Mechanism of Polyphosphoric Acid and Phosphorus Pentoxide-Methanesulfonic Acid as Synthetic Reagents for Benzoxazole Formation

Article abstract of DOI:10.1021/jo960441u

The mechanism of 2-phenylbenzoxazole formation from benzoic acid and o-aminophenol in polyphosphoric acid (PPA) is studied by NMR spectroscopy and chemical analysis. Benzoic acid reacts with PPA to form benzoic-phosphoric anhydride and benzoic-polyphosphoric anhydride. The ratio of mixed anhydride to free carboxylic acid increases dramatically as the P₂O₅ content of PPA increases, but this ratio is independent of reaction temperature and time. When o-aminophenol dissolves in PPA, part of the hydroxyl group is converted to phosphate ester, and only protonated amine is detected. Benzoic acid, mixed anhydride, and PPA are in dynamic equilibrium, and so are PPA, o-aminophenol, and its phosphate ester. The mixed anhydride and o-aminophenol react to form 2-aminophenyl benzoate as the first reaction intermediate which undergoes rapid acyl migration to generate 2-hydroxybenzanilide. Ring closure of 2-hydroxybenzanilide to form 2-phenylbenzoxazole is acid catalyzed. The reactive components in phosphorus pentoxide-methanesulfonic acid (P₂O₅-MSA) which is a convenient alternative to PPA are very similar to those present in PPA. Benzoic acid is also converted into mixed anhydride in P₂O₅-MSA.

Full text of DOI:10.1021/jo960441u

3552
J . Org. Chem. 1997, 62, 3552-3561
Mech a n ism of P olyp h osp h or ic Acid a n d P h osp h or u s
P en toxid e-Meth a n esu lfon ic Acid a s Syn th etic Rea gen ts for
Ben zoxa zole F or m a tion
Ying-Hung So* and J erry P. Heeschen
Central Research & Development, 1712 Building, The Dow Chemical Company,
Midland, Michigan 48674
Received March 4, 1996X
The mechanism of 2-phenylbenzoxazole formation from benzoic acid and o-aminophenol in
polyphosphoric acid (PPA) is studied by NMR spectroscopy and chemical analysis. Benzoic acid
reacts with PPA to form benzoic-phosphoric anhydride and benzoic-polyphosphoric anhydride.
The ratio of mixed anhydride to free carboxylic acid increases dramatically as the P2O5 content of
PPA increases, but this ratio is independent of reaction temperature and time. When o-aminophenol
dissolves in PPA, part of the hydroxyl group is converted to phosphate ester, and only protonated
amine is detected. Benzoic acid, mixed anhydride, and PPA are in dynamic equilibrium, and so
are PPA, o-aminophenol, and its phosphate ester. The mixed anhydride and o-aminophenol react
to form 2-aminophenyl benzoate as the first reaction intermediate which undergoes rapid acyl
migration to generate 2-hydroxybenzanilide. Ring closure of 2-hydroxybenzanilide to form
2-phenylbenzoxazole is acid catalyzed. The reactive components in phosphorus pentoxide-
methanesulfonic acid (P2O5-MSA) which is a convenient alternative to PPA are very similar to
those present in PPA. Benzoic acid is also converted into mixed anhydride in P2O5-MSA.
In tr od u ction
synthesis, process, and properties of these polymers have
been actively pursued.9-11
Polyphosphoric acid (PPA) is a good solvent for many
organic compounds and has been used extensively in
organic synthesis. It is one of the most effective reagents
for carrying out acylation, alkylation, cyclization, and
acid-catalyzed reactions. It is often the reagent of choice
for a variety of synthetic transformations such as dehy-
drations, rearrangements, and synthesis of nitrogen-
containing heterocycles.1-4 PPA has also proved to be
very useful in polymer synthesis.5-7
2-Phenylbenzoxazole is readily prepared from o-ami-
nophenol and benzoic acid in PPA.8 The reaction is one
of the most convenient methods for benzoxazole synthesis
and also has very important applications in polymer
chemistry. Polybenzimidazoles, poly(benzo[1,2-d:4,5-d′]-
bisthiazole-2,6-diyl-1,4-phenylene) (PBT), and poly(benzo-
[1,2-d:5,4-d′]bisoxazole-2,6-diyl-1,4-phenylene) (PBO) are
synthesized by the reaction of terephthalic acid (TA) with
aromatic tetraamines, 1,4-diamino-3,6-dithiohydroxyben-
zene (DADTB), and 1,3-diamino-4,6-dihydroxybenzene in
PPA. PBT and PBO have unique extended rigid-rodlike
configurations. These polymers have excellent thermal
and oxidative stability and outstanding hydrolytic and
solvent resistance. Fibers of these polymers have ex-
tremely high tensile strength and tensile modulus. The
In spite of the large number of publications on the
synthetic applications of PPA, little is established on how
PPA works as a synthetic reagent. The high viscosity
and complex composition of PPA make it extremely
difficult to investigate the mechanism of reactions oc-
curring in it. Indeed, most of the proposed mechanistic
pathways involving PPA are not accompanied with
experimental data.
X Abstract published in Advance ACS Abstracts, May 1, 1997.
(1) Popp, F. D.; McEwen, W. E. Chem. Rev. 1958, 58, 321-401.
(2) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; Wiley:
New York, Vol. I, 1967; pp 894-950.
(3) Uhlig, F.; Snyder, H. R. Adv. Org. Chem. 1960, 1, 35-81.
