On the purity of 2-[ortho-anilinyl]-1,3-benzoxazole derived from 2H-3,1-benzoxazine-2,4(1H)dione (isatoic anhydride) [1,2]

Article abstract of DOI:10.1002/jhet.326

(Chemical Equation Presented) The Lewis acid catalyzed synthesis and chromatographic purification of isatoic anhydride-derived 2-(2′-anilinyl)- 1,3-benzoxazole (2) can result in the co-isolation of 2 and a light pink colored impurity (<5%). This latter species has been identified (NMR, single crystal X-ray diffraction, mp) as 2′-hydroxy-2-aminobenzanilide (3), which represents a predictable intermediate in the formation of 2. Compound 3 crystallizes in an orthorhombic crystal system of space group P2 ₁2₁2₁ with four molecules in the unit cell (α = β = γ = 90°; a = 6.715 (2) A, b = 12.100 (4) A, c = 13.321 (4) A; V = 1082.2 (6) A³). Pure 2 is characterized as a colorless, high-melting solid; unlike the dark colored oil that is isolated if 2 contains traces of 3.

Full text of DOI:10.1002/jhet.326

268
On the Purity of 2-[ortho-Anilinyl]-1,3-benzoxazole Derived from
2H-3,1-Benzoxazine-2,4(1H)dione (Isatoic Anhydride) [1,2]
Vol 47
Karen M. Button,a Robert A. Gossage,a,b* Hilary A. Jenkins,c Tayseer Mahdi,b
b
´
and Sanja Resanovic
aDepartment of Chemistry, Acadia University, Wolfville, Nova Scotia, Canada B4P 2R6
bDepartment of Chemistry and Biology, Ryerson University, Toronto, Ontario, Canada M5B 2K3
cDepartment of Chemistry, MAX Diffraction Facility, McMaster University, Hamilton, Ontario,
Canada L8S 4M1
*E-mail: gossage@ryerson.ca
Received September 14, 2009
DOI 10.1002/jhet.326
Published online 20 January 2010 in Wiley InterScience (www.interscience.wiley.com).
The Lewis acid catalyzed synthesis and chromatographic purification of isatoic anhydride-derived 2-
(20-anilinyl)-1,3-benzoxazole (2) can result in the co-isolation of 2 and a light pink colored impurity
(<5%). This latter species has been identified (NMR, single crystal X-ray diffraction, mp) as 20-
hydroxy-2-aminobenzanilide (3), which represents a predictable intermediate in the formation of 2.
Compound 3 crystallizes in an orthorhombic crystal system of space group P212121 with four molecules
ꢀ
˚
˚
˚
in the unit cell (a ¼ b ¼ c ¼ 90 ; a ¼ 6.715 (2) A, b ¼ 12.100 (4) A, c ¼ 13.321 (4) A; V ¼ 1082.2
3
(6) A ). Pure 2 is characterized as a colorless, high-melting solid; unlike the dark colored oil that is iso-
˚
lated if 2 contains traces of 3.
J. Heterocyclic Chem., 47, 268 (2010).
INTRODUCTION
(n ¼ 2 or 3), oAC6H4). Our independent study of this
reaction using ZnCl2 [23] or ZnBr2 [24,25] as catalyst
had revealed that the desired product of the above reac-
tion between 1 and o-aminophenol, viz. 2-(1,3-benzoxa-
zol-2-yl)aniline (2: i.e., 2-[o-anilinyl]-1,3-benzoxazole:
Scheme 1), can be problematic to isolate in pure form
by these reaction protocols [22,23]. Details of this inves-
tigation are reported herein.
Oxazoles, 2-oxazolines (i.e., 4,5-dihydro-1,3-oxazoles)
and 1,3-benzoxazoles represent an important group of
organic heterocyclic compounds. These materials have
found widespread applications as ligands in transition
metal and main group coordination chemistry and as im-
portant monomers in polymer science. In addition, these
heterocycles are used in medicinal chemistry and in
regio-selective and enantio-selective synthesis [3–12].
