Intramolecular acylation of aryl- and aroyl-aliphatic acids by the action of pyrophosphoryl chloride and phosphorus oxychloride

Article abstract of DOI:10.3390/60300279

Both pyrophosphoryl chloride and phosphorus oxychloride react with aryl aliphatic acids to form mixed anhydrides which undergo intramolecular acylation to afford cyclic ketones without the addition of a Friedel-Crafts catalyst. Aryl and aroyl-benzoic acids could be cyclized to the corresponding anthrones and anthraquinones respectively.

Full text of DOI:10.3390/60300279

Molecules 2001, 6, 279-286
molecules
ISSN 1420-3049
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Intramolecular Acylation of Aryl- and Aroyl-Aliphatic Acids by
the Action of Pyrophosphoryl Chloride and Phosphorus
Oxychloride
Sami El-Sayrafi* and Saleh Rayyan
Department of Chemistry, Birzeit University, Birzeit, PO Box 14, Palestine- Via Israel, Fax No: 9722-
2
810656.
*Author to whom correspondence should be addressed; e-mail: ssayrafi@science.birzeit.edu
Abstract: Both pyrophosphoryl chloride and phosphorus oxychloride react with aryl
aliphatic acids to form mixed anhydrides which undergo intramolecular acylation to
afford cyclic ketones without the addition of a Friedel-Crafts catalyst. Aryl and aroyl-
benzoic acids could be cyclized to the corresponding anthrones and anthraquinones
respectively.
Keywords: Pyrophosphoryl chloride, Phosphorus oxychloride, Cyclodehydration,
Cyclic ketones, Anthraquinones.
Introduction:
Intramolecular acylation of aryl aliphatic acids is an important route for the preparation of cyclic
ketones. A very useful method for effecting such acylation is the Friedel-Crafts reaction that employs
the acid chloride or anhydride in the presence of catalysts like aluminum chloride or stannic chloride.
The acylation can also be achieved by treating the free acid with a variety of condensing agents. These
include liquid hydrogen fluoride [1], concentrated sulfuric acid [2], phosphorus pentoxide [3],
polyphosphoric acid [4] and fluorosulfonic acid [5]. Shah used a combination of phosphorus
oxychloride and zinc chloride to synthesize 4-hydroxycoumarins from phenols and malonic acid [6]. In
some cases, cyclic ketones could be obtained by heating the free acid chloride under reduced pressure
[
7].

Molecules 2001, 6
280
The Friedel-Crafts type of reaction involving the action of aluminum chloride or stannic chloride
on the acid chloride requires the conversion of the acid into the corresponding chloride by thionyl
chloride or phosphorus pentachloride. Purification of the resulting acid chloride is wasteful and may
lead to decomposition. Acylation by liquid hydrogen fluoride has some drawbacks. The reagent is very
difficult to handle as it is highly corrosive to tissues and its vapors are very toxic. Cyclization by
concentrated sulfuric acid is more prone to undesired side-reactions such as enolization and aromatic
substitution.
In view of these precedents, we sought to investigate the potential of pyrophosphoryl chloride and
phosphorus oxychloride in effecting intramolecular acylation, thus hoping to overcome some of the
shortcomings of other condensing reagents. Pyrophosphoryl chloride is a mobile liquid and it is
reasonably easy to handle. It can be prepared by heating phosphorus pentoxide with phosphorus
pentachloride according to the method developed by Crofts [8]. Both pyrophosphoryl chloride and
phosphorus oxychloride are commercially available from a number of suppliers.
Both reagents had been used to prepare aryl- and alkylcarboxylic dichlorophosphoric anhydrides,
which were fully characterized by Effenberger [9,10]. Their high reactivity was demonstrated by their
ability to form esters of tertiary alcohols under mild conditions [10]. Furthermore, these anhydrides
reacted with activated arenes without the addition of Friedel-Crafts catalyst to give good yields of aryl
ketones [11]. In a related reaction, Heaney and Shuhaibar [12] used pyrophosphoryl chloride to effect
Bischler-Napieralski reaction which is essentially a cyclodehydration process that affords heterocyclic
compounds.
Results and Discussion:
Initial investigations indicated that pyrophosphoryl chloride effected the cyclization of o-benzyl-
benzoic acid to anthrone in excellent yield. Carboxylic acids with deactivating groups on the ring
could be cyclized (with modest yields) by this method. The cyclization conditions and the reaction
workup were simple.
Acylation of activated rings was achieved under mild conditions and generally gave excellent yields
of the cyclized products. Thus, 2-benzylbenzoic and 4-phenylbutyric acid gave the corresponding
ketones in excellent yields (Scheme 1, Table 1).
P O Cl or POCl
3
2
3
4
HOOC
O
HOOC
O
Scheme 1