(4) Rowlands, D. A. In Synthetic Reagents; Pizey, J . S., Ed.; Ellis
Horwood Ltd.: West Sussex, England, 1985; Vol. 6, pp 156-414.
(5) Krongauz, E. S.; Rusanov, A. L.; Renard, T. L. Russ. Chem. Rev.
1970, 39, 747-765.
The previously proposed mechanism for PBT and PBO
formation involves the generation of a mixed anhydride
(9) The Materials Science and Engineering of Rigid-Rod Polymers;
Adams, W. W., Edy, R. K., McLemore, D. E., Eds.; Symposium
Proceedings; Materials Research Society, Pittsburgh, PA, 1989; Vol.
134.
(10) Yang, H. H. Aromatic High-Strength Fibers; Wiley-Inter-
science: New York, 1989; Chapter 2.
(11) Rosenberg, S.; Quarderer, G. J ., J r.; Sen, A.; Nakagawa, M.;
Faley, T. L.; Serrano, M.; Teramoto, Y.; Chau, C. C. U.S. Patent
5,294,390, 1994.
(6) Buckley, A.; Stuetz, D. E.; Serad, G. A. In Encyclopedia of
Polymer Science, 2nd ed.; Mark, H. F., Kroschmitz, J . I., Eds.; Wiley-
Interscience: New York, 1988; Vol. 11, pp 572-601.
(7) Wolfe, J . F. In Encyclopedia of Polymer Science, 2nd ed.; Mark,
H. F., Kroschmitz, J . I., Eds.; Wiley-Interscience: New York, 1988;
Vol. 11, pp 602-635.
(8) Hein, D. W.; Alheim, R. J .; Leavitt, J . J . J . Am. Chem. Soc. 1957,
79, 427-429.
S0022-3263(96)00441-0 CCC: $14.00 © 1997 American Chemical Society

Synthetic Reagents for Benzoxazole Formation
J . Org. Chem., Vol. 62, No. 11, 1997 3553
Sch em e 1
from TA and PPA. The amino group reacts with the
activated carbonyl to form an amide which then cyclizes
to benzothiazole or benzoxazole.12,13 The cyclization
reaction is acid catalyzed.14 Scheme 1 shows the pro-
posed reaction mechanism for PBT formation from TA
and DADTB in PPA.
In this article, we report the mechanistic study of
benzoxazole formation from benzoic acid and o-ami-
nophenol in PPA. The fate of benzoic acid and o-
aminophenol in PPA was studied by NMR spectroscopy.
The several roles which PPA plays in this reaction are
thoroughly investigated. The results are valuable for
understanding other PPA-promoted reactions and pro-
viding guidelines to the use of PPA as a synthetic
reagent.
be present. The 31P NMR spectrum of PPA at 100 °C is
shown in Figure 1. Phosphoric acid, chain end phospho-
rus, and phosphorus in the middle of the chains were
distinctively observed. Absorption at -46.2 ppm was
attributed to branched phosphorus.19
Figure 1 also shows the 31P NMR spectrum of PPA with
17% benzoic acid at 100 °C.20 Orthophosphoric acid and
chain end phosphorus peaks were broadened as compared
to those of PPA alone, while peaks for phosphorus in the
middle of the chains remained sharp. The absorption
peak at -8.0 ppm was attributed to PhCO2PO(OH)2. The
peak for phosphorus bonded to benzoate in PhCO2P(O)-
(OH)[OP(O)(OH)]nOH, where n g 1, had merged with
peaks for phosphorus in the middle of free PPA chains
at about -30 ppm. At 60 °C, this peak was distinctively
observed at -22.0 ppm.
Figure 2 is the 13C NMR spectrum of PPA with 17%
benzoic acid in PPA at 100 °C. There were two carbonyl
absorptions, assigned as carboxylic acid at 173 ppm and
anhydride at 161 ppm. The 161 ppm absorption was
broader, and sometimes, at low temperatures, seen as
two lines with about 1 ppm separation. One or both of
the anhydride peaks must be mixed anhydride with PPA.
The presence of benzoic anhydride was investigated by
comparing the carbonyl as benzoic-phosphoric and ben-
zoic-polyphosphoric mixed anhydrides from the 31P NMR
spectrum with the anhydride carbonyl from the 13C NMR
spectrum of the same NMR sample. The number of
moles of PPA mixed anhydrides was about equal to that
for anhydride carbonyl. The results suggested no sig-
nificant amount of benzoic anhydride was formed from
benzoic acid dissolved in PPA.
A mixture of P2O5 and methanesulfonic acid (P2O5-
MSA) is a convenient alternative to PPA.15-17 It provides
the advantages of a less viscous solution and sometimes
better solubility of certain organic compounds. Like PPA,
“the important reactant in the P2O5-MSA reagent is not
certain; most probably it is a very active mixed anhy-
dride.” 15 Although MSA anhydride is present in P2O5-
MSA, a MSA anhydride-MSA solution is a less effective
reagent than P2O5-MSA for intramolecular acylation and
the Beckmann rearrangement, and in other cases such
as the synthesis of 2-phenylbenzoxazole, it does not work
at all. Pure MSA or a mixture of P2O5 and sulfuric acid
does not promote the reactions as PPA or P2O5-MSA.18
The components in P2O5-MSA are studied by 31P, 13C,
1
and H NMR spectroscopy. The reactive species found
in P2O5-MSA are very similar to those present in PPA.