Our own interests lie in the design and application
of novel oxazoles for metal-mediated catalysis and
in fundamental studies of inorganic structural chemistry
[13–18]. Several years ago, Gajare et al. demonstrated
that isatoic anhydride (i.e., 2H-3,1-benzoxazine-2,4(1H)
dione: 1; Scheme 1) [19–21] can be used as a useful
synthon for the production of o-anilinyl-oxazolines,
-oxazines, and -benzoxazoles [22]. Their coupling strat-
egy involved the application of kaolinitic clay as a
Lewis acid promoter of decarboxylative coupling and
subsequent dehydrative ring formation reactions between
1 and x-aminoalcohols (Scheme 1; E ¼ A(CRR0)nA
RESULTS AND DISCUSSION
We were perplexed by the earlier disclosure (and
indeed in our own synthesis and purification by similar
means) [23,24] that compound 2, following chromato-
graphic isolation, often takes the form of a dark colored
analytically pure oil. Compared with the variety of other
structurally analogous materials that we had made, it
seemed unusual that this compound should exist as a
liquid under ambient conditions. A thorough search of
the literature reveals that compound 2 has in fact been
previously reported by several different synthetic
C
V
2010 HeteroCorporation

March 2010 On the Purity of 2-[ortho-Anilinyl]-1,3-benzoxazole Derived from 2H-3,1-Benzoxazine-
2,4(1H)dione (Isatoic Anhydride)
269
Table 1
˚
Selected bond distances (A), bond angles (deg), and dihedral angles
(deg) for compound 3 with estimated standard deviations in
parentheses (see Fig. 1).
Bond distances
O1–C1
O2–C9
N1–C1
1.235 (2)
1.364 (2)
1.349 (2)
1.410 (2)
1.371 (2)
N1–C8
N2–C3
Bond angles
C8–N1–C1
O1–C1–N1
Dihedral angle
C8–N1–C1–C2
129.68 (11)
121.86 (11)
173.11 (11)
N 13.33; found [22]: C 74.48, H 4.26, N 13.61%). We
have succeeded in isolating 2 that is free of 3 by careful
fractional crystallization of the resulting mixture dis-
solved in EtOAc/hexanes. Slow solvent removal by
evaporation under ambient conditions (in open test
tubes) leads to the gradual precipitation of a white mate-
rial in the form of needles (identified as 2) and a second
crystalline light pink-colored solid (3), which is present
in quite small amounts relative to that of 2. Investigation
Figure 1. (a) A molecular representation of 3. (b) An ORTEP diagram
of a molecule of 3 found in the unit cell. [Color figure can be viewed
in the online issue, which is available at www.interscience.wiley.com.]
methodologies and in all cases reported as a colorless
solid. However, there is considerable discrepancy as to
the exact mp of 2 (reported mps: 126ꢀC [26]; 113–
115ꢀC [27]; 105–105.5ꢀC [28]; 105ꢀC [29]). On one
occasion in our own laboratories, we also obtained the
said material as an off-white solid with a mp of 103–
105ꢀC (which we likewise reported in 2003 [23]), a
property consistent with that reported independently by
both Culbertson et al. [29] and Igeta and coworkers
[28]. These conflicting observations promoted us to re-
examine both 2 and the ‘‘oil’’ material more closely,
and we have thus found that flash chromatographic iso-
lation of 2 using EtOAc/hexanes (v/v: 50/50 or 25/75)
mixtures often leads [22,23] to the contamination of 2
with a small amount of a second light pink-colored
compound (3). When this impurity is present, impure 2
does indeed take the form of a viscous tar-like oil which
is typically dark in color. This material is usually iso-
lated when the accompanying solvent is removed expe-
ditiously by, for example, rotary evaporation. An inter-
esting facet of this oil is the acceptable level of analyti-
cal purity (calculated for C13H10N2O: C 74.28, H 4.76,
1
of this latter material isolated in this way via H NMR
spectroscopy and mp measurements (mp: 136–136.5ꢀC)
reveals very similar properties to those reported [30]
some 40 years ago for 20-hydroxy-2-aminobenzanilide
(lit. mp: 139–140ꢀC: Fig. 1). This compound is an
obvious and predictable intermediate [19–21,23] in the
synthesis of 2 from 1. To obtain unequivocal evidence
on the nature of 3, a single crystal X-ray diffraction
study was carried out. Compound 3, 20-hydroxy-2-ami-
nobenzanilide (Fig. 1), crystallizes in the P212121 space
group with four molecules in the unit cell (see Table 1).