Molecules 2001, 6
281
When 2-(4-substituted benzoyl) benzoic acids were used as substrates, the yield of the anthraquinone
was very much dependent on the activation offered by the groups on the ring. While 2-(4-methoxy-
benzoyl)benzoic acid gave a good yield of the expected product, 2-benzoylbenzoic acid gave a
moderate yield and 2-(4-chlorobenzoyl) benzoic acid gave a much lower yield. It appears that the
presence of two deactivating groups on the ring (-Cl and –C=O) caused a further reduction in yield
(Table 1, Scheme 2) .
HOOC
O
O
G
G
+
P O Cl
2 3 4
O
G = H, Cl, OCH3
Scheme 2
While attempting to investigate the potential of pyrophosphoryl chloride to act on other substrates, we
found that it converted 2-hydroxyphenylacetic acid into the lactone, 2-coumaronone, in nearly
quantitative yield (Scheme 3).
OH
O
+
P O Cl
2 3 4
COOH
O
Scheme 3
Our attempt to carry out double acylation of an ordinary ring gave an interesting result. Thus refluxing
the reagent with phthalic acid in benzene afforded phthalic anhydride in a quantitative yield and no
anthraquinone was obtained. Similarly, benzene could not be acylated by succinic acid. The refluxed
mixture of pyrophosphoryl chloride, succinic acid and benzene gave succinic anhydride (Scheme 4).
P O Cl or POCl
3
2
3
4
COOH
COOH
COOH
COOH
O
O
O
O
O
O
Scheme 4

Molecules 2001, 6
282
Our findings can be rationalized by considering the importance of intramolecular reactions.
Whenever intramolecular dehydration is possible, it appears to be the preferred route. Thus, instead of
reacting with the ring, a dicarboxylic acid favors dehydration to form the corresponding anhydride.
It was surprising to find that β-phenylpropionic acid gave a poor yield of 1-indanone. The major
product was an unidentified viscous liquid. Cyclization under milder conditions slightly improved the
yield of 1-indanone (Scheme 5), but considerable amounts of the viscous liquid were obtained.
O
HOOC
+
P O Cl or POCl
2 3 4
3
Scheme 5
The mode of action of pyrophosphoryl chloride on carboxylic acids had been investigated by
Effenberger, König and Klenk. They proposed that pyrophosphoryl chloride reacts with carboxylic
acids to produce mixed anhydrides(Scheme 6). The identity of theses anhydrides was proved by NMR
studies.
O
O
O
O
O
R-C-OH + Cl-P-O-P-Cl
Cl Cl
R-C-O- P- Cl + HOPOCl2
Cl
Scheme 6
Similarly, the reactions reported in this communication are expected to proceed via the mixed
-
anhydride then cyclization follows by ejecting the good leaving group PO Cl (Scheme 7).
2
2
O
O
OPCl2
O
HOOC
C
+
+
P O Cl
4
HOP(O)Cl2
2
3
Scheme 7

Molecules 2001, 6
283
Table 1: Yield of cyclized products obtained by cyclodehydration with POCl and P O Cl
4
3
2
3
Dehydrating Agent: POCl3
Dehydrating Agent: P O Cl
2 3 4
Cyclized Product
%
Yield / Conditions
reflux 3 hrs
% Yield / Conditions
Reflux in CH NO , 2.5 hrs
Anthraquinone
Anthrone
53
65
Quant * Room temperature, 30 min.
3
2
90
43
20
70
18
90
reflux 30 min
reflux 1.5 hrs
reflux 3 hrs
2
2
1
1
2
-Methoxyanthraquinone
-Chloroanthraquinone
-Tetralone
75
20
Warm at 40°, 2 hrs
Heat at 150°, 1 hr
room temp, 2 days
reflux 5 min
90
Room temperature, 30 min.
Warm at 35°C, 30 min.,
Warm at 35°C, 20 min.,
-Indanone
20
-Coumaranone
reflux 5 min.
Quant*
*
Quant. = Quantitative
Conclusions
In conclusion, the use of pyrophosphoryl chloride and phosphorus oxychloride offers an attractive
alternative for cyclodehydration. The procedure is simple and it obviates some difficulties encountered
in other cyclodehydrating agents.
Acknowledgements
The authors are grateful to Dr.P.C.Crofts of the University of Manchester-UMIST for the helpful
discussions.
Experimental
General
Mass spectra were measured on a Shimadzu GC-MS QB 500 spectrometer at 70 ev. IR spectra
-1
1
(
nujol) were recorded on Perkin Elmer 843 spectrometer (ν in cm ). H-NMR spectra were recorded
on a Bruker AMX 300 spectrometer at 300 MHz, δ (ppm) are reported referenced to TMS used as an
internal standard.
Synthetic procedures
In a typical experiment the carboxylic acid (0.01 mole) was mixed with a slight excess (0.015
mole) of pyrophosphoric chloride or a large excess of phosphorus oxychloride (0.05 mole). The
mixture was warmed for a certain period of time, ranging from a few minutes for the active substrates
to several hours for the less active ones (see Table 1). The reaction mixture was quenched with cold
water and the ketone was extracted with ether or chloroform. The organic layer was washed with a