Resu lts a n d Discu ssion
Raising the temperature to 120 °C caused the anhy-
dride and acid peaks to broaden and then merge to a
single line, in both the 13C and 31P NMR spectra. The
benzoic acid-mixed anhydride chemical shift separations
(in Hz) are about the same in the 13C NMR spectra (12
ppm × 90 MHz in Figure 2) and the 31P NMR spectra (8
ppm × 145 MHz in Figure 1), and the merger occurred
at the same temperature for both nuclei. Peak broaden-
ing and merging of peaks at higher temperatures sug-
gested the species are in dynamic equilibrium as shown
in Scheme 2.21
A. Ben zoic Acid , Ben zoyl Ch lor id e, a n d Ben zoic
An h yd r id e in P P A. PPA is a continuous series of
mixtures of condensed phosphoric acid oligomers as
represented in Scheme 1. The average chain length
depends on the ratio of water to P2O5. Small amounts
of cyclic and cross-linked molecules are also thought to
(12) Wolfe, J . F.; Sybert, P. D. AFWAL-TR-82-4191, J anuary 1983.
(13) Choe, E. W.; Kim, S. N. Macromolecules 1981, 14, 920-924.
(14) (a) Hodd, K. A. Thermal Analysis; ICTA: Budapest, 1974; Vol.
2, pp 91-103. (b) Ghaffari, F.; Hodd, K. A. Thermochim. Acta 1980,
41, 213-224.
(15) Eaton, P. E.; Carlson, G. R.; Lee, J . T. J . Org. Chem. 1973, 38,
4071-4073.
(19) (a) Phosphorus-31 NMR, Principles and Applications; Goren-
stein, D. G., Ed.; Academic Press: New York, 1984. (b) Handbook of
Phosphorus-31 Nuclear Magnetic Resonance Data; Tebby, J . C., Ed.;
CRC Press: Boca Raton, FL, 1991.
(20) Percentages are wt % unless specified.
(21) Sandstrom, J . Dynamic NMR Spectroscopy; Academic Press:
New York, 1982.
(16) Boger, D. L. J . Org. Chem. 1978, 43, 2296-2297.
(17) Ueda, M.; Sugita, H.; Sato, M. J . Polym. Sci., Part A: Polym.
Chem. 1986, 24, 1019-1026.
(18) When benzoic acid and o-aminophenol were stirred in a mixture
of 10 wt % P2O5 in sulfuric acid at 50 °C for 4 h, no 2-hydroxybenz-
anilide nor 2-phenylbenzoxazole was formed.

3554 J . Org. Chem., Vol. 62, No. 11, 1997
So and Heeschen
F igu r e 1. 31P NMR spectra of PPA at 100 °C and PPA with 17% benzoic acid at 100 and 60 °C.
Sch em e 2
31P and 13C NMR spectroscopy showed that benzoyl
chloride and benzoic anhydride in PPA were converted
to benzoic acid and mixed anhydride. A lower percentage
of mixed anhydride was observed for samples prepared
from benzoic acid in PPA than samples from benzoyl
chloride and benzoic anhydride because water was liber-
ated in mixed anhydride formation from benzoic acid. The
ratio of acid to mixed anhydride did not seem to change
with prolonged heating or with temperature as shown
in Table 1.21 Figure 3 shows phosphorus in the middle
of the chains in PPA and PPA with 17% benzoic acid.
The percentage of longer chains decreased in the sample
of benzoic acid in PPA.
The ratio of benzoic acid to mixed anhydride as a
function of P2O5 content in PPA was studied, and the
results are shown in Table 2. The amount of mixed
anhydride increased dramatically when P2O5 content
changed from 77% to 87%. In PPA with 77% P2O5
content, no anhydride was observed, whereas at 87%
P2O5 content in PPA, the ratio of anhydride to acid was
80:20. In reactions in which a large amount of water is
liberated, extra P2O5 is required to adjust the P2O5
content to keep PPA effective.7
Ta ble 1. Ra tios of Acid to An h yd r id es of Ben zoic Acid ,
Ben zoyl Ch lor id e, a n d Ben zoic An h yd r id e in P P A
initial composition
T (°C)
time (h)a
1
acid:anhydrideb
71:29
17 wt % benzoic
acid in PPA
100
100
120
12
71:29
2 peaks began
to merge
peaks merged
61:39
150
60
17 wt % benzoyl
chloride in PPA
1
2
100
60
60:40
61:39
8 wt % benzoic
anhydride in PPA
100
100
100
1
2
3
58:42
57:43
60:40
a
Sample in NMR tube was heated for this period of time before
b
data accumulation. Acid:anhydride means the ratio of benzoic
acid to total benzoic-phosphoric anhydride and benzoic-poly-
phosphoric anhydride.
B. An ilin e, P h en ol, a n d o-Am in op h en ol in P P A.
Aniline in PPA was studied by NMR spectroscopy. The
31P NMR spectrum of aniline in PPA was the same as

Synthetic Reagents for Benzoxazole Formation
J . Org. Chem., Vol. 62, No. 11, 1997 3555
Ta ble 2. Ben zoic Acid to An h yd r id es Ra tio vs In itia l
P 2O5 Con ten t in P P A
initial P2O5
contenta,b (%)
acid:anhydridec
77
no anhydride was observed; 31P NMR showed
PPA existed mostly as orthophosphoric
acid, pyrophosphoric acid, and some linear
tripolyphosphoric acid
83.5
85
87
71/29
52/48
20/80
a
17 wt % benzoic acid was dissolved in PPA. b Temperature was
100 °C. c Acid/Anhydride means the ratio of benzoic acid to total
benzoic-phosphoric anhydride and benzoic-polyphosphoric an-
hydride.