The molecules contain virtually co-planar aromatic
groupings and intra-molecular H-bonding between the
amide oxygen atom (O1) and the NH2 group
˚
(O1ꢁꢁꢁHAN2 ¼ 2.024 A) and the amide H-atom and the
O-atom of the phenolic AOH functionality
˚
(O2ꢁꢁꢁH1AN1 ¼ 2.132 A). In addition, a close inter-mo-
lecular contact is found between the H of this AOH
˚
group (i.e., H2C) and O1 (O1ꢁꢁꢁH2C ¼ 1.773 A). An
ORTEP representation of a molecule of 3 from the unit
cell is shown in Figure 1.
The off-white needle form of 2 (mp: 103–105ꢀC) iso-
lated above was subjected to recrystallization from boil-
ing pet. spirit (60–80ꢀC bp range) to yield initially a
cream colored material in the form of very thin needles
(mp: 106–108ꢀC). This crop was subsequently recrystal-
lized a second time from the same solvent to give color-
less needles (mp: 109–111ꢀC). The variability in mp
behavior of 2 may be due to its sensitivity to gradual
yellowing (presumably oxidation) under ambient
Scheme 1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

´
K. M. Button, R. A. Gossage, H. A. Jenkins, T. Mahdi, and S. Resanovic
270
Vol 47
0.9479, 0.9265, refinement method: full-matrix least-squares
on F2, data/restraints/parameters: 3893/0/202, GOF on F2:
1.042, final R indices [I > 2r(I)] R1 ¼ 0.0446, wR2 ¼
0.1126, R indices (all data): R1 ¼ 0.0544, wR2 ¼ 0.1193,
absolute structure parameter: 0.7 (10), largest diff. peak and
conditions. We have been unable to recrystallize 2 from
hydrocarbon media to a point in which the measured mp
mimics that disclosed by Padmaja et al. (126ꢀC: to our
knowledge the highest mp reported for 2) [26]. Their
method used glacial acetic acid for recrystallization.
Using this solvent gave white material of mp 113–
114ꢀC. It should also be noted that the analytical purity
of 2, as described in [22], could contain traces of 3. For
example, the contamination of a sample of 2 by 1% by
weight of 3 (corresponding to 9.3 molecules of 3 per
100 that of 2) gives a calculated elemental analysis
(calc.: C 74.16; H 4.79; N 13.38%) consistent with 2
(vide supra) and this concentration of impurity makes it
unlikely that 3 would be easily spotted by NMR spec-
troscopy. Despite these facts, it does appear as if all
these levels of purity of 2 are still of sufficient quality
for the use of this material in subsequent syntheses
[23,31,32].
hole: 0.241–0.272 eAꢄ3. The molecular representation found
˚
in Figure 1 was drawn using ORTEP-III for Windows [34]. CCDC
#747662 contains the supplementary crystallographic data for
this article. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
CONCLUSIONS
This investigation has demonstrated that compound 2
(i.e., 2-[1,3-benzoxazol-2-yl]aniline) can be problematic
to isolate in very pure form under the reaction condi-
tions described independently by us and Gajare et al.
Contamination of 2 by its ring opened precursor (20-
hydroxy-2-aminobenzanilide: 3) can lead to the isolation
of analytically ‘‘pure’’ material in an oil-like form. Cau-
tion is likewise advised as to the measurement of the
purity of solid 2 by mp determination although lower
melting point material appears to be of sufficient purity
for later synthetic applications. Material with the most
pronounced mp behavior is that which has been recrys-
tallized from glacial acetic acid as described previously
[26]. The contaminant of 2, viz. 3, has been fully char-
acterized (mp, NMR, X-ray diffraction).
EXPERIMENTAL
Isolation of 2-(1,3-benzoxazol-2-yl)aniline (2) and 20-
hydroxy-2-aminobenzanilide (3). The synthesis of com-
pounds 2 and 3 was carried out as described in reference [23].