Molecules 2001, 6
284
dilute solution of sodium bicarbonate and dried over MgSO . Evaporation of the organic solvent
4
afforded the cyclized product. The products were either recrystallized or purified by flash
chromatography. Each product was identified by IR, NMR, melting point and mass spectra. The
physical properties and the spectra were in agreement with those of authentic samples prepared
according to literature procedures. An authentic sample of anthrone was prepared by the method
outlined by Meyer [13]. The anthraquinones were prepared by cyclizing the parent carboxylic acid with
polyphosphoric acid [14] or sulfuric acid [15]. 1-Indanone and α-tetralone were prepared according to
the method of Thomson and coworkers [16] . An authentic sample of coumaranone was obtained by
refluxing o-hydroxyphenyl acetic acid with p-toluenesulfonic acid according to the lactonization
method of Johnson [17].
Spectral Data
-1
Anthraquinone: mp 284°; IR, cm : 3320, 1700, 1624, 1574, 1450, 1375, 1205, 1165, 1100, 970, 912,
1
8
20, 720, 625; H-NMR (CDCl ) δ (ppm): 7.83 (ddd, 8.1, 7.6, 1.2 Hz, 4H, aromatic), 8.34 (dd, 8.1, 1.2
3
+
Hz, 4H, aromatic); MS(%): 208 (M ), 180, 152, 76.
-1
Anthrone: mp 152°; IR, cm : 3068, 2870, 1660, 1590, 1480, 1466, 1451,1402, 1387, 1325, 1180,
1
1
160, 1105, 1080, 965, 925, 820, 720, 675; H-NMR (CDCl ) δ (ppm): 4.38 (s, 2H, benzylic) 7.45 (~
3
d, overlapping 4H), 7.58 (m-unresolved ddd, 2H, aromatic), 8.35 (dd, 8.0,1.1Hz, 2H); MS(%): 194
+
(
M ), 166, 165, 164, 139, 115, 83, 82, 63.
-
1
2
1
7
2
-Methoxyanthraquinone: mp 196°; IR, cm : 3068, 2960, 1760, 1655, 1605, 1451, 1402, 1385, 1295,
1
255, 1188, 1104, 1090, 1022, 925, 835, 755, 722, 698; H-NMR(CDCl ) δ (ppm): 3.84 (s,3H,-OCH )
3
3
.38 (m, 2H), 7.65 (m, 1H), 7.86 (dd, 8.1,1.5 Hz, 2H), 8.05 (m,1H), 8.15(d, 7.6 Hz, 1H); MS(%): 239,
+
38(M ), 224, 223, 196, 195, 194, 181, 167, 166, 152, 149, 139, 135, 105, 104, 103, 91, 76, 55.
-
1
2
1
7
-Chloroanthraquinone: mp 209°; IR, cm : 3082, 2955, 1680, 1668, 1584, 1465, 1370, 1320, 1174,
1
112, 1076, 972, 963, 912, 870, 817, 721, 655, 650; H-NMR(CDCl ) δ (ppm):7.48 (d, 8.0 Hz, 1H),
3
.78 (m, 3H), 8.15 (dd, 7.4,1.2 Hz 1H) 8.21(dd, 7.6,1.5 Hz 1H), 8.27 (d, 8.0 Hz, 1H); MS(%): 244
+
+
(
M+2 ), 242 (M ), 216, 214, 207, 188, 186, 179, 151, 150, 125, 107, 93, 75, 50.
-
1
1
-Tetralone: bp 118-120°/8 mm.; IR, cm : 3068, 2955, 2870, 1680, 1600, 1470, 1450, 1400, 1351,
1
1
315, 1282, 1220, 1176, 1156, 1136, 1020, 900, 893, 794, 758, 730; H-NMR (CDCl ) δ (ppm): 2.12
3
(
m,2H), 2.70 (m, 2H), 3.00 (m, 2H), 7.18 (d, 8.2 Hz, 1H), 7.29 (m, 1H), 7.43 (m, 1H), 8.05(d, 7.7 Hz,
+
1
H); MS(%): 146 (M ), 131, 118, 115, 104, 91, 90, 89, 77, 63, 51.
-
1
1
-Indanone: mp 40°C; IR, cm : 3072, 3050, 3030, 2925, 1710, 1600, 1775, 1440, 1402, 1320, 1277,
1
1
244, 1203, 1176, 1150, 1088, 1034, 1015, 980, 880, 828, 770; H-NMR (CDCl ) δ (ppm): 2.70 (m,
3

Molecules 2001, 6
285
2
H), 3.15 (m, 2H), 7.38 (m, 1H), 7.47 (d, 7.5 Hz, 1H), 7.57(m, 1H), 7.74(d, 7.7 Hz, 1H); MS(%): 132
+
(M ), 104, 103, 78, 77, 52, 50.
-
1
2
1
7
-Coumaranone: mp 49°; IR, cm : 1808, 1832, 1618, 1590, 1475, 1390, 1333, 1235, 1205, 1124,
1
050, 952, 890, 826, 813, 750, 707, 670; H-NMR(CDCl ) δ (ppm): 3.73 (s,2H), 7.10 (d, 8.0 Hz, 1H),
3
+
.14 (m,1H), 7.28 (d, 8.0 Hz, 1H), 7.30 (m, 1H); MS(%): Prominent Peaks: 134(M ), 106, 78.
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