzoylation, solvent-free conditions, microwave activation, PhCOCl, basic
alumina.
Introduction
Benzoylation is an important transformation in Organic Synthesis [1]. A number of reagents can be
used for carrying out this reaction, such as benzoyl chloride [1], benzoic anhydride [2],
benzoyltetrazole [3], 2-benzoyl-1-methylpyridinium chloride [4], S-benzoic-O,O-diethylphosphoro-
dithoic anhydride [5], benzoyl cyanide [6], etc. Though benzoyl chloride may be a health hazard due to
its toxicity, nevertheless it is widely used because of its ready availability and low cost. The reaction is
usually catalyzed by bases like pyridine, triethylamine and sodium hydroxide[7].
Recently, organic reactions on solid supports [8], and those assisted by microwaves, especially
under solvent-free conditions [9], have attracted much attention because of their enhanced selectivity,
milder reaction conditions and associated ease of manipulation. Recently, we have reported an

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375
acetylation using Ac2O-py/basic alumina [10a]. Acetyl chloride did not work under these conditions,
consequently development of a solvent-free protocol, meeting Green Chemistry principles is desirable.
Results and Discussion
For the aforementioned reasons, and in light of our general interest in using microwaves for the
development of environmentally friendlier synthetic alternatives [10], we became interested in an
expeditious synthesis of these compounds. We now report a simple procedure for the benzoylation of
amino, hydroxy and thiol groups under solvent-free conditions using PhCOCl-Py/basic alumina.
Benzoylation of aniline using benzoyl chloride over different solid supports in presence of various
catalysts was studied in order to select the most efficient combination (Table 1). In order to optimize
the results, we also carried out benzoylation of aniline under different conditions by testing various
molar ratios and amounts of support. From the results it is clear that PhCOCl-Py/basic alumina was the
most efficient reagent and that a ratio of 1 mmole of the substrate, 2 mmole of PhCOCl, 0.6 mmole of
pyridine and 2 gm of support gave optimum results, hence we have extended the use of this reagent
and conditions for the benzoylation of –NH2, -OH and –SH groups (Table 2).
Table 1. Preparation of benzanilide from aniline using various reagents (power=300 W)
Timea
(min)
Reaction Tempb
(°C)
Yield
(%)c
89
Reagent
PhCOCl/SiO2
3
62-64
PhCOCl/K10
8
59-61
71
PhCOCl/p-TsOH/SiO2
PhCOCl/Acidic Al2O3
PhCOCl/TFA/SiO2
PhCOCl/H2SO4/SiO2
PhCOCl/DMSO/SiO2
PhCOCl-Py/Basic Al2O3
10
8
10
4
2
1
39-41
52-54
51-53
52-54
50-52
92-94
48
64
45
84
77
100
Notes: a Time at which maximum yield was obtained.
b Final temperature was measured by immersing a glass thermometer into the reaction
mixture at the end of exposure to microwave irradiation and gives the approximate
temperature range.
c Yield of isolated products.
Further, the support can be reused several times without loss of activity. The method is
environmentally friendly as hydrochloric acid (the by-product) remains adsorbed on the basic alumina
and does not escape into the atmosphere. The method can be used for selective mono and
dibenzoylation (cf. Table 2, entries 19, 20, 21, 22 and 33, 34).