Purification of the reaction mixture via flash chromatography
(1/1 v/v hexanes/EtOAc) using ꢂ50 g of silica on a column of
2 cm diameter yielded ꢂ40 fractions (ꢂ15 mL each in test
tubes). These extractions were left to evaporate in open air
(fumehood) of which the first 15 contained solid pure (NMR)
2 (yield 36% [23]); fractions 16–18, which were slightly pink
in color, yielded about 50 mg of 3 (0.4%) and a small amount
of 2. Compounds 2 and 3 were then separated manually from
these fractions. The latter fractions contained species which
could not be unequivocally identified (NMR). Properties of 2:
mp 113–114ꢀC (AcOH; lit.: see text); pmr (d, 400 MHz, deu-
terochloroform): data was consistent to within experimental
error to that reported (lit. [28]). Properties of 3: mp: 136–
136.5ꢀC (1/1 v/v hexanes/EtOAc; lit. [30] 139–140ꢀC); pmr
(d, 600 MHz, deuterochloroform containing ꢂ10% hexadeu-
tero-dmso), 9.11 (s, br, 1H, NH), 8.75 (s, br, 1H, OH), 7.71
(dd, 1H, J ¼ 1.7, 7.8, ArH), 7.34 (dd, 1H, J ¼ 1.5, 7.9, ArH),
7.00 (td, 1H, J ¼ 1.2, 7.2, ArH), 6.75 (m, 1H, ArH), 6.72 (dd,
1H, J ¼ 1.8, 7.8, ArH), 6.63 (m, 2H, ArH), 6.52 (dd, 1H, J ¼
1.2, 7.8, ArH), 6.46 (td, 1H, J ¼ 1.2, 7.2, ArH), 2.60 (s, v. br,
NH2); cmr (d, 150 MHz, deuterochloroform containing ꢂ10%
hexadeutero-dmso), 167.5 (C¼¼O), 148.7, 147.1, 132.1, 127.6,
126.3, 124.4, 121.0, 119.3, 117.0, 116.0, 115.9, 115.5.
Acknowledgments. This work has been funded by a gener-
ous donation from Research Corporation. The authors are
also indebted to the support of both Acadia and Ryerson
Universities and NSERC (Canada) in the form of a Discov-
ery Grant (RAG) and via an NSERC USRATM. Prof. K. J.
Haller (Suranaree University of Technology) is also
thanked for his preliminary examination of compound 3.
Mr. Shawn McFadden (RUAC) and Dr. D. W. Hughes
(MAX Facility) are also thanked for their contributions to
this research.
REFERENCES AND NOTES
[1] 2-[ortho-Anilinyl]-1,3-benzoxazole is also referred to as 2-
(1,3-benzoxazol-2-yl)aniline.
[2] Oxazoles XXIV. Part XXIII. See Deshpande et al. [13].
[3] Desimoni, G.; Faita, G.; Jørgensen, K. A. Chem Rev 2006,
106, 3561.
Crystal data for 3. The structure of complex 3 was solved
using previously described methods [33]. Formula
C13H12N2O2, MW: 229.24, orthorhombic, space group
[4] Hargaden, G. C.; Guiry, P. J. Chem Rev 2009, 109, 2505.
[5] Meyers, A. I. J Org Chem 2005, 70, 6137.
[6] Pfaltz, A. Acta Chem Scand 1996, 50, 189.
[7] Rasappan, R.; Laventine, D.; Reiser, O. Coord Chem Rev
2008, 252, 702.
˚
˚
P212121, a ¼ 6.715 (2) A, b ¼ 12.100 (4) A, c ¼ 13.320 (4)
3
3
ꢀ
˚
˚
A, a ¼ b ¼ c ¼ 90 , V ¼ 1082.2 (6) A , Dc ¼ 1.401 g/cm ,
Z ¼ 4. Crystal size: 0.80 ꢃ 0.71 ꢃ 0.56 mm3, light pink. Tem-
˚
perature ¼ 173 (2) K, k(MoKa) ¼ 0.71073 A, Absolute coeffi-
[8] Gade, L. H.; Bellemin-Laponnaz, S. Coord Chem Rev
2007, 251, 718.
cient ¼ 0.097 mmꢄ1, F(000) ¼ 480, y range for data collec-
tion: 2.27–32.46ꢀ, hkl range: –4 to 10, –17 to 18, –20 to 18.