F igu r e 2. 13C NMR spectra of 17% benzoic acid in PPA at
100 °C.
F igu r e 4. 31P NMR spectra of phenol in PPA at 100 °C.
C. Ben zoic Acid a n d o-Am in op h en ol in P P A.22 In
PPA at 60 °C, benzoic acid and o-aminophenol produced
2-hydroxybenzanilide (1) as almost the only product with
less than 3% of 2-phenylbenzoxazole by GC peak area
integration. Conversion of benzoic acid was 80%.
F igu r e 3. 31P NMR of midchain phosphorus in PPA and PPA
with 17% benzoic acid at 100 °C.
Benzoic acid and p-aminophenol, however, reacted in
PPA to produce 4-aminophenyl benzoate (2) as the only
product at 60 or 90 °C.
that of PPA itself. Both the 13C and 1H NMR spectra
were consistent with protonated aniline. Phosphoramide
was not formed detectably.
Figure 4 is the 31P NMR spectrum of phenol in PPA
which shows peaks attributed to phenol phosphate esters.
13C NMR spectroscopy detected phenol phosphate ester
as the only component. Phenol and its phosphate ester
were in equilibrium, but phenol in PPA was not detected
by this technique.
The 31P NMR spectrum of o-aminophenol in PPA is
essentially the same as Figure 4. Phenol phosphate
esters were observed. Figure 5 displays the 13C NMR
spectra of aniline, phenol, and o-aminophenol in PPA.
The 13C NMR spectrum suggests that the amino group
was protonated, and the phenol group existed as free
-OH and phosphate ester. Peak intensities suggested
the ratio of o-aminophenol to o-aminophenol phosphate
ester to be 1:10.
When o-anisidine and o-(N,N-dimethylamino)phenol com-
peted for benzoic acid at 60 or 90 °C in PPA, o-(N,N-
dimethylamino)phenyl benzoate was the only reaction
product, and unreacted o-anisidine was quantitatively
recovered.
(22) A detailed description of this part has been published; see: So,
Y. H.; Heeschen, J . P.; Murlick, C. L. Marcomolecules 1995, 28, 7289-
7290.

3556 J . Org. Chem., Vol. 62, No. 11, 1997
So and Heeschen
F igu r e 5. 13C NMR spectra of aniline, phenol, and o-aminophenol in PPA at 100 °C.
Ta ble 3. Rea ction of o-Am in op h en ol w ith Ben zoic Acid
in P P A w ith Differ en t In itia l P 2O5 Con ten t a t 70 °Ca
initial P2O5 content
time (h)
77%b
84%
87%
0.5
2
4
44, 56
17, 83
17, 83
10, 90, 0.1
14, 86, 0.1
98, 2
97, 3
95, 5
26
a
b
4.9% benzoic acid in PPA was used. The first number is
The above experiments clearly demonstrated that
o-aminophenol and benzoic acid in PPA first produce the
ester,23 2-aminophenyl benzoate, which then undergoes
rapid acyl migration to form the amide24 1, as shown in
Scheme 3.25 The lack of proximity prevented acyl migra-
tion in the case of 2.
The reaction of o-aminophenol and benzoic acid in PPA
with different initial P2O5 content was monitored. Re-
sults in Table 3 shows the reaction was faster with higher
initial P2O5 content. Higher reaction rates and higher
anhydride to benzoic acid ratios (Table 2), when the P2O5
content was increased, suggest that the mixed anhydride
is the reacting intermediate.
The fate of 2-hydroxybenzanilide in PPA was studied
by 13C NMR spectroscopy. A sample of 2-hydroxybenz-
anilide-carbonyl-13C was made from benzoic-carboxyl-13C
acid and o-aminophenol. A 2% solution of 2-hydroxy-
benzanilide-carbonyl-13C in PPA was prepared by stirring
the compound in PPA at room temperature. A series of
percentage of benzoic acid, the second number is the combined
percentages of 2-hydroxybenzanilide and 2-phenylbenzoxazole, and
the third number is the percentage of a side product, 2-phenyl-5-
benzoylbenzoxazole (3).22
13C NMR spectra was acquired at 60 °C. The resulting
spectra are shown in Figure 6, where the times shown
are the mid-points of the scans.
Signals in the range of 160-175 ppm are attributed
to benzoxazole and carbonyl carbons. These signals were
stronger than others because these carbons had been
enriched in carbon-13. The earliest spectrum showed two
signals in this region, at 173.5 and 170.1 ppm. The 170.1
ppm line was assigned to the amide CdO of 2-hydroxy-
benzanilide. It was present at first, then weakened, and
became undetectable after 119 min. The line at 173.5
ppm was assigned tentatively to benzoic acid as a
hydrolysis product. Figure 6 suggests possibly some
2-hydroxybenzanilide-carbonyl-13C was converted to ben-
zoic acid and o-aminophenol during sample preparation.
The oxazole would be seen at 162.3 ppm under these
conditions, and no signal was found near that chemical
shift. The sample was returned to room temperature
after the kinetic run and was unchanged after 6 days.