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376
Table 2. Microwave-assisted N-, O- and S-benzoylations using PhCOCl-Py/basic alumina
(power = 300W).
Temperaturea Time Yieldb
m.p./Lit. m.p.
(°C)
162-3/164-6 [11]
96-7/98 [12]
155-6/157 [12]
198-9/199[12]
58-59/60 [12]
153-54/154 [12]
124-5/125 [12]
156-7/158 [12]
194-5/196 [12]
317/320-21 [13]c
73-4/74-5 [13]
Entry
Reactant
Aniline
Product
Benzanilide
2-Nitrobenzanilide
3-Nitrobenzanilide
(°C)
92-94
85-87
94-96
99-100
134-36
100-02
84-86
84-86
94-96
91-93
103-05
(min)
1
2
(%)
100
87
60
92
60
65
94
55
55
70
64
1
2
3
4
5
6
7
8
9
2-Nitroaniline
3-Nitroaniline
4-Nitroaniline
2-Anisidine
4-Anisidine
3-Toluidine
4-Toluidine
Piperazine
5
6
3
2
1
2
1
1.5
2
4-Nitrobenzanilide
2-Methoxybenzanilide
4-Methoxybenzanilide
3-Methylbenzanilide
4-Methylbenzanilide
N-Benzoylpiperazine
N-Benzoylpiperidine
N-Benzoylmorpholine
10
11
Piperidine
Morpholine
12
13
Benzylamine
Cyclohexylamine
N-Benzoylbenzylamine
N-Benzoylcyclohexyl-
amine
104-06
96-98
1
1
93
79
104-5/105-6 [13]
145-6/147 [12]
14
15
16
17
Phenol
Phenylbenzoate
109-11
128-30
98-100
81-83
4
6
5
3
74
70
71
69
68-9/69-72 [11]
52-53/55 [11]
70-71/71 [11]
220-21/221-23
[13]
3-Cresol
4-Cresol
4-Hydroxybenzoic
acid
3-Methylphenyl-benzoate
4-Methylphenylbenzoate
4-Benzoyloxybenzoic
acid
18
19
20
21
22
Vanillin
4-Benzoyloxy-3-methoxy
benzaldehyde
3-Hydroxyphenyl-
benzoate
1,3-Dibenzoyloxy-
benzene
4-Benzoyloxy-2-Hydroxy-
acetopheneone
97-99
41-43
92-94
74-76
78-80
4
9
9
7
8
64
65
55
59
65
77-78/78 [12]
Resorcinol
134/135-7 [13]
115-17/117 [13]
105-6/106-7 [13]
78-9/80-1 [13]
Resorcinol
Resacetophenone
Resacetophenone
2,4-Dibenzoyloxyaceto
phenone
23
24
25
2-Nitrophenol
4-Nitrophenol
1-Naphthol
2-Nitrophenylbenzoate
4-Nitrophenylbenzoate
1-Benzoyloxy-
98-100
74-76
108-10
7
6
4
60
65
62
49-50/50 [12]
139-40/142 [12]
54-5/56 [12]
naphthalene

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377
Table 2. (cont.)
Temperaturea Time Yieldb
m.p./Lit. m.p.
(°C)
105-06/107 [12]
Entry
26
Reactant
Product
2-Benzoyloxy-
(°C)
(min)
(%)
2-Naphthol
104-06
2
60
naphthalene
27
28
29
Ethylenediamine
N,N-Dibenzoylethylene-
diamine
2-(N-Benzoylamino)-4-
phenylthiazole
112-14
113-15
81-83
2
3
2
39
72
99
242-43/244 [13]
156-57
2-Amino-4-phenyl-
thiazole
2-Amino-4-(4-bromo- 2-(N-Benzoylamino)-4-
phenyl)thiazole (4-bromophenyl)thiazole
115-16
30
31
32
33
2-Amino-4-(4-chloro- 2-(N-Benzoylamino)-4-
phenyl)thiazole (4-chlorophenyl)thiazole
2-Amino-4-(4-fluoro- 2-(N-Benzoylamino)-4-
115-17
119-21
62-64
2
10
5
65
98
97
60
156-57
123-24
phenyl)thiazole
2-Aminobenzene-
thiol
(4-fluorophenyl)thiazole
1-Thiobenzoyloxy-2-
aminobenzene
115-16
2-Aminobenzene-
1-Thiobenzoyloxy-2-N-
benzoylaminobenzene
98-100
2
153-4/154-5 [13]
thiol
a
Notes: Final temperature was measured by immersing a glass thermometer in the reaction mixture at the end of
the exposure to microwave irradiation and gives an approximate temperature range.
b
Yield of isolated products
Boiling point
c
Figure 1. Effect of microwave power on the benzoylation of aniline and 2-nitroaniline
2-Nitroaniline
Aniline
100
95
90
85
80
75
70
100
200
300
400
500
Power (watt)