Reflexions collected: 16,294, Independent reflexions: 3893
[R(int) ¼ 0.0581], Completeness to y ¼ 32.46ꢀ: 99.9%,
Absorption corr.: numerical, max. and min. transmission:
´
[9] Fraile, J. M.; Garcıa, J. I.; Mayoral, J. A. Coord Chem Rev
2008, 252, 624.
´
[10] Lorcy, D.; Bellec, N.; Fourmigue, M.; Avarvari, N. Coord
Chem Rev 2009, 253, 1398.
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DOI 10.1002/jhet

March 2010 On the Purity of 2-[ortho-Anilinyl]-1,3-benzoxazole Derived from 2H-3,1-Benzoxazine-
2,4(1H)dione (Isatoic Anhydride)
271
[11] Maggini, S. Coord Chem Rev 2009, 253, 1793.
[12] Culbertson, B. M. Prog Polym Sci 2002, 27, 579.
[13] Deshpande, A. A.; Gossage, R. A.; Jackson, S. M.; Quail, J.
W.; Sadowy, A. L.; Yadav, P. N. Z Naturforsch 2009, 64b, 1046.
[14] Gossage, R. A.; Yadav, P. N.; MacInnis, T. D.; Quail, J.
W.; Decken, A. Can J Chem 2009, 87, 368.
[23] Button, K. M.; Gossage, R. A. J Heterocycl Chem 2003,
40, 513.
[24] Gossage, R. A. Curr Org Chem 2006, 10, 923.
[25] Gossage, R. A. In Experiments in Green and Sustainable
Chemistry; Roesky, H. W., Kennepohl, D., Eds.; Wiley-VCH: Wein-
heim, 2009; Chapter 4, p 19.
[15] Gossage, R. A.; Jenkins, H. A.; Jones, N. D.; Jones, R. C.;
Yates, B. F. Dalton Trans 2008, 3115.
´
[16] Cabeza, J. A.; da Silva, I.; del Rıo, I.; Gossage, R. A.;
[26] Padmaja, J.; Satyanarayana Reddy, M.; Ratnam, C. V. In-
dian J Chem 1987, 26B, 951.
[27] Kini, S. G.; Saraswat, G.; Gandhi, A. M. Indian J Hetero-
cycl Chem 2005, 15, 99.
Miguel, D.; Suarez, M. Dalton Trans 2006, 2450.
[17] Decken, A.; Eisnor, C. R.; Gossage, R. A.; Jackson, S. M.
Inorg Chim Acta 2006, 359, 1743.
[28] Ohsawa, A.; Kawaguchi, T.; Igeta, H. Chem Pharm Bull
1982, 30, 4352.
´
[18] del Rıo, I.; Gossage, R. A. Acta Crystallogr 2009, E65,
[29] Haskell, T. H.; Peterson, F. E.; Watson, D.; Plessas, N. R.;
Culbertson, T. J Med Chem 1970, 13, 697.
m103.
[19] (a) Shvekhgeimer, M.-G. Khim Geterosiklicheskikh Soed
2001, 435; (b) Shvekhgeimer, M.-G. Chem Heterocycl Compd 2001,
37, 385.
[30] Sam, J.; Richmond, C. W. J Heterocycl Chem 1964, 1, 245.
[31] Dubey, S. K.; Sharma, S.; Iyer, R. N. Z Naturforsch 1979,
34b, 99.
[20] Coppola, G. M. Synthesis 1980, 505.
[21] Kappe, T.; Stadlbauer, W. Adv Heterocycl Chem 1981, 28,
127.
[32] Barni, E.; Pasquino, S.; Savarino, P.; Di Modica, G. Dyes
Pigm 1985, 6, 1.
[33] Gossage, R. A.; Jenkins, H. A. Acta Chim Slov 2009, 56,
329.
[22] Gajare, A. S.; Shaikh, N. S.; Jnansehwara, G. K.; Desh-
pande, V. H.; Ravindranathan, T.; Bedekar, A. V. J Chem Soc Perkin
Trans 1 2000, 999.
[34] Farrugia, L. J. J Appl Crystallogr 1997, 30, 565.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet