Facile and efficient synthesis of C3-symmetric benzoxazine: A novel tri-arm molecular scaffold

Article abstract of DOI:10.1016/j.tetlet.2011.10.162

Six novel C₃-symmetric benzoxazines (1a-f) were synthesized via a one-pot condensation, in which twelve covalent bonds were formed up to 96% yield. Two X-ray crystal structures confirmed their proposed conformations and showed their potential a

Full text of DOI:10.1016/j.tetlet.2011.10.162

Tetrahedron Letters 53 (2012) 173–175
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile and efficient synthesis of C3-symmetric benzoxazine: a novel
tri-arm molecular scaffold
⇑
Rajiv Singh, Matthew Schober, Xiaodong Hou, Alys Seay, Qianli Chu
Department of Chemistry, University of North Dakota, Grand Forks, ND 58202, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Six novel C3-symmetric benzoxazines (1a–f) were synthesized via a one-pot condensation, in which
twelve covalent bonds were formed up to 96% yield. Two X-ray crystal structures confirmed their pro-
posed conformations and showed their potential as a novel tri-arm molecular scaffold.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 11 October 2011
Revised 28 October 2011
Accepted 31 October 2011
Available online 7 November 2011
Keywords:
Molecular scaffold
C3-symmetric benzoxazines
Mannich aminomethylation
One-pot condensation
With a diverse array of known applications, calixarenes and
their derivatives are one of the most useful macrocyclic scaffolds.1
Their applications include: self-organized nanostructures,2 supra-
molecular assemblies,3 ionophores,4 as well as sensors for cations,5
anions,6 and neutral organic molecules.7 The versatility of the cal-
ixarene scaffold is a result of its preorganized ‘chalice’ shape,8
which consists of four phenolic units connected by methylene
bridges. Synthetic advances over the last several decades have pro-
duced methodology to append various functional groups to the
aromatic rings.1 These groups are selected to interact with specific
guest molecules.9
Recently, a new family of bowl-shaped compounds have been
synthesized from phloroglucinol and ninhydrin.10 They exhibit
interesting cavities, but their applications are limited because they
are difficult to be further functionalized.
Herein we report a facile and efficient synthesis of a new family
of cup-shaped benzoxazines (1a–f, Scheme 1). By a one-pot con-
densation between phloroglucinol, formaldehyde, and anilines,11
the C3-symmetric benzoxazine was synthesized in 79–96% yield.
It is notable that twelve covalent bonds are formed in a single reac-
tion step with medium to nearly quantitative yield.
A diverse array of C3-symmetric benzoxazines can be easily syn-
thesized because of the multitude of amine and aniline derivatives
that are commercially available and/or easy to synthesize. The
reaction between phloroglucinol, formaldehyde, and n-propyl-
amine only offered polybenzoxazine.12 However, Table 1 includes
six examples with different substituents attached to the three aro-
matic arms in the symmetrical molecule. The ability to introduce
different functionality onto C3-symmetric benzoxazine shows its
potential application in serving as a novel tri-arm molecular scaf-
fold.13 Either electron donating groups (OMe and NHCOCH3) or
weak electron withdrawing groups (Cl and Br) can be introduced
onto the benzoxazines with electron donating groups offering bet-
ter yields with shorter reaction time. This is presumably due to
change in nucleophilicity of the anilines in the Mannich aminome-
thylation and sequential ring closure condensation. The trihalides
are valuable since they can be converted into a large variety of
functional derivatives by metal-catalyzed transformations.
X-ray quality crystals of 1d were obtained by diffusion of water
vapor into DMSO solution of 1d. The X-ray structure of 1d shows a
In a typical reaction, phloroglucinol, formaldehyde, and aniline
were mixed in 1:6:3 ratios in EtOH in the presence of catalytic
amount of glacial acetic acid. Requisite tri-arm benzoxazines
started to precipitate from the reaction mixture within an hour
and was isolated by simple filtration. The reaction could be carried
out in an open flask with wet solvent.
R
N
OH
O
O
N
H+, EtOH
79-96%
6 HCHO
3 RNH2
+
+
N
R
HO
OH
O
R
R= -n-C3H7, -C6H5, -p-C6H4Cl, -p-C6H4Br, -p-C6H4NHCOCH3,
-m-C6H4NHCOCH3, -p-C6H4OMe
1a-f
⇑
Corresponding author. Tel.: +1 701 777 3941; fax: +1 701 777 2331.
E-mail address: chu@chem.und.edu (Q. Chu).
Scheme 1. Synthesis of C3-symmetric benzoxazines (1a–f).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.162