An absorption peak at 159.8 ppm which was assigned as
the mixed anhydride was observed when 1000 scans were
used for acquisition.
(23) Imai and co-workers proposed esters as the intermediates for
polybenzoxazole and polybenzothiazole formation based on the obser-
vation that high molecular weight polybenzoxazole and polybenzothia-
zole were prepared much faster than the corresponding polybenzim-
idazole; see: Imai, J .; Taoka, I.; Uno, K.; Iwakura, J . Makromol. Chem.
1965, 83, 167-178.
(24) Raiford, L. C.; Couture, J . R. J . Am. Chem. Soc. 1924, 46, 2305-
2318.
(25) In the reaction of benzoyl chloride and o-aminophenol in PPA,
2-benzamidophenyl benzoate and 2-hydroxybenzanilide were isolated.
The result suggests direct amide formation from o-aminophenol and
benzoyl chloride is possible.
At 60 °C in PPA, the rate of 2-hydroxybenzanilide ring
closure to form 2-phenylbenzoxazole is significantly

Synthetic Reagents for Benzoxazole Formation
J . Org. Chem., Vol. 62, No. 11, 1997 3557
F igu r e 6. Hydrolysis of 2-hydroxybenzanilide-carbonyl-13C in PPA as monitored by 13C NMR spectroscopy.
Sch em e 3
slower than the rate of hydrolysis to generate benzoic
acid and o-aminophenol. Since it was a dilute solution
with no agitation, the formation of 2-hydroxybenzanilide
from the hydrolyzed products was not detected by this
technique.
The reaction mechanism of benzoic acid and o-ami-
nophenol in PPA to form 2-phenylbenzoxazole is of high
complexity. The proposed pathways which are consistent
with our experimental results are shown in Scheme 3.
Benzoic acid is activated through the formation of ben-
zoic-phosphoric anhydride. Benzoic acid, mixed anhy-
dride, and PPA are in dynamic equilibrium. The amino
group of o-aminophenol is protonated, and about 90% of
the hydroxyl group exists as phosphate ester. All the
o-aminophenol derivatives and PPA are also in dynamic
equilibrium. 2-Aminophenyl benzoate is proposed as the

3558 J . Org. Chem., Vol. 62, No. 11, 1997
So and Heeschen
F igu r e 8. 1H NMR spectra of 25% P2O5 in MSA (A) and 10%
P2O5 in MSA (B) at 60 °C.
phosphoric anhydride in P2O5-MSA. Higher percentage
of anhydrides was generated with higher P2O5 content.
Polyphosphoric chains were formed in P2O5-MSA. They
are of similar nature to the polyphosphoric acid chains
in PPA.
F igu r e 7. 13C NMR spectra of 25% P2O5 in MSA (A) and 10%
Figure 10 is the 13C NMR spectra of benzoic acid in
P2O5-MSA. They are similar to the 13C NMR spectrum
of benzoic acid in PPA. The 31P NMR spectra of benzoic
acid in P2O5-MSA (Figure 11) are also very similar to
that of benzoic acid in PPA. Peaks assigned to phospho-
rus in benzoic-phosphoric anhydride and benzoic-poly-
phoshoric anhydrides were observed. Both 13C and 31P
NMR spectroscopy demonstrate that part of the benzoic
acid was transformed into activated carbonyls, benzoic-
phosphoric anhydride, and benzoic-polyphosphoric an-
hydride.
The components found in P2O5-MSA are very similar
to those present in PPA. The carboxylic acid group in
benzoic acid is transformed to benzoic-phosphoric an-
hydride and benzoic-polyphosphoric anhydride which
are activated for esterification, amidation, acylation,
alkylation, and many other reactions. These species are
not found in a mixture of P2O5 and sulfuric acid. 13C
NMR spectrum of a solution of benzoic acid in a mixture
of 10% P2O5 in sulfuric acid showed only one carbonyl
peak at 179.80 ppm which is assigned as carboxylic acid.
Neither MSA anhydride-MSA solutions nor pure MSA
have the reactive phosphorus species to promote reac-
tions as PPA or P2O5-MSA. 2-Phenylbenzoxazole was
also made from benzoic acid and o-aminophenol in PPA-
MSA which is less viscous than PPA and does not require
the handling of solid P2O5.26
P2O5 in MSA (B) at 60 °C.
first reaction intermediate. Rapid equilibrium is ex-
pected between protonated amine, and free amine al-
though only protonated amine is detected by 13C NMR
spectroscopy. Rapid acyl migration of the ester generates
2-hydroxybenzanilide which undergoes acid-catalyzed
ring closure to generate 2-phenylbenzoxazole.14,22 This
study does not rule out the possibility of 2-aminophenyl
benzoate cyclization to form 2-phenylbenzoxazole. For-
mation of 2-phenyl-5-benzoylbenzoxazole (3) suggests
that benzoyl cation might be developed in the reaction.
D. Rea ctive Sp ecies in P h osp h or u s P en toxid e-
Meth a n esu lfon ic Acid . The components in P2O5-MSA
and the fate of benzoic acid in this mixture were studied
1
by 31P, 13C, and H NMR spectroscopy. Two samples with
9% and 25% P2O5 in MSA were prepared by adding P2O5
to MSA with stirring. Figure 7 shows the 13C NMR
spectra. Peaks were assigned for CH3SO2OH, CH3SO2-
OP(O)(OH)[OP(O)(OH)]nOH (with n g 0), and (CH3-
SO2)2O. In the sample with higher P2O5 content, a higher
percentage of CH3SO2OP(O)(OH)[OP(O)(OH)]nOH was
observed. 1H NMR spectroscopy (Figure 8) showed
protons in methanesulfonic acid, methanesulfonic anhy-
dride, methanesulfonic-phosphorus anhydride, and meth-
anesulfonic-polyphosphoric anhydride. The percentage
of anhydride protons was higher in the sample with 25%
P2O5.
Con clu sion
The reaction mechanism of benzoic acid and o-ami-
nophenol to produce 2-phenylbenzoxazole in PPA is
investigated. Benzoic acid reacts with PPA to form mixed
anhydride. The ratio of anhydride to free benzoic acid
increases dramatically as the P2O5 content in PPA
increases. In PPA, the amino group of o-aminophenol is
31P NMR spectra of the two samples showed H3PO4 and
CH3SO2OP(O)(OH)[OP(O)(OH)]nOH, with n g 0 (Figure
9). 13C, 1H, and 31P NMR spectroscopy demonstrated
formation of methanesulfonic anhydride, methanesulfon-
ic-phosphoric anhydride, and methanesulfonic-poly-
(26) When P2O5-MSA or PPA-MSA was used as the reagent for
2-phenylbenzoxazole synthesis from benzoic acid and o-aminophenol,
both 2-hydroxybenzanilide and 2-methanesulfonamidophenyl benzoate
were isolated as reaction intermediates.

Synthetic Reagents for Benzoxazole Formation
J . Org. Chem., Vol. 62, No. 11, 1997 3559
F igu r e 9. 31P NMR spectra of 25% P2O5 in MSA (A) and 10%
P2O5 in MSA at (B) 60 °C.
F igu r e 10. 13C NMR spectra of 7.5% benzoic acid in a mixture
of 25% P2O5 in MSA (A) and 1.7% benzoic acid in a mixture of
10% P2O5 in MSA (B) at 60 °C.
protonated, and about 90% of the hydroxyl group exists
as hydroxyl phosphate ester. Benzoic acid, mixed anhy-
dride, and PPA are in dynamic equilibrium and so are
o-aminophenol, o-aminophenol phosphate ester, and PPA.
NMR spectroscopy is a very valuable tool in studying
reaction mechanisms involving PPA.
of PPA. Since the water content in this reaction changes
continuously, it is extremely difficult to study its kinetics.
The components in a mixture of P2O5 and MSA are very
similar to those found in PPA. Benzoic acid in P2O5-
MSA is also activated through the formation of mixed
anhydride. To lower PPA viscosity and also avoid
handling of the highly hygroscopic solid P2O5, PPA-MSA
is a convenient alternative.
o-Aminophenol reacts with the activated carbonyl,
mixed anhydride, to produce an ester, 2-aminophenyl
benzoate, as the first intermediate which undergoes rapid
acyl migration to generate 2-hydroxyanilide. Ring clo-
sure to form 2-phenylbenzoxazole is acid catalyzed.
PPA plays several roles in this reaction. It activates
the carbonyl group, reduces the viscosity of PPA by
releasing water in phenol phosphate ester formation at
the beginning of the reaction, picks up water of conden-
sation, and catalyzes benzoxazole ring closure. The rate
of this reaction is critically influenced by the P2O5 content
Exp er im en ta l Section
Ma ter ia ls. Benzoic acid, o-aminophenol, o-anisidine, ben-
zoic-carboxyl-13C acid, and PPA were purchased from Aldrich
Chemical Co. 2-Phenylbenzoxazole and MSA-d4 were from

3560 J . Org. Chem., Vol. 62, No. 11, 1997
So and Heeschen
NMR spectra were obtained on the following instruments:
resonance frequency (MHz)
instrument
1H
31P
13C
GE Omega-600
Bruker WM-360
IBM AF-300
600
360
300
300
242
145
150
90
75
GE/Nicolet NT-300
75
The conditions used are as follows: field/frequency lock on
internal deuterated solvent, proton decoupling for 13C NMR
spectra, no proton decoupling for 31P NMR spectra, ambient
temperature of 20-25 °C, and pulse-Fourier transform (FT)
technique with multiple scans coadded.
31P NMR spectra were obtained using an approximately 45°
flip angle and a 5-10 s repeat time. These conditions gave
the same signal strength as for spectra run using 2 times the
repeat time. 13C NMR spectra were obtained using an ap-
proximately 70° flip angle at 6 s repeat time. 1H NMR spectra
were obtained using a flip angle of less than 20° and 1-5 s
between scans.
Ch em ica l Sh ift Refer en ces. The chemical shift is re-
ported as fractional frequency difference, in parts per million,
from a reference signal. For 1H and 13C NMR spectra of PPA
samples, the reference is TMS in the sample. For 31P NMR,
the reference is a separate sample of 85% phosphoric acid set
at 0.00 ppm. Measurement was made by sample interchange
at a fixed magnetic field value. On the Omega-600 spectrom-
eter, the system gave chemical shift values which were within
a few tenths of 1 ppm.