Molecules 2003, 8
378
Further, the reaction has been carried out at different power levels from 80-800 watts in the cases
of aniline and 2-nitroaniline in order to select the more appropriate power level. The results are shown
graphically in Figure 1. It is clear that power level of 300 W gave the maximum yield.
Conclusions
A rapid, economic and environmentally friendly method has been developed for benzoylation of
-NH2, -OH and –SH groups using PhCOCl-Py/basic alumina. The reagent system described here may
be a good alternative to well known methods since the benzoylation proceeds expeditiously with high
yields under solvent-free conditions.
Experimental
General
Melting points were recorded on a Toshniwal melting point apparatus and are uncorrected. All
reactions were carried out in a commercially available BPL BMO 800T domestic microwave oven
having a maximum power output of 800 W operating at 2450 MHz. IR spectra were obtained on a
1
Hitachi 270-30 spectrophotometer using KBr discs. H-NMR spectra were recorded using a JNM-
PMX 60 NMR Spectrometer (60 MHz). Mass spectra were recorded using JEOL D-300 spectrometer.
General Synthetic Procedure
Substrate (2 mmole), benzoyl chloride (4 mmole), pyridine (0.6 mmole) and basic alumina (2 g)
were added in a 50 mL beaker. The mixture was stirred to obtain a free flowing powder, which was
irradiated in a microwave oven at 300 W for an appropriate time (Table 2, as monitored by TLC).
After cooling to room temperature, the product was extracted with methylene chloride (3 x15 mL). The
combined extracts were washed with water and dried over sodium sulfate. The product obtained after
removal of solvent under reduced pressure was crystallized from a suitable solvent (EtOAc-pet. ether;
1
EtOH). The structure of the products was confirmed by H-NMR, IR and mass spectral data and
comparison with authentic samples prepared according to literature methods.
Spectral and Analytical Data of Selected Compounds
1
2-(N-Benzoylamino)-4-phenylthiazole (entry 28): IR cm-1: 1586 (C=N), 1720 (COPh); H-NMR
(CDCl3+ DMSO-d6): δ 5.06 (bs, 1H, NH, exchangeable with D2O), 7.1-7.8 (m, 11H, Harom); m/z(%):
M+ 280 (77.5); Anal. calcd. for C16H12N2OS: C, 68.57; H, 4.28; N, 10.00. Found: C, 68.53; H, 4.25; N,
9.98.

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379
2-(N-Benzoylamino)-4-(4-bromophenyl)thiazole (entry 29): IR cm-1: 1590 (C=N), 1722 (COPh);
1H-NMR (CDCl3+ DMSO-d6): δ 4.95 (bs, 1H, NH, exchangeable with D2O), 7.06-8.0 (m, 10H, Harom);
m/z(%): M+ 359 (40.2); Anal. calcd. for C16H11BrN2OS: C, 53.48; H, 3.06; N, 7.79. Found: C, 53.43;
H, 3.02; N, 7.75.
2-(N-Benzoylamino)-4-(4-chlorophenyl)thiazole (entry 30): IR cm-1: 1582 (C=N), 1720 (COPh);
1H-NMR (CDCl3+ DMSO-d6): δ 4.89 (bs, 1H, NH, exchangeable with D2O), 7.26-8.5 (m, 10H, Harom);
m/z(%): M+ 314 (37.5); Anal. calcd. for C16H11ClN2OS: C, 61.04; H, 3.49; N, 8.90. Found: C, 61.07;
H, 3.43; N, 8.95.
2-(N-Benzoylamino)-4-(4-fluorophenyl)thiazole (entry 31): IR cm-1: 1596 (C=N), 1730 (COPh);
1H-NMR (CDCl3+ DMSO-d6): δ 5.41 (bs, 1H, NH, exchangeable with D2O), 7.1-8.6 (m, 10H, Harom);
m/z(%): M+ 298 (53.1); Anal. calcd. for C16H11FN2OS: C, 64.42; H, 3.69; N, 9.39. Found: C, 64.39; H,
3.75; N, 9.33.
1
1-Thiobenzoyloxy-2-aminobenzene (entry 32): IR cm-1: 3300, 3469 (NH2), 1730 (COPh); H-NMR
(CDCl3+ DMSO-d6): δ 7.1-8.5 (m, 9H, Harom), 9.16 (bs, 2H, NH2, exchangeable with D2O); m/z (%):
M+ 229 (53.1); Anal. calcd. for C13H11NOS: C, 68.12; H, 4.80; N, 6.11. Found: C, 68.09; H, 4.75; N,
6.08.
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