174
R. Singh et al. / Tetrahedron Letters 53 (2012) 173–175
Table 1
Reaction conditions and yields of benzoxazines
Entry
R
Temp
Time (h)
Product
Yielda (%)
1
2
3
4
5
6
7
–n-C3H7
–C6H5
–p-C6H4Cl
–p-C6H4Br
–p-C6H4NHCOCH3
–m-C6H4NHCOCH3
–p-C6H4OMe
rt
rt
rt
rt
rt
rt
rt
12
10
12
12
12
12
8
polymer
1a
NA
84b
82
79
95
91
96
1b
1cc
1d
1e
1f
a
b
c
Yield of isolated product by simple filtration.
Containing some polymer.
9% 1,3,5-tri-p-bromophenyl-hexahydro-1,3,5-triazine was isolated as
a by-
product.
Figure 2. Crystal structure of 1f. (a) ORTEP representation at 50% electron density;
(b) top view in space filling style; (c) a sliced top view in space filling style.
guests by introducing suitable binding groups.9,10a C3-symmetric
benzoxazine will also provide useful precursors for the generation
of new molecular hosts, synthetic ionophores, and chemical sen-
sors.2–7,16 In addition, they might also be used as monomers for
newly developed thermosetting polybenzoxazine resins.12
Acknowledgments
The authors appreciate the financial support received from Na-
tional Science Foundation (NSF, Grant #EPS-0814442) and kind
help in crystallography from Dr. K. Travis Holman at Georgetown
University.
Figure 1. Crystal structure of 1d. (a) Oak Ridge Thermal Ellipsoid Plot (ORTEP)
representation at 50% electron density; (b) top view in space filling style; (c) a sliced
top view in space filling style showing the prism-shaped cavity.
Supplementary data
cup-shaped conformation (Fig. 1).14,15 Three aromatic arms are
approximately perpendicular to benzo-trioxazine ring. As a conse-
quence of the conformation, a small prism-shaped cavity has
formed. The compound is chiral due to the orientation of three oxa-
zine rings.11b It crystallized out as a racemic mixture with a pair of
enantiomers in each unit cell. However, the two enantiomers are
inseparable because they undergo interconversion in solution by
pyramidal inversion of nitrogen trigonal pyramids at room
temperature.
Supplementary data (experimental procedures, 1H, 13C NMR
and IR data of the compounds and CIF files of the crystal struc-
tures.) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2011.10.162.
References and notes
1. Gutsche, C. D. Calixarenes Revisited; The Royal Society of Chemistry: Cambridge,
1998.
2. Orr, G. W.; Barbour, L. J.; Atwood, J. L. Science 1999, 285, 1049–1052.
3. Ugono, O.; Holman, K. T. Chem. Commun. 2006, 2144–2146.
4. (a) Chu, Q.; O’Neal, K.; Osipov, M.; Ngwendson, J. N.; Geib, S. J.; Weber, S. G.;
Curran, D. P. New J. Chem. 2010, 34, 2732–2734; (b) Osipov, M.; Chu, Q.; Geib, S.
J.; Curran, D. P.; Weber, S. G. Beilstein J. Org. Chem. 2008, 4, 36.
5. Casnati, A.; Barboso, S.; Rouquette, H.; Schwing-Weill, M.-J.; Arnaud-Neu, F.;
Dozol, J.-F.; Ungaro, R. J. Am. Chem. Soc. 2001, 123, 12182–12190.
6. Sun, X. H.; Li, W.; Xia, P. F.; Luo, H.-B.; Wei, Y.; Wong, M. S.; Cheng, Y.-K.;
Shuang, S. J. Org. Chem. 2007, 72, 2419–2426.
Just as calix[4]arenes can exist in four possible conformations,1
the tri-arm benzoxazines exist as ‘cup’ or ‘chair’ conformer. The
cup-shaped conformation of 1d is presumably due to the favorable
hydrogen bonding between the amide substituents. Each amide
group forms hydrogen bonds either within the cup-shaped mole-
cule or between the two neighboring molecules (See Supplemen-
tary material).
ˇ
7. Smirnov, S.; Sidorov, V.; Pinkhassik, E.; Havlicek, J.; Stibor, I. Supramol. Chem.
1997, 8, 187–196.
The chair-shaped conformation was observed by the crystal
structure of 1f, which is obtained by slow evaporation of CH2Cl2
solution of 1f (Fig. 2).14,15 It is interesting to notice that the aro-
matic arms twist around the N–Ar bond to achieve close packing
in the solid-state.
8. Steed, J. W.; Atwood, J. Supramolecular Chemistry; John Wiley & Sons, Ltd.:
Chichester, 2000.
9. Arnaud-Neu, F.; Schwing-Weill, M.-J. Synth. Met. 1997, 90, 157–164.
10. (a) Almoga, J.; Rozina, R.; Kleina, A.; Shamuilov-Levintona, G.; Cohenb, S.
Tetrahedron 2009, 65, 7954–7962; (b) Na, J. E.; Lee, K. Y.; Seo, J.; Kim, J. N.
Tetrahedron Lett. 2005, 46, 4505–4508.
In summary, we have synthesized and characterized six C3-
symmetric benzoxazines with different substituents attached.
The facile and efficient synthesis will make the tri-arm benzox-
azine a novel C3-symmetric molecular scaffold.13 Two crystal
structures confirmed their conformation and showed the flexibility
of the three aromatic arms, which can be tailored toward specific
11. (a) Atwood, J. L.; Szumna, A. Chem. Commun. 2003, 940–941; (b) Arnecke, R.;
Boehmer, V.; Paulus, E. F.; Vogt, W. J. Am. Chem. Soc. 1995, 117, 3286–3287.
12. (a) Ghosh, N. N.; Kiskana, B.; Yagci, Y. Prog. Polym. Sci. 2007, 32, 1344–1391; (b)
Ishida, H.; Allen, D. J. J. Polym. Sci., Part B: Polym. Phys 1998, 34, 1019–1030.
13. Recently reported C3-symmetric molecular scaffold: (a) Hennrich, G.; Lynch, V.
M.; Anslyn, E. V. Chem. Eur. J. 2002, 8, 2274–2278; (b) Moberg, C. Angew. Chem.,
Int. Ed. 2006, 45, 4721–4723; (c) Bomkamp, M.; Siering, C.; Landrock, K.;

R. Singh et al. / Tetrahedron Letters 53 (2012) 173–175
175
Stephan, H.; Frçhlich, R.; Waldvogel, S. R. Chem. Eur. J. 2007, 13, 3724–3732; (d)
a
= 70.936(5ꢁ), b = 83.198(5ꢁ),
c
= 89.978(6ꢁ), V = 2670.6(4) Å3; T = 173 (2) K,
Alajarín, M.; Pastor, A.; Orenes, R.-A.; Goeta, A. E.; Steed, J. W. Chem. Commun.
2008, 3992–3994; (e) Fabris, F.; Zonta, C.; Borsato, G.; De Lucchi, O. Acc. Chem.
Res. 2011, 44, 416–423.
Dcalc = 1.342 g cmÀ3
,
Z = 4, reflections collected = 82580, independent
values [I (I), 7134 reflections]:
R1 = 0.1018, wR2 = 0.2450; S = 1.069; CCDC 833789.
reflections = 9257 (Rint = 0.0545),
R
> 2r
14. Crystal data for compound 1d: colorless, 0.10 Â 0.10 Â 0.20 mm, C36H36N6O6,
15. (a) All crystallographic calculations were conducted using SHELXL-97: G. M.
Sheldrick, SHELXL-97, Program for Refinement of Crystal Structure, University
of Göttingen, Göttingen, Germany, 1997; (b) Crystal figures are generated by
X-Seed: Barbour, L. J. J. Supramol. Chem., 2001, 1, 189–191.
16. (a) Leung, A. N.; Degenhardt, D. A.; Bühlmann, P. Tetrahedron 2008, 64, 2530–
2536; (b) Hancock, R. D.; Martell, A. E. Chem. Rev. 1989, 89, 1875–1914.
ꢀ
M = 648.71, Triclinic, p1, a = 10.8717(3) Å, b = 12.6249(3) Å, c = 12.8831(3) Å,
a
= 71.8360(10ꢁ), b = 72.8500(10ꢁ),
(2) K, Dcalc = 1.407 g cmÀ3
Z = 2, reflections collected = 19634, independent
reflections = 5401 (Rint = 0.0267), values [I (I), 4232 reflections]:
R1 = 0.0382, wR2 = 0.1060; S = 0. 914; CCDC 833788.
c
= 68.5970(10ꢁ), V = 1531.14(7) Å3; T = 173
,
R
>
2r
Crystal data for compound 1f: colorless, 0.25 Â 0.30 Â 0.60 mm, C33H33N3O6,
ꢀ
M = 539.60, Triclinic, p1, a = 10.1872(9) Å, b = 16.4822(15) Å, c = 16.9613(16) Å,