For P2O5-MSA samples, the methyl signal of MSA was used
as the reference for 1H and 13C chemical shifts because TMS
has extremely low solubility in MSA and may be subject to
1
decomposition. The H and 13C reference shifts were derived
from a MSA solution containing n-propanol (10%), tetrameth-
ylammonium chloride (2%), and a trace amount of TMS. For
31P shifts in P2O5-MSA solutions, the internal H3PO4 signal
serves as the reference. The 31P chemical shift of H3PO4 in
P2O5-MSA solutions was found to be 2.7 ppm relative to a
separate 85% H3PO4 sample by sample interchange on the
Omega-600 spectrometer. Internal chemical shift reference
values for P2O5-MSA solutions are listed below, and these
shift values are not necessarily the same for a dilute solution
in a nonprotonating solvent:
Chemical Shift Response in P2O5-MSA Solution, ppm
MSA
(CH3)
propanol
(CH3)
nucleus H3PO4
Me4N+
TMS
1H
3.16
40.1
3.11
56.6
0.98
10.27
0.00
not detected
13C
31P
+2.7
sample interchange with
85% H3PO4
NMR Sa m p les. NMR sample of benzoic acid in PPA was
prepared by stirring 17 g of benzoic acid in 83 g of PPA at 100
°C for 1 h under nitrogen. A portion of the solution was
transferred into a 10 mm NMR tube. NMR samples of other
compounds in PPA were prepared similarly. A 9% P2O5 in
MSA mixture was made by adding 9 g of P2O5 to 91 g of MSA
with stirring. In the preparation of 25% P2O5-MSA, solid P2O5
was added to MSA at 60 °C. For MSA solutions, a 5-20%
addition of MSA-d4 served as the field/frequency lock; 1 drop
of MSA-d4 was used for the 13C NMR signal lock.
F igu r e 11. 31P NMR spectra of 7.5% benzoic acid in a mixture
of 25% P2O5 in MSA (A) and 1.7% benzoic acid in a mixture of
10% P2O5 in MSA (B) at 60 °C.
TCI and Cambridge Isotope Laboratories, respectively. The
P2O5 content in PPA was determined by NaOH titration.27
Samples with 83.5% P2O5 content were used unless specified.
The synthesis and characterization of 2-hydroxybenzanilide,
4-aminophenyl benzoate, o-(N,N-dimethylamino)phenol, and
o-(N,N-dimethylamino)phenyl benzoate were previously re-
ported.22 2-Hydroxybenzanilide-carbonyl-13C was prepared
and isolated with the same procedure as that for the unlabeled
compound.
NMR Sp ectr a . In units of ppm, with peak area integration
in parentheses.28
P P A a t 100 °C: 31P NMR 0.351 (H3PO4, 4), -14.770,
-15.089, -15.157, -16.028 (chain end phosphorus, 45),
Measu r em en ts. GC analysis was performed on a HP5840A
chromatograph with a 30 m J &W fused silica gel capillary
column. Benzophenone was the internal standard.
(28) 31P and 13C NMR spectra signal peaks were assigned with the
following references: (a) Reference 19. (b) Kalinowski, H.-A.; Berger,
S.; Braun, S. Carbon-13 NMR Spectroscopy; Wiley: New York, 1988.
(c) Sadtler Spectra, Carbon-13 NMR Collection; BIORAD, Sadtler
Division, Philadelphia, PA, 1995. Peak assignments of of 13C NMR
spectrum for protonated aniline were based on (c) 6822C which are
different from assignments in (b) p 315.
(27) Standard Test Method 01-04-01, Polyphosphoric Acid Assay by
Chain Length Determination; Stauffer Chemical Co., Basic Products
Group, May 30, 1984.

Synthetic Reagents for Benzoxazole Formation
J . Org. Chem., Vol. 62, No. 11, 1997 3561
-29.580, -30.801, -31.257, -31.713, -32.729, -33.007 (mid-
chain phosphorus, 50), -46.199 (branched phosphorus, 1).
P P A w ith 17% ben zoic a cid a t 100 °C: 31P NMR 0.865
(H3PO4, 11), -8.00 (PhCO2P(O)(OH)2, 2), -14.575, -15.434
(chain end phosphorus, 102), -30.055, -30.498, -30.920
(midchain phosphorus, 95), -45.10 (branched phosphorus, 1);
13C NMR 173.24 (71), 160.85 (29), 134.87 (129), 129.66 (297),
128.00 (281), 125.31 (95); mol of carbonyl anhydride in 100 g
of sample was 0.29(17/122) ) 0.0403.
-13.592, -14.170 (chain end phosphorus, 53.4), -27.473,
-28.544, -29.246, -29.447, -30.031, -30.663 (midchain
phosphorus, 23.5).
Ben zoic a cid (7.5%) in P 2O5 (25%)-MSA: 13C NMR
172.24 (6.06), 159.84 (9.97), 135.21 (12.91), 130.17 (27.61),
128.51 (27.82), 125.58 (12.62), 40.33, 40.07, 39.99, 39.72, 38.40
(180.26); 31P NMR 2.75 (H3PO4, 6.91), -5.377 (PhCO2P(O)-
(OH)2, 1.60), -12.751, -13.594, -14.098, -15.008 (chain end
phosphorus, 43.91), -21.138, -22.429 (PhCO2P(O)(OH)[OP(O)-
(OH)]nOH, 4.09), -27.591, -28.692, -29.242, -29.654, -30.214,
-30.778, -32.117 (midchain phosphorus, 43.18).
P P A w ith 17% ben zoic a cid a t 60 °C: 31P NMR 1.773 (H3-
PO4, 2.47), -7.03 (PhCO2P(O)(OH)2, 0.83), -13.528, -13.878
(chain end phosphorus, 38.98), -22.01 (PhCO2P(O)(OH)[OP-
(O)(OH)]nOH, 3.12), -29.732, -30.160, -30.569 (midchain
phosphorus, 53.55), -44.20 (branched phosphorus, 0.78);
phosphorus existed as mixed anhydrides ) 3.95/99.73 ) 3.96%;
mol of P2O5 in 100 g of sample ) (83 × 83.5%)/142 ) 0.488;
mol of mixed anhydride phosphorus ) 0.488 × 2 × 3.96% )
0.0387.
Ben zoic a cid (1.7%) in P 2O5 (9%)-MSA: 13C NMR 174.63
(0.72), 160.23 (0.92), 135.89 (0.54), 135.43 (1.05), 130.39 (3.25),
128.75 (3.20), 125.69 (0.94), 42.80, 40.43, 39.77 (21.70), 38.46,
37.21 (75.79); 31P NMR 2.75 (H3PO4, 21.87), -5.230 (PhCO2P-
(O)(OH)2, 1.11), -12.762, -13.596, -14.171 (chain end phos-
phorus, 50.83), -21.5 (PhCO2P(O)(OH)[OP(O)(OH)]nOH, 1.69),
-27.482, -28.531, -29.246, -29.422, -30.008, -30.578 (mid-
chain phosphorus, 22.37).
An ilin e in P P A a t 100 °C: 13C NMR 129.61 (ipso, meta),
126.17 (para), 121.18 (ortho); 1H NMR 11.242, 7.345, 6.658,
6.478; 31P NMR 1.70 (H3PO4), -13.860, -14.174, -14.216,
-15.142 (chain end phosphorus), -28.938, -29.927, -30.379,
-30.827, -31.869, -32.156 (midchain phosphorus), -45.187
(branched phosphorus).
Stu d y of 2-Hyd r oxyben za n ilid e-ca r bon yl-13C in P P A
by 13C NMR Sp ectr oscop y. A series of 13C NMR spectra
was acquired at 60 °C, 256 scans each covering 851 min.
Timing started when the sample was dropped into the heated
probe. Pulse width was 20 µs, corresponding to a flip angle of
70° or less.
Rea ction of o-Am in op h en ol a n d Ben zoic Acid in Dif-
fer en t In itia l P 2O5 Con ten t P P A. o-Aminophenol (4.36 g,
0.04 mol) and benzoic acid (4.88 g, 0.04 mol) were stirred in
95 g of PPA. Samples were removed from the reactor,
quenched with ice water, extracted with ethyl acetate, and
analyzed by GC.
P h en ol in P P A a t 100 °C: 31P NMR 0.946 (H3PO4), -5.127
(PhOP(O)(OH)2), -13.720, -13.996, -14.053 (chain end phos-
phorus), -20.0 (PhOP(O)(OH)[OP(O)(OH)]nOH), -23.816 (mid-
chain phosphorus); 13C NMR 148.27, 129.28, 125.71, 118.72.
o-Am in op h en ol in P P A a t 100 °C: 13C NMR 147.51 (0.69),
142.06 (14.97), 131.49, 130.95 (15.01), 126.02 (15.78), 124.20
(14.66), 122.01, 121.43 (3.53), 120.14 (13.95), 118.73 (15.61),
116.69, 115.39 (3.30); Figure 5 (a + b + c + d + f)/(a′ + b′ +
c′ + d′ + f′) ) (3.30 + 3.53 + 0.69)/(15.61 + 13.95 + 14.66 +
15.78 + 14.97) ) 1/10; 31P NMR 0.289 (H3PO4), -6.526 (PhOP-
(O)(OH)2), -13.942, -14.183 (chain end phosphorus), -20.438,
-20.954, -21.225 (PhOP(O)(OH)[OP(O)(OH)]nOH), -27.559,
-28.505, -28.897, -29.284, -29.644, -30.613 (midchain
phosphorus).
Ben zoic Acid in P 2O5-Su lfu r ic Acid . To 25 g of con-
centrated sulfuric acid was added 2.5 g of P2O5 with stirring.
Benzoic acid (2.75 g) was added. The solution was clear. 13C
NMR: 179.80, 139.85, 133.28, 131.30, 125.62.
Ack n ow led gm en t. We thank Drs. Don McLemore
and Nelson Rondan for helpful discussions and Rick
DeCaire for assistance.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
and IR spectra of 1-3 and o-(N,N-dimethylamino)phenyl
benzoate and 1H NMR spectrum of o-(N,N-dimethylamino)-
phenol (16 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
P 2O5 (25%)-MSA a t 60 °C: 13C NMR 41.161, 40.812,
40.507, 39.109; 1H NMR 10.924 (37.6), 3.064 (anhydrides,
49.0), 2.781 (MSA, 61.1); 31P NMR 2.75 (H3PO4, 4.86), -12.886,
-13.756, -14.229, -14.394, -15.168 (chain end phosphorus,
36.49), -27.751, -28.823, -28.909, -29.469, -29.878, -30.418,
-30.951, -32.246 (midchain phosphorus, 45.73), -45 (branched
phosphorus, 7.15).
P 2O5 (9%)-MSA a t 60 °C: 13C NMR 40.440, 38.454; 1H
NMR 10.827 (25.10), 3.183, 2.909, 2.883 (CH3 of anhydrides
and MSA, 71.66); 31P NMR 2.75 (H3PO4, 22.0), -12.748,
J O960